Sharon Worcester

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

CHICAGO – High levels of blood and tissue tumor mutational burden appear to have value as biomarkers for checkpoint inhibition response in patients with non–small cell lung cancer, according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.

The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.

Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.

“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.

The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.

Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.

In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.

The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.

B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.

Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.

The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.

Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.

This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.

Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.

“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”

The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.

Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.

SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.

CHICAGO – High levels of blood and tissue tumor mutational burden appear to have value as biomarkers for checkpoint inhibition response in patients with non–small cell lung cancer, according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.

The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.

Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.

“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.

The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.

Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.

In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.

The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.

B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.

Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.

The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.

Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.

This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.

Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.

“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”

The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.

Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.

SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.

CHICAGO – High levels of blood and tissue tumor mutational burden appear to have value as biomarkers for checkpoint inhibition response in patients with non–small cell lung cancer, according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.

The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.

Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.

“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.

The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.

Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.

In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.

The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.

B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.

Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.

The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.

Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.

This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.

Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.

“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”

The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.

Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.

SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.

CHICAGO – Preoperative chemotherapy improves outcomes in patients with resectable or borderline resectable pancreatic cancer, preliminary findings from the phase 3 PREOPANC-1 trial suggest.

Overall survival in 127 patients randomized to immediate surgery followed by adjuvant chemotherapy was 13.7 months vs. 17.1 months in 119 patients randomized to receive preoperative chemoradiotherapy and postoperative adjuvant chemotherapy, Geertjan van Tienhoven, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The difference did not quite reach statistical significance, but final analysis requires an additional 26 events, Dr. van Tienhoven of Academic Medical Center, Amsterdam explained in a video interview at the meeting.

Other differences between the groups, which included disease-free survival, local control, and metastasis-free survival, did differ significantly in favor of preoperative chemotherapy, he said.

Of note, 72% and 62% of patients in the immediate surgery and preoperative chemoradiotherapy groups, respectively, underwent resection and a greater proportion of patients in the latter group achieved microscopically complete resection, he said (63% vs. 31%).

Should these results hold up in the final analysis, particularly if the difference in overall survival reaches statistical significance, “then this is a proof of principle and practice-changing trial,” Dr. van Tienhoven said.

Dr. van Tienhoven reported having no disclosures.

SOURCE: van Tienhoven et al. ASCO 2108, Abstract LBA4002.

CHICAGO – Preoperative chemotherapy improves outcomes in patients with resectable or borderline resectable pancreatic cancer, preliminary findings from the phase 3 PREOPANC-1 trial suggest.

Overall survival in 127 patients randomized to immediate surgery followed by adjuvant chemotherapy was 13.7 months vs. 17.1 months in 119 patients randomized to receive preoperative chemoradiotherapy and postoperative adjuvant chemotherapy, Geertjan van Tienhoven, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The difference did not quite reach statistical significance, but final analysis requires an additional 26 events, Dr. van Tienhoven of Academic Medical Center, Amsterdam explained in a video interview at the meeting.

Other differences between the groups, which included disease-free survival, local control, and metastasis-free survival, did differ significantly in favor of preoperative chemotherapy, he said.

Of note, 72% and 62% of patients in the immediate surgery and preoperative chemoradiotherapy groups, respectively, underwent resection and a greater proportion of patients in the latter group achieved microscopically complete resection, he said (63% vs. 31%).

Should these results hold up in the final analysis, particularly if the difference in overall survival reaches statistical significance, “then this is a proof of principle and practice-changing trial,” Dr. van Tienhoven said.

Dr. van Tienhoven reported having no disclosures.

SOURCE: van Tienhoven et al. ASCO 2108, Abstract LBA4002.

CHICAGO – Preoperative chemotherapy improves outcomes in patients with resectable or borderline resectable pancreatic cancer, preliminary findings from the phase 3 PREOPANC-1 trial suggest.

Overall survival in 127 patients randomized to immediate surgery followed by adjuvant chemotherapy was 13.7 months vs. 17.1 months in 119 patients randomized to receive preoperative chemoradiotherapy and postoperative adjuvant chemotherapy, Geertjan van Tienhoven, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The difference did not quite reach statistical significance, but final analysis requires an additional 26 events, Dr. van Tienhoven of Academic Medical Center, Amsterdam explained in a video interview at the meeting.

Other differences between the groups, which included disease-free survival, local control, and metastasis-free survival, did differ significantly in favor of preoperative chemotherapy, he said.

Of note, 72% and 62% of patients in the immediate surgery and preoperative chemoradiotherapy groups, respectively, underwent resection and a greater proportion of patients in the latter group achieved microscopically complete resection, he said (63% vs. 31%).

Should these results hold up in the final analysis, particularly if the difference in overall survival reaches statistical significance, “then this is a proof of principle and practice-changing trial,” Dr. van Tienhoven said.

Dr. van Tienhoven reported having no disclosures.

SOURCE: van Tienhoven et al. ASCO 2108, Abstract LBA4002.

CHICAGO – Findings from four recent, phase 3 gastrointestinal cancer studies mark a step forward toward “the answers we need” for patients with pancreatic, colorectal, or esophageal cancer, according to Andrew S. Epstein, MD.

In this video interview, Dr. Epstein summarizes and provides context for the findings, which were presented at the annual meeting of the American Society of Clinical Oncology and highlighted during a press briefing there. Dr. Epstein, an ASCO Expert and a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, who was invited to discuss each of the studies at the briefing, said the UNICANCER-sponsored Prodige 7 trial addressed an important, long-unanswered question about the value of hyperthermic intraperitoneal chemotherapy (HIPEC) with surgery for colorectal peritoneal carcinomatosis.

“This randomized study, very importantly, answered that longstanding question and showed us in a less-is-more type of way that the addition of the chemotherapy during surgery actually did not improve the overall survival of these patients,” he said, adding that, at 60 days, HIPEC actually had done more harm than good.

The findings are helpful, as HIPEC has been widely used without a solid data foundation, and now the use of an “additional toxic nonbeneficial treatment” can be avoided in a subset of patients.

Two studies regarding chemotherapy in patients with pancreatic cancer also provided important information about treatment. Preliminary data from one, the PREOPANC-1 trial, suggested that perioperative chemoradiotherapy significantly improves outcomes in resectable and borderline resectable patients, compared with immediate surgery; the other – the Prodige 24/CCTG PA.6 trial – demonstrated that adjuvant mFOLFIRINOX, a four-agent regimen, improved disease-free, metastasis-free, and overall survival, with treated patients living a median of 20 months longer and being cancer free for a median of 9 months longer than those who received gemcitabine therapy.

“We saw a very impressive, encouraging, statistically and clinically significant improvement,” he said regarding survival outcomes in Prodige 24. In patients with good performance status who can tolerate the regimen, mFOLFIRINOX “seems to be the way to go now,” he added, noting that patients receiving the regimen require close monitoring by a medical oncologist.

The fourth study, a prevention trial known as the ASPECT trial, showed that high-dose esomeprazole and low-dose aspirin taken for at least 7 years moderately reduces the risk of high-grade dysplasia and esophageal cancer, and may delay death from any cause in patients with Barrett’s esophagus.

“[It is] obviously of huge importance to be able to prevent a cancer before its onset. ... So with esophagus cancer, which also is a very difficult disease to treat in whatever stage it is, it would be a huge benefit to have a way in which to effectively prevent it,” Dr. Epstein said.

However, more information is needed about the actual benefits in terms of all-cause mortality and the contributors from aspirin versus the proton pump inhibitor versus both, he noted, adding that it is important for the public to know that the findings only apply to those with Barrett’s esophagus and shouldn’t be attempted with over-the-counter treatments as some treatments are associated with complications, and the proton pump inhibitor dose used in this study is not available over the counter.

“So I think it is an intriguing study which needs more clarity and more follow-up, as the author himself said,” he added.

In summing up the findings presented at the briefing, Dr. Epstein said that “collectively we see that the challenge of cancer remains significant and we need high-quality studies like the ones presented today in order to best present ...what the best therapies are for [patients].

“With good sound science like this we continue to inch closer to the answers we need,” he concluded.

Dr. Epstein reported having no disclosures.

CHICAGO – Findings from four recent, phase 3 gastrointestinal cancer studies mark a step forward toward “the answers we need” for patients with pancreatic, colorectal, or esophageal cancer, according to Andrew S. Epstein, MD.

In this video interview, Dr. Epstein summarizes and provides context for the findings, which were presented at the annual meeting of the American Society of Clinical Oncology and highlighted during a press briefing there. Dr. Epstein, an ASCO Expert and a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, who was invited to discuss each of the studies at the briefing, said the UNICANCER-sponsored Prodige 7 trial addressed an important, long-unanswered question about the value of hyperthermic intraperitoneal chemotherapy (HIPEC) with surgery for colorectal peritoneal carcinomatosis.

“This randomized study, very importantly, answered that longstanding question and showed us in a less-is-more type of way that the addition of the chemotherapy during surgery actually did not improve the overall survival of these patients,” he said, adding that, at 60 days, HIPEC actually had done more harm than good.

The findings are helpful, as HIPEC has been widely used without a solid data foundation, and now the use of an “additional toxic nonbeneficial treatment” can be avoided in a subset of patients.

Two studies regarding chemotherapy in patients with pancreatic cancer also provided important information about treatment. Preliminary data from one, the PREOPANC-1 trial, suggested that perioperative chemoradiotherapy significantly improves outcomes in resectable and borderline resectable patients, compared with immediate surgery; the other – the Prodige 24/CCTG PA.6 trial – demonstrated that adjuvant mFOLFIRINOX, a four-agent regimen, improved disease-free, metastasis-free, and overall survival, with treated patients living a median of 20 months longer and being cancer free for a median of 9 months longer than those who received gemcitabine therapy.

“We saw a very impressive, encouraging, statistically and clinically significant improvement,” he said regarding survival outcomes in Prodige 24. In patients with good performance status who can tolerate the regimen, mFOLFIRINOX “seems to be the way to go now,” he added, noting that patients receiving the regimen require close monitoring by a medical oncologist.

The fourth study, a prevention trial known as the ASPECT trial, showed that high-dose esomeprazole and low-dose aspirin taken for at least 7 years moderately reduces the risk of high-grade dysplasia and esophageal cancer, and may delay death from any cause in patients with Barrett’s esophagus.

“[It is] obviously of huge importance to be able to prevent a cancer before its onset. ... So with esophagus cancer, which also is a very difficult disease to treat in whatever stage it is, it would be a huge benefit to have a way in which to effectively prevent it,” Dr. Epstein said.

However, more information is needed about the actual benefits in terms of all-cause mortality and the contributors from aspirin versus the proton pump inhibitor versus both, he noted, adding that it is important for the public to know that the findings only apply to those with Barrett’s esophagus and shouldn’t be attempted with over-the-counter treatments as some treatments are associated with complications, and the proton pump inhibitor dose used in this study is not available over the counter.

“So I think it is an intriguing study which needs more clarity and more follow-up, as the author himself said,” he added.

In summing up the findings presented at the briefing, Dr. Epstein said that “collectively we see that the challenge of cancer remains significant and we need high-quality studies like the ones presented today in order to best present ...what the best therapies are for [patients].

“With good sound science like this we continue to inch closer to the answers we need,” he concluded.

Dr. Epstein reported having no disclosures.

CHICAGO – Findings from four recent, phase 3 gastrointestinal cancer studies mark a step forward toward “the answers we need” for patients with pancreatic, colorectal, or esophageal cancer, according to Andrew S. Epstein, MD.

In this video interview, Dr. Epstein summarizes and provides context for the findings, which were presented at the annual meeting of the American Society of Clinical Oncology and highlighted during a press briefing there. Dr. Epstein, an ASCO Expert and a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, who was invited to discuss each of the studies at the briefing, said the UNICANCER-sponsored Prodige 7 trial addressed an important, long-unanswered question about the value of hyperthermic intraperitoneal chemotherapy (HIPEC) with surgery for colorectal peritoneal carcinomatosis.

“This randomized study, very importantly, answered that longstanding question and showed us in a less-is-more type of way that the addition of the chemotherapy during surgery actually did not improve the overall survival of these patients,” he said, adding that, at 60 days, HIPEC actually had done more harm than good.

The findings are helpful, as HIPEC has been widely used without a solid data foundation, and now the use of an “additional toxic nonbeneficial treatment” can be avoided in a subset of patients.

Two studies regarding chemotherapy in patients with pancreatic cancer also provided important information about treatment. Preliminary data from one, the PREOPANC-1 trial, suggested that perioperative chemoradiotherapy significantly improves outcomes in resectable and borderline resectable patients, compared with immediate surgery; the other – the Prodige 24/CCTG PA.6 trial – demonstrated that adjuvant mFOLFIRINOX, a four-agent regimen, improved disease-free, metastasis-free, and overall survival, with treated patients living a median of 20 months longer and being cancer free for a median of 9 months longer than those who received gemcitabine therapy.

“We saw a very impressive, encouraging, statistically and clinically significant improvement,” he said regarding survival outcomes in Prodige 24. In patients with good performance status who can tolerate the regimen, mFOLFIRINOX “seems to be the way to go now,” he added, noting that patients receiving the regimen require close monitoring by a medical oncologist.

The fourth study, a prevention trial known as the ASPECT trial, showed that high-dose esomeprazole and low-dose aspirin taken for at least 7 years moderately reduces the risk of high-grade dysplasia and esophageal cancer, and may delay death from any cause in patients with Barrett’s esophagus.

“[It is] obviously of huge importance to be able to prevent a cancer before its onset. ... So with esophagus cancer, which also is a very difficult disease to treat in whatever stage it is, it would be a huge benefit to have a way in which to effectively prevent it,” Dr. Epstein said.

However, more information is needed about the actual benefits in terms of all-cause mortality and the contributors from aspirin versus the proton pump inhibitor versus both, he noted, adding that it is important for the public to know that the findings only apply to those with Barrett’s esophagus and shouldn’t be attempted with over-the-counter treatments as some treatments are associated with complications, and the proton pump inhibitor dose used in this study is not available over the counter.

“So I think it is an intriguing study which needs more clarity and more follow-up, as the author himself said,” he added.

In summing up the findings presented at the briefing, Dr. Epstein said that “collectively we see that the challenge of cancer remains significant and we need high-quality studies like the ones presented today in order to best present ...what the best therapies are for [patients].

“With good sound science like this we continue to inch closer to the answers we need,” he concluded.

Dr. Epstein reported having no disclosures.

CHICAGO – Hyperthermic intraperitoneal chemotherapy (HIPEC) following surgery for colorectal peritoneal carcinomatosis provides no survival benefit and may cause harm, according to findings from the randomized phase 3 UNICANCER Prodige 7 trial.

At a median follow up of 63.8 months, median overall survival – the primary endpoint of the study – was “completely comparable” at 41.7 and 41.2 months, respectively, in 133 patients randomized to receive HIPEC with oxaliplatin after cytoreductive surgery and 132 randomized to the cytoreductive surgery–only arm, François Quenet, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Sharon Worcester/MDedge News

The use of HIPEC with cytoreductive surgery was introduced about 15 years ago and has become an accepted treatment option – and in some centers, a standard of care; the combination has been considered an effective treatment for peritoneal carcinomatosis, a metastatic tumor of the peritoneum that occurs in about 20% of colorectal cancer patients. The role of HIPEC in the success of the approach, however, has been unclear.

The current findings suggest that cytoreductive surgery alone is as effective as surgery with HIPEC, which “does not influence the survival result,” in most patients, Dr. Quenet said, noting that about 15% of patients were cured.

Additional study is needed to determine if there are certain subsets of patients who might benefit from HIPEC, he added, explaining that a subgroup analysis in the current study suggested that those with a midrange amount of disease in the abdominal cavity (peritoneal cancer index of 11-15) might experience some benefit with HIPEC, but the numbers were too small to be conclusive.

More research also is needed to determine if chemotherapy agents other than the oxaliplatin used with HIPEC in this study might be more effective, he said.

Prodige 7 was funded by UNICANCER. Dr. Quenet has received honoraria from Sanofi/Aventis, Ethicon, and Gamida Cell, as well as travel/accommodations/expenses from Sanofi, Novartis, and Ethicon.

SOURCE: Quenet F et al. ASCO 2018, Abstract LBA3503.

CHICAGO – Hyperthermic intraperitoneal chemotherapy (HIPEC) following surgery for colorectal peritoneal carcinomatosis provides no survival benefit and may cause harm, according to findings from the randomized phase 3 UNICANCER Prodige 7 trial.

At a median follow up of 63.8 months, median overall survival – the primary endpoint of the study – was “completely comparable” at 41.7 and 41.2 months, respectively, in 133 patients randomized to receive HIPEC with oxaliplatin after cytoreductive surgery and 132 randomized to the cytoreductive surgery–only arm, François Quenet, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Sharon Worcester/MDedge News

The use of HIPEC with cytoreductive surgery was introduced about 15 years ago and has become an accepted treatment option – and in some centers, a standard of care; the combination has been considered an effective treatment for peritoneal carcinomatosis, a metastatic tumor of the peritoneum that occurs in about 20% of colorectal cancer patients. The role of HIPEC in the success of the approach, however, has been unclear.

The current findings suggest that cytoreductive surgery alone is as effective as surgery with HIPEC, which “does not influence the survival result,” in most patients, Dr. Quenet said, noting that about 15% of patients were cured.

Additional study is needed to determine if there are certain subsets of patients who might benefit from HIPEC, he added, explaining that a subgroup analysis in the current study suggested that those with a midrange amount of disease in the abdominal cavity (peritoneal cancer index of 11-15) might experience some benefit with HIPEC, but the numbers were too small to be conclusive.

More research also is needed to determine if chemotherapy agents other than the oxaliplatin used with HIPEC in this study might be more effective, he said.

Prodige 7 was funded by UNICANCER. Dr. Quenet has received honoraria from Sanofi/Aventis, Ethicon, and Gamida Cell, as well as travel/accommodations/expenses from Sanofi, Novartis, and Ethicon.

SOURCE: Quenet F et al. ASCO 2018, Abstract LBA3503.

CHICAGO – Hyperthermic intraperitoneal chemotherapy (HIPEC) following surgery for colorectal peritoneal carcinomatosis provides no survival benefit and may cause harm, according to findings from the randomized phase 3 UNICANCER Prodige 7 trial.

At a median follow up of 63.8 months, median overall survival – the primary endpoint of the study – was “completely comparable” at 41.7 and 41.2 months, respectively, in 133 patients randomized to receive HIPEC with oxaliplatin after cytoreductive surgery and 132 randomized to the cytoreductive surgery–only arm, François Quenet, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Sharon Worcester/MDedge News

The use of HIPEC with cytoreductive surgery was introduced about 15 years ago and has become an accepted treatment option – and in some centers, a standard of care; the combination has been considered an effective treatment for peritoneal carcinomatosis, a metastatic tumor of the peritoneum that occurs in about 20% of colorectal cancer patients. The role of HIPEC in the success of the approach, however, has been unclear.

The current findings suggest that cytoreductive surgery alone is as effective as surgery with HIPEC, which “does not influence the survival result,” in most patients, Dr. Quenet said, noting that about 15% of patients were cured.

Additional study is needed to determine if there are certain subsets of patients who might benefit from HIPEC, he added, explaining that a subgroup analysis in the current study suggested that those with a midrange amount of disease in the abdominal cavity (peritoneal cancer index of 11-15) might experience some benefit with HIPEC, but the numbers were too small to be conclusive.

More research also is needed to determine if chemotherapy agents other than the oxaliplatin used with HIPEC in this study might be more effective, he said.

Prodige 7 was funded by UNICANCER. Dr. Quenet has received honoraria from Sanofi/Aventis, Ethicon, and Gamida Cell, as well as travel/accommodations/expenses from Sanofi, Novartis, and Ethicon.

SOURCE: Quenet F et al. ASCO 2018, Abstract LBA3503.

CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.

Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.

The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.

Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.

“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.

The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.

Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.

KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.

The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.

Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.

Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.

“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.

Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.

“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.

Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.

Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.

SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.

CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.

Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.

The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.

Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.

“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.

The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.

Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.

KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.

The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.

Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.

Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.

“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.

Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.

“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.

Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.

Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.

SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.

CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.

Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.

The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.

Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.

“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.

The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.

Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.

KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.

The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.

Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.

Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.

“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.

Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.

“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.

Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.

Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.

SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – High frequency microsatellite instability (MSI-high) predicts Lynch Syndrome– and does so across more tumor types than previously expected, according to “absolutely practice changing” findings from a prospective analysis of more than 15,000 tumor samples.

Sharon Worcester/MDedge News

“The impact of these findings cannot be understated,” ASCO expert Shannon N. Westin, MD, said during a discussion of the findings presented by Zsofia K. Stadler, MD, at a press briefing at the annual meeting of the American Society of Clinical Oncology.

Lynch Syndrome (LS), an autosomal dominant inherited cancer predisposition syndrome caused by germline mutation in the DNA mismatch repair genes, is responsible for about 3% of colorectal and endometrial cancers; universal testing for tumor markers of LS is recommended in all patients with these types of cancers, said Dr. Stadler, director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York.

“This is usually done either via MSI analysis or immunohistochemical staining for the DNA mismatch repair proteins,” she said, noting that genetic testing and counseling is recommended in patients with tumors suggestive of LS, and increased surveillance and/or risk-reducing surgery is recommended in those recognized as having LS.

MSI-high is a hallmark of LS-associated cancers and has recently been implicated as a marker for response to immunotherapy. This has led to increased MSI testing in metastatic cancer regardless of cancer type.

However, the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of LS across all MSI-high tumors is unknown, she said.

In 15,045 tumor samples across more than 50 cancer types, germline mutations were analyzed across tumor types and according to MSI status.

SOURCE: Schwark A et al., ASCO 2018 LBA1509.

CHICAGO – High frequency microsatellite instability (MSI-high) predicts Lynch Syndrome– and does so across more tumor types than previously expected, according to “absolutely practice changing” findings from a prospective analysis of more than 15,000 tumor samples.

Sharon Worcester/MDedge News

“The impact of these findings cannot be understated,” ASCO expert Shannon N. Westin, MD, said during a discussion of the findings presented by Zsofia K. Stadler, MD, at a press briefing at the annual meeting of the American Society of Clinical Oncology.

Lynch Syndrome (LS), an autosomal dominant inherited cancer predisposition syndrome caused by germline mutation in the DNA mismatch repair genes, is responsible for about 3% of colorectal and endometrial cancers; universal testing for tumor markers of LS is recommended in all patients with these types of cancers, said Dr. Stadler, director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York.

“This is usually done either via MSI analysis or immunohistochemical staining for the DNA mismatch repair proteins,” she said, noting that genetic testing and counseling is recommended in patients with tumors suggestive of LS, and increased surveillance and/or risk-reducing surgery is recommended in those recognized as having LS.

MSI-high is a hallmark of LS-associated cancers and has recently been implicated as a marker for response to immunotherapy. This has led to increased MSI testing in metastatic cancer regardless of cancer type.

However, the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of LS across all MSI-high tumors is unknown, she said.

In 15,045 tumor samples across more than 50 cancer types, germline mutations were analyzed across tumor types and according to MSI status.

SOURCE: Schwark A et al., ASCO 2018 LBA1509.

CHICAGO – High frequency microsatellite instability (MSI-high) predicts Lynch Syndrome– and does so across more tumor types than previously expected, according to “absolutely practice changing” findings from a prospective analysis of more than 15,000 tumor samples.

Sharon Worcester/MDedge News

“The impact of these findings cannot be understated,” ASCO expert Shannon N. Westin, MD, said during a discussion of the findings presented by Zsofia K. Stadler, MD, at a press briefing at the annual meeting of the American Society of Clinical Oncology.

Lynch Syndrome (LS), an autosomal dominant inherited cancer predisposition syndrome caused by germline mutation in the DNA mismatch repair genes, is responsible for about 3% of colorectal and endometrial cancers; universal testing for tumor markers of LS is recommended in all patients with these types of cancers, said Dr. Stadler, director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York.

“This is usually done either via MSI analysis or immunohistochemical staining for the DNA mismatch repair proteins,” she said, noting that genetic testing and counseling is recommended in patients with tumors suggestive of LS, and increased surveillance and/or risk-reducing surgery is recommended in those recognized as having LS.

MSI-high is a hallmark of LS-associated cancers and has recently been implicated as a marker for response to immunotherapy. This has led to increased MSI testing in metastatic cancer regardless of cancer type.

However, the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of LS across all MSI-high tumors is unknown, she said.

In 15,045 tumor samples across more than 50 cancer types, germline mutations were analyzed across tumor types and according to MSI status.

SOURCE: Schwark A et al., ASCO 2018 LBA1509.

LOS ANGELES – Patients with multiple sclerosis in the CARE-MS II study who switched from interferon beta-1a therapy to the humanized monoclonal antibody alemtuzumab experienced continued reductions in brain volume loss and lesions on MRI through 5 years, according to follow-up data from the CARE-MS II extension study known as TOPAZ.

These outcomes support core findings from the CARE-MS II study, and suggest that alemtuzumab (Lemtrada) provides a unique treatment approach for patients with prior subcutaneous interferon beta-1a (IFNB-1a) treatment, Daniel Pelletier, MD, reported in a poster discussion session at the annual meeting of the American Academy of Neurology.

In CARE-MS II, relapsing-remitting multiple sclerosis patients with inadequate response to prior therapy experienced improvements in MRI lesions and brain volume loss with two courses of alemtuzumab versus IFNB-1a through 2 years, and in a 4-year extension in which participants discontinued subcutaneous IFNB-1a and initiated alemtuzumab at 12 mg/day, they experienced durable efficacy in the absence of continuous treatment, explained Dr. Pelletier, a professor of neurology at the University of Southern California, Los Angeles.

In the extension, patients could receive alemtuzumab retreatment as needed for relapse/MRI activity or receive other disease-modifying therapies at the investigator’s discretion. Patients completing the extension could enter the 5-year TOPAZ study for further evaluation, he said.

Of 119 patients who completed TOPAZ year 1, and thus had 5 years of follow-up after initiating alemtuzumab, 78% were free of new, gadolinium-enhancing lesions in IFNB-1a year 2; this increased significantly to 92% in post-alemtuzumab year 2, and remained high at 85%-89% in years 3-5. Additionally, 48% of patients were free of new/enlarging T2 lesions in IFNB-1a year 2; this increased significantly to 81% in post-alemtuzumab year 2 and remained high in years 3-5.

Further, 47% of the TOPAZ patients were MRI disease activity–free in IFNB-1a year 2; this increased significantly to 81% in post-alemtuzumab year 2, and remained high at 67%-72% in years 3-5.

[email protected]

SOURCE: Pelletier D et al. Neurology. 2018 Apr 10. 90(15 Suppl.):P5.031.

LOS ANGELES – Patients with multiple sclerosis in the CARE-MS II study who switched from interferon beta-1a therapy to the humanized monoclonal antibody alemtuzumab experienced continued reductions in brain volume loss and lesions on MRI through 5 years, according to follow-up data from the CARE-MS II extension study known as TOPAZ.

These outcomes support core findings from the CARE-MS II study, and suggest that alemtuzumab (Lemtrada) provides a unique treatment approach for patients with prior subcutaneous interferon beta-1a (IFNB-1a) treatment, Daniel Pelletier, MD, reported in a poster discussion session at the annual meeting of the American Academy of Neurology.

In CARE-MS II, relapsing-remitting multiple sclerosis patients with inadequate response to prior therapy experienced improvements in MRI lesions and brain volume loss with two courses of alemtuzumab versus IFNB-1a through 2 years, and in a 4-year extension in which participants discontinued subcutaneous IFNB-1a and initiated alemtuzumab at 12 mg/day, they experienced durable efficacy in the absence of continuous treatment, explained Dr. Pelletier, a professor of neurology at the University of Southern California, Los Angeles.

In the extension, patients could receive alemtuzumab retreatment as needed for relapse/MRI activity or receive other disease-modifying therapies at the investigator’s discretion. Patients completing the extension could enter the 5-year TOPAZ study for further evaluation, he said.

Of 119 patients who completed TOPAZ year 1, and thus had 5 years of follow-up after initiating alemtuzumab, 78% were free of new, gadolinium-enhancing lesions in IFNB-1a year 2; this increased significantly to 92% in post-alemtuzumab year 2, and remained high at 85%-89% in years 3-5. Additionally, 48% of patients were free of new/enlarging T2 lesions in IFNB-1a year 2; this increased significantly to 81% in post-alemtuzumab year 2 and remained high in years 3-5.

Further, 47% of the TOPAZ patients were MRI disease activity–free in IFNB-1a year 2; this increased significantly to 81% in post-alemtuzumab year 2, and remained high at 67%-72% in years 3-5.

[email protected]

SOURCE: Pelletier D et al. Neurology. 2018 Apr 10. 90(15 Suppl.):P5.031.

LOS ANGELES – Patients with multiple sclerosis in the CARE-MS II study who switched from interferon beta-1a therapy to the humanized monoclonal antibody alemtuzumab experienced continued reductions in brain volume loss and lesions on MRI through 5 years, according to follow-up data from the CARE-MS II extension study known as TOPAZ.

These outcomes support core findings from the CARE-MS II study, and suggest that alemtuzumab (Lemtrada) provides a unique treatment approach for patients with prior subcutaneous interferon beta-1a (IFNB-1a) treatment, Daniel Pelletier, MD, reported in a poster discussion session at the annual meeting of the American Academy of Neurology.

In CARE-MS II, relapsing-remitting multiple sclerosis patients with inadequate response to prior therapy experienced improvements in MRI lesions and brain volume loss with two courses of alemtuzumab versus IFNB-1a through 2 years, and in a 4-year extension in which participants discontinued subcutaneous IFNB-1a and initiated alemtuzumab at 12 mg/day, they experienced durable efficacy in the absence of continuous treatment, explained Dr. Pelletier, a professor of neurology at the University of Southern California, Los Angeles.

In the extension, patients could receive alemtuzumab retreatment as needed for relapse/MRI activity or receive other disease-modifying therapies at the investigator’s discretion. Patients completing the extension could enter the 5-year TOPAZ study for further evaluation, he said.

Of 119 patients who completed TOPAZ year 1, and thus had 5 years of follow-up after initiating alemtuzumab, 78% were free of new, gadolinium-enhancing lesions in IFNB-1a year 2; this increased significantly to 92% in post-alemtuzumab year 2, and remained high at 85%-89% in years 3-5. Additionally, 48% of patients were free of new/enlarging T2 lesions in IFNB-1a year 2; this increased significantly to 81% in post-alemtuzumab year 2 and remained high in years 3-5.

Further, 47% of the TOPAZ patients were MRI disease activity–free in IFNB-1a year 2; this increased significantly to 81% in post-alemtuzumab year 2, and remained high at 67%-72% in years 3-5.

[email protected]

SOURCE: Pelletier D et al. Neurology. 2018 Apr 10. 90(15 Suppl.):P5.031.

NEW YORK – Female physicians are at higher risk for burnout compared with their male counterparts, and the reasons and potential solutions for the problem were addressed at a symposium during the annual meeting of the American Psychiatric Association.

The work environment for women has improved over time, but lingering implicit and unconscious biases are part of the reason for the high burnout rate among women who are physicians, as are some inherent biological differences, according to Cynthia M. Stonnington, MD, of the Mayo Clinic, Phoenix.

In this video interview, Dr. Stonnington, symposium chair, discussed potential solutions, including facilitated peer mentorship and group support. She also reviewed recent data on how group support can be of benefit, and noted that “there is power in numbers.

“It is imperative that women ... band together and find a way to support each other,” she said.

Dr. Stonnington reported having no disclosures.

[email protected]

NEW YORK – Female physicians are at higher risk for burnout compared with their male counterparts, and the reasons and potential solutions for the problem were addressed at a symposium during the annual meeting of the American Psychiatric Association.

The work environment for women has improved over time, but lingering implicit and unconscious biases are part of the reason for the high burnout rate among women who are physicians, as are some inherent biological differences, according to Cynthia M. Stonnington, MD, of the Mayo Clinic, Phoenix.

In this video interview, Dr. Stonnington, symposium chair, discussed potential solutions, including facilitated peer mentorship and group support. She also reviewed recent data on how group support can be of benefit, and noted that “there is power in numbers.

“It is imperative that women ... band together and find a way to support each other,” she said.

Dr. Stonnington reported having no disclosures.

[email protected]

NEW YORK – Female physicians are at higher risk for burnout compared with their male counterparts, and the reasons and potential solutions for the problem were addressed at a symposium during the annual meeting of the American Psychiatric Association.

The work environment for women has improved over time, but lingering implicit and unconscious biases are part of the reason for the high burnout rate among women who are physicians, as are some inherent biological differences, according to Cynthia M. Stonnington, MD, of the Mayo Clinic, Phoenix.

In this video interview, Dr. Stonnington, symposium chair, discussed potential solutions, including facilitated peer mentorship and group support. She also reviewed recent data on how group support can be of benefit, and noted that “there is power in numbers.

“It is imperative that women ... band together and find a way to support each other,” she said.

Dr. Stonnington reported having no disclosures.

[email protected]