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Immunotherapy’s cardiac effects require early monitoring, management
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
REPORTING FROM ACC CARDIO-ONCOLOGY
Key clinical point: Monitor for cardiac symptoms and treat or interrupt immunotherapy as needed.
Major finding: Immune checkpoint inhibitors and CAR T-cell therapies are associated with distinct cardiovascular adverse events.
Study details: Review of strategies for managing the cardiovascular consequences of cancer immunotherapies.
Disclosures: Dr. Cornell reported having nothing to disclose.
The Use of Immuno-Oncology Treatments in the VA (FULL)
The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.
Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.
Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.1 We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.
Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.
Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work. 
The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.
Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.2
Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.3,4 The landscape is going to change dramatically in the next couple of years.
Accessing Testing For First-Line Treatments
Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.
Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.
A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.
In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.
Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.
Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.
Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.
Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.
Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.
All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.
Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.
Dr. Kambhampati. I agree.
Rural Challenges In A Veterans Population
Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.
Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.
Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.
Comorbidities
Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.
Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.
Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.
Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.
Measuring Success
Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.
Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.
Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.
Role of Pharmacists
Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.
And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.
Dr. Kaster. As an oncology pharmacist, I have to second that.
Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.
Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.
Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.7 And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.
Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.
With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.
Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.
Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.
Areas For Further Investigation
Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.3 How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?
Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.
Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.
For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.
In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.
Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.
Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.
1. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab vs chemotherapy for PD-L1-positive non-small cell lung cancer. N Engl J Med. 2016;375(19):1823-1833.
2. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–smallcell lung cancer. N Engl J Med. 2017;377(20):1919-1929.
3. Hellmann MD, Ciuleanu T-E, Pluzansk A, et al. Nivolumab plus ipilimumab in Lung Cancer with a high tumor mutational burden. N Engl J Med. 2018 April 16. [Epub ahead of print.]
4. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate214 Investigators. Nivolumab plus ipilimumab versus sunitinibin advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290.
5. Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small cell
lung cancer. Ann Oncol. 2018 March 30. [Epub ahead of print.]
6. Heinrichs A, Dessars B, El Housni H, et al. Identification of chronic myeloid leukemia patients treated with imatinib who are potentially eligible for treatment discontinuation by assessingreal-life molecular responses on the international scale in a EUTOS-certified lab. Leuk Res. 2018;67:27-31.
7. Keefe S, Kambhampati S, Powers B. An electronic chemotherapy ordering process and template. Fed Pract. 2015;32(suppl 1):21S-25S.
8. Lynch JA, Berse B, Rabb M, et al. Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 - 2013. BMC Cancer. 2018;18(1):306.
The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.
Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.
Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.1 We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.
Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.
Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work.
The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.
Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.2
Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.3,4 The landscape is going to change dramatically in the next couple of years.
Accessing Testing For First-Line Treatments
Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.
Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.
A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.
In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.
Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.
Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.
Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.
Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.
Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.
All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.
Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.
Dr. Kambhampati. I agree.
Rural Challenges In A Veterans Population
Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.
Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.
Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.
Comorbidities
Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.
Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.
Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.
Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.
Measuring Success
Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.
Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.
Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.
Role of Pharmacists
Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.
And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.
Dr. Kaster. As an oncology pharmacist, I have to second that.
Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.
Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.
Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.7 And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.
Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.
With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.
Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.
Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.
Areas For Further Investigation
Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.3 How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?
Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.
Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.
For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.
In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.
Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.
Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.
The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.
Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.
Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.1 We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.
Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.
Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work.
The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.
Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.2
Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.3,4 The landscape is going to change dramatically in the next couple of years.
Accessing Testing For First-Line Treatments
Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.
Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.
A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.
In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.
Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.
Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.
Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.
Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.
Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.
All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.
Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.
Dr. Kambhampati. I agree.
Rural Challenges In A Veterans Population
Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.
Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.
Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.
Comorbidities
Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.
Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.
Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.
Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.
Measuring Success
Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.
Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.
Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.
Role of Pharmacists
Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.
And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.
Dr. Kaster. As an oncology pharmacist, I have to second that.
Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.
Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.
Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.7 And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.
Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.
With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.
Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.
Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.
Areas For Further Investigation
Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.3 How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?
Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.
Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.
For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.
In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.
Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.
Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.
1. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab vs chemotherapy for PD-L1-positive non-small cell lung cancer. N Engl J Med. 2016;375(19):1823-1833.
2. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–smallcell lung cancer. N Engl J Med. 2017;377(20):1919-1929.
3. Hellmann MD, Ciuleanu T-E, Pluzansk A, et al. Nivolumab plus ipilimumab in Lung Cancer with a high tumor mutational burden. N Engl J Med. 2018 April 16. [Epub ahead of print.]
4. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate214 Investigators. Nivolumab plus ipilimumab versus sunitinibin advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290.
5. Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small cell
lung cancer. Ann Oncol. 2018 March 30. [Epub ahead of print.]
6. Heinrichs A, Dessars B, El Housni H, et al. Identification of chronic myeloid leukemia patients treated with imatinib who are potentially eligible for treatment discontinuation by assessingreal-life molecular responses on the international scale in a EUTOS-certified lab. Leuk Res. 2018;67:27-31.
7. Keefe S, Kambhampati S, Powers B. An electronic chemotherapy ordering process and template. Fed Pract. 2015;32(suppl 1):21S-25S.
8. Lynch JA, Berse B, Rabb M, et al. Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 - 2013. BMC Cancer. 2018;18(1):306.
1. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab vs chemotherapy for PD-L1-positive non-small cell lung cancer. N Engl J Med. 2016;375(19):1823-1833.
2. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–smallcell lung cancer. N Engl J Med. 2017;377(20):1919-1929.
3. Hellmann MD, Ciuleanu T-E, Pluzansk A, et al. Nivolumab plus ipilimumab in Lung Cancer with a high tumor mutational burden. N Engl J Med. 2018 April 16. [Epub ahead of print.]
4. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate214 Investigators. Nivolumab plus ipilimumab versus sunitinibin advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290.
5. Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small cell
lung cancer. Ann Oncol. 2018 March 30. [Epub ahead of print.]
6. Heinrichs A, Dessars B, El Housni H, et al. Identification of chronic myeloid leukemia patients treated with imatinib who are potentially eligible for treatment discontinuation by assessingreal-life molecular responses on the international scale in a EUTOS-certified lab. Leuk Res. 2018;67:27-31.
7. Keefe S, Kambhampati S, Powers B. An electronic chemotherapy ordering process and template. Fed Pract. 2015;32(suppl 1):21S-25S.
8. Lynch JA, Berse B, Rabb M, et al. Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 - 2013. BMC Cancer. 2018;18(1):306.
The personal cancer vaccine NEO-PV-01 shows promise in metastatic cancers
WASHINGTON – according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.
No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.
Most adverse events that occurred were mild and related to the local injection, she noted.
Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.
All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.
“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.
The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.
As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.
“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.
Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.
An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.
The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.
“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.
Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
WASHINGTON – according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.
No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.
Most adverse events that occurred were mild and related to the local injection, she noted.
Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.
All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.
“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.
The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.
As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.
“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.
Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.
An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.
The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.
“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.
Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
WASHINGTON – according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.
No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.
Most adverse events that occurred were mild and related to the local injection, she noted.
Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.
All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.
“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.
The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.
As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.
“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.
Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.
An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.
The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.
“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.
Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
REPORTING FROM SITC 2018
Key clinical point: The NEO-PV-01 personalized cancer vaccine shows good tolerability and safety and appears to have clinical efficacy.
Major finding: There were no vaccine-related serious adverse events, and all patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T-cell responses.
Study details: A study of the NEO-PV-01 personalized cancer vaccine in 34 patients.
Disclosures: Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.
Source: Hu-Lieskovan S et al. SITC 2018, Abstract 07.
Cancer vaccine fails in CRC but trial yields lessons
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Tecemotide did not improve outcomes among patients with resected liver-only metastases of CRC.
Major finding: Tecemotide was not superior to placebo with respect to median recurrence-free survival (6.1 vs. 11.4 months; P = .1754) or overall survival (62.8 months vs. not reached; P = .2141).
Study details: A phase 2 randomized controlled trial among 121 patients having had R0/R1 resection of isolated liver CRC metastases (LICC trial).
Disclosures: Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
Source: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
Novel bispecific CAR shows promise in B-cell malignancies
SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.
Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.
Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.
“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.
“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.
“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.
The dose assessed in the current analysis was 1 x 106 CAR T cells/kg; other planned doses include 3 x 106 CAR T cells/kg and 1 x 107 CAR T cells/kg, he said.
All patients underwent lymphodepletion with cyclophosphamide (500 mg/m2 daily x 3 doses) and fludarabine (30 mg/m2 daily x 3 doses) followed by CAR T-cell infusion 2 days later.
The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.
Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.
“But questions remain about determining the durability of response and the causes of therapy failure,” he said.
One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.
“We have now escalated the dose to 3 x 106 CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.
A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.
Dr. Hossain reported having no financial disclosures.
SOURCE: Hossain N et al. ASH 2018, Abstract 490.
SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.
Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.
Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.
“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.
“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.
“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.
The dose assessed in the current analysis was 1 x 106 CAR T cells/kg; other planned doses include 3 x 106 CAR T cells/kg and 1 x 107 CAR T cells/kg, he said.
All patients underwent lymphodepletion with cyclophosphamide (500 mg/m2 daily x 3 doses) and fludarabine (30 mg/m2 daily x 3 doses) followed by CAR T-cell infusion 2 days later.
The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.
Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.
“But questions remain about determining the durability of response and the causes of therapy failure,” he said.
One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.
“We have now escalated the dose to 3 x 106 CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.
A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.
Dr. Hossain reported having no financial disclosures.
SOURCE: Hossain N et al. ASH 2018, Abstract 490.
SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.
Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.
Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.
“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.
“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.
“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.
The dose assessed in the current analysis was 1 x 106 CAR T cells/kg; other planned doses include 3 x 106 CAR T cells/kg and 1 x 107 CAR T cells/kg, he said.
All patients underwent lymphodepletion with cyclophosphamide (500 mg/m2 daily x 3 doses) and fludarabine (30 mg/m2 daily x 3 doses) followed by CAR T-cell infusion 2 days later.
The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.
Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.
“But questions remain about determining the durability of response and the causes of therapy failure,” he said.
One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.
“We have now escalated the dose to 3 x 106 CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.
A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.
Dr. Hossain reported having no financial disclosures.
SOURCE: Hossain N et al. ASH 2018, Abstract 490.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Grade 1 cytokine release syndrome occurred in five patients, and grade 2 CRS occurred in one patient; there were no dose-limiting toxicities.
Study details: A phase 1 dose escalation study of nine patients.
Disclosures: Dr. Hossain reported having no financial disclosures.
Source: Hossain N et al. ASH 2018, Abstract 490.
Uninterrupted ibrutinib with CAR T could improve CLL outcomes
SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.
The findings come from a comparison of sequential cohorts from a phase 1/2 study.
At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.
Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.
Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.
In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.
Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.
The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 106 CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.
The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 106 CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.
The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.
The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”
Dr. Gauthier reported having no financial disclosures.
SOURCE: Gauthier J et al. ASH 18, Abstract 299.
SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.
The findings come from a comparison of sequential cohorts from a phase 1/2 study.
At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.
Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.
Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.
In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.
Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.
The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 106 CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.
The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 106 CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.
The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.
The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”
Dr. Gauthier reported having no financial disclosures.
SOURCE: Gauthier J et al. ASH 18, Abstract 299.
SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.
The findings come from a comparison of sequential cohorts from a phase 1/2 study.
At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.
Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.
Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.
In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.
Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.
The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 106 CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.
The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 106 CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.
The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.
The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”
Dr. Gauthier reported having no financial disclosures.
SOURCE: Gauthier J et al. ASH 18, Abstract 299.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Severe cytokine release syndrome occurred in 0% versus 25% of patients in the ibrutinib and no-ibrutinib cohorts, respectively.
Study details: A retrospective comparison of 43 patients in two cohorts from a phase 1/2 study.
Disclosures: Dr. Gauthier reported having no financial disclosures.
Source: Gauthier J et al. ASH 2018, Abstract 299.
Avelumab active in recurrent or refractory ovarian cancer
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
FROM JAMA ONCOLOGY
Key clinical point: Single-agent treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients.
Major finding: Treatment yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months.
Study details: Phase 1b results from the JAVELIN solid tumor trial, which included 125 women with recurrent or refractory ovarian cancer.
Disclosures: The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Study authors reported disclosures related to Pfizer, Merck, Celgene, EMD Serono, Epithany, Janssen, and Seattle Genetics, among others.
Source: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Pembrolizumab bests chemo in PD-L1-positive esophageal cancer
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: .
Major finding: Among patients with a PD-L1 combined positive score of 10 or higher, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy (hazard ratio, 0.69; P = .0074).
Study details: A phase 3 randomized controlled trial among 628 patients having progression after first-line therapy for advanced cancer of the esophagus or GEJ (KEYNOTE-181).
Disclosures: Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
Source: Kojima T et al. GI Cancers Symposium, Abstract 2.
Checkpoint inhibitors linked to rare, but serious immune-related side effects
Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.
“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”
Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.
The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.
Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.
The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).
Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.
These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.
In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.
“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.
This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.
“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”
Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.
The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.
Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.
The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).
Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.
These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.
In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.
“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.
This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.
“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”
Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.
The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.
Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.
The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).
Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).
Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.
These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.
In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.
“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.
This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
FROM THE LANCET HAEMATOLOGY
Key clinical point:
Major finding: Checkpoint inhibitor therapy led to hematological toxicity in 0.5% of patients.
Study details: A study of 948 patients in French registries who were observed prospectively or retrospectively, including a case series of 35 patients treated with checkpoint inhibitor therapy who developed hematologic, immune-related adverse events.
Disclosures: This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.
Source: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.
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Stories include: uUing low-dose tamoxifen, the latest findings from the KATHERINE trial, results of a meta-analysis of neoadjuvant chemotherapy, and capecitabine in early stage triple negative breast cancer.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Stories include: uUing low-dose tamoxifen, the latest findings from the KATHERINE trial, results of a meta-analysis of neoadjuvant chemotherapy, and capecitabine in early stage triple negative breast cancer.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
