Patient & Survivor Care

Survivors of cancer diagnosed at early ages, compared with healthy controls, face higher risk of chronic medical problems, according to two independent studies.

Survivors of adolescent and young adult (AYA) cancer had an overall 38% increased risk of hospitalization, which persisted throughout life, according to a Danish Cancer Registry study. The St. Jude Lifetime Study found that long-term survivors of childhood osteosarcoma had significant neurocognitive deficits in attention, memory, processing speed, executive function, and academics. “The morbidity pattern … underscores the need for further implementation of strict evidence-based sex,-, age-, and cancer-specific follow-up plans for survivors, thereby increasing the likelihood for early detection and ultimately prevention of treatment-induced morbidities,” wrote Kathrine Rugbjerg, Ph.D., of the Danish Cancer Society Research Center, Copenhagen, and colleagues (JAMA Onc. 2015 Nov. 19 doi: 10.1001/jamaoncol.2015.4393).

Analysis of the Danish Cancer Registry from 1943 to 2009 included 33,555 5-year survivors of cancer diagnosed between age 15 and 39 years, and 228,447 matched population comparisons. During the median 14-year follow up, cancer survivors had 53,032 hospital admissions, with 38,423 expected, for a standardized hospitalization rate ratio of 1.38 (95% CI, 1.37-1.39). The absolute excess risk (difference between observed and expected hospitalization rates per 100,000 person years of follow-up) remained relatively stable, ranging from 2 to 4 disease-specific hospitalizations per 100 survivors for each year of follow-up.

Categories that carried the highest relative risk of hospitalization for cancer survivors were diseases of blood and blood-forming organs (RR men, 2.36; women, 1.85), infectious and parasitic diseases (men, 1.81; women, 1.62), and malignant neoplasms (men, 1.80; women, 1.52). Treatments for these cancers tend to be intensive and lengthy, the researchers noted.

The AYA cancers that had the highest risk of subsequent hospitalization among survivors included leukemia (RR, 2.21), brain cancer (RR, 1.93), and Hodgkin lymphoma (RR, 1.87).

The large size of the study made possible the calculation of relative risks for hospitalization according to disease category and AYA cancer type. Survivors of brain cancer had high risk of endocrine, nervous system, and sense organ diseases (RR, 5.5); leukemia survivors had high risks of diseases of blood and blood-forming organs, respiratory system diseases, and infectious and parasitic diseases (RRs, 6.3, 4.9, and 6.3, respectively): Hodgkin lymphoma survivors had high risk of malignant neoplasms (RR, 3.7).

On average, AYA survivors spent 50% more days in hospitals than did the comparison cohort.

A separate study compared neurocognitive performance of long-term survivors of childhood osteosarcoma with community controls and found lower reading scores (P = .01), more variability in sustained attention (P = .002), poorer short-term memory (P = .01), slower motor processing speed (P less than .001), and poorer cognitive fluency (P = .006), reported Michelle N. Edelmann, Ph.D., of St Jude Children’s Research Hospital, Memphis, Tenn., and colleagues (JAMA Onc. 2015 Nov. 19. doi: 10.1001/jamaoncol.2015.4398).

The St. Jude Lifetime Cohort Study evaluated 80 survivors of childhood osteosarcoma at a mean 24.7 years after diagnosis, and compared their neurocognitive function results with 39 community controls.

All osteosarcoma survivors had undergone treatment with high-dose methotrexate, but neurocognitive outcomes were not related to cumulative dose or pharmacokinetic indices of methotrexate exposure.

Chronic health conditions can affect neurocognitive functions in survivors of childhood cancers, and the study found that osteosarcoma survivors with grade 3 or 4 adverse chronic health conditions showed poorer memory and processing speeds.

Survivors of cancer diagnosed at early ages, compared with healthy controls, face higher risk of chronic medical problems, according to two independent studies.

Survivors of adolescent and young adult (AYA) cancer had an overall 38% increased risk of hospitalization, which persisted throughout life, according to a Danish Cancer Registry study. The St. Jude Lifetime Study found that long-term survivors of childhood osteosarcoma had significant neurocognitive deficits in attention, memory, processing speed, executive function, and academics. “The morbidity pattern … underscores the need for further implementation of strict evidence-based sex,-, age-, and cancer-specific follow-up plans for survivors, thereby increasing the likelihood for early detection and ultimately prevention of treatment-induced morbidities,” wrote Kathrine Rugbjerg, Ph.D., of the Danish Cancer Society Research Center, Copenhagen, and colleagues (JAMA Onc. 2015 Nov. 19 doi: 10.1001/jamaoncol.2015.4393).

Analysis of the Danish Cancer Registry from 1943 to 2009 included 33,555 5-year survivors of cancer diagnosed between age 15 and 39 years, and 228,447 matched population comparisons. During the median 14-year follow up, cancer survivors had 53,032 hospital admissions, with 38,423 expected, for a standardized hospitalization rate ratio of 1.38 (95% CI, 1.37-1.39). The absolute excess risk (difference between observed and expected hospitalization rates per 100,000 person years of follow-up) remained relatively stable, ranging from 2 to 4 disease-specific hospitalizations per 100 survivors for each year of follow-up.

Categories that carried the highest relative risk of hospitalization for cancer survivors were diseases of blood and blood-forming organs (RR men, 2.36; women, 1.85), infectious and parasitic diseases (men, 1.81; women, 1.62), and malignant neoplasms (men, 1.80; women, 1.52). Treatments for these cancers tend to be intensive and lengthy, the researchers noted.

The AYA cancers that had the highest risk of subsequent hospitalization among survivors included leukemia (RR, 2.21), brain cancer (RR, 1.93), and Hodgkin lymphoma (RR, 1.87).

The large size of the study made possible the calculation of relative risks for hospitalization according to disease category and AYA cancer type. Survivors of brain cancer had high risk of endocrine, nervous system, and sense organ diseases (RR, 5.5); leukemia survivors had high risks of diseases of blood and blood-forming organs, respiratory system diseases, and infectious and parasitic diseases (RRs, 6.3, 4.9, and 6.3, respectively): Hodgkin lymphoma survivors had high risk of malignant neoplasms (RR, 3.7).

On average, AYA survivors spent 50% more days in hospitals than did the comparison cohort.

A separate study compared neurocognitive performance of long-term survivors of childhood osteosarcoma with community controls and found lower reading scores (P = .01), more variability in sustained attention (P = .002), poorer short-term memory (P = .01), slower motor processing speed (P less than .001), and poorer cognitive fluency (P = .006), reported Michelle N. Edelmann, Ph.D., of St Jude Children’s Research Hospital, Memphis, Tenn., and colleagues (JAMA Onc. 2015 Nov. 19. doi: 10.1001/jamaoncol.2015.4398).

The St. Jude Lifetime Cohort Study evaluated 80 survivors of childhood osteosarcoma at a mean 24.7 years after diagnosis, and compared their neurocognitive function results with 39 community controls.

All osteosarcoma survivors had undergone treatment with high-dose methotrexate, but neurocognitive outcomes were not related to cumulative dose or pharmacokinetic indices of methotrexate exposure.

Chronic health conditions can affect neurocognitive functions in survivors of childhood cancers, and the study found that osteosarcoma survivors with grade 3 or 4 adverse chronic health conditions showed poorer memory and processing speeds.

Survivors of cancer diagnosed at early ages, compared with healthy controls, face higher risk of chronic medical problems, according to two independent studies.

Survivors of adolescent and young adult (AYA) cancer had an overall 38% increased risk of hospitalization, which persisted throughout life, according to a Danish Cancer Registry study. The St. Jude Lifetime Study found that long-term survivors of childhood osteosarcoma had significant neurocognitive deficits in attention, memory, processing speed, executive function, and academics. “The morbidity pattern … underscores the need for further implementation of strict evidence-based sex,-, age-, and cancer-specific follow-up plans for survivors, thereby increasing the likelihood for early detection and ultimately prevention of treatment-induced morbidities,” wrote Kathrine Rugbjerg, Ph.D., of the Danish Cancer Society Research Center, Copenhagen, and colleagues (JAMA Onc. 2015 Nov. 19 doi: 10.1001/jamaoncol.2015.4393).

Analysis of the Danish Cancer Registry from 1943 to 2009 included 33,555 5-year survivors of cancer diagnosed between age 15 and 39 years, and 228,447 matched population comparisons. During the median 14-year follow up, cancer survivors had 53,032 hospital admissions, with 38,423 expected, for a standardized hospitalization rate ratio of 1.38 (95% CI, 1.37-1.39). The absolute excess risk (difference between observed and expected hospitalization rates per 100,000 person years of follow-up) remained relatively stable, ranging from 2 to 4 disease-specific hospitalizations per 100 survivors for each year of follow-up.

Categories that carried the highest relative risk of hospitalization for cancer survivors were diseases of blood and blood-forming organs (RR men, 2.36; women, 1.85), infectious and parasitic diseases (men, 1.81; women, 1.62), and malignant neoplasms (men, 1.80; women, 1.52). Treatments for these cancers tend to be intensive and lengthy, the researchers noted.

The AYA cancers that had the highest risk of subsequent hospitalization among survivors included leukemia (RR, 2.21), brain cancer (RR, 1.93), and Hodgkin lymphoma (RR, 1.87).

The large size of the study made possible the calculation of relative risks for hospitalization according to disease category and AYA cancer type. Survivors of brain cancer had high risk of endocrine, nervous system, and sense organ diseases (RR, 5.5); leukemia survivors had high risks of diseases of blood and blood-forming organs, respiratory system diseases, and infectious and parasitic diseases (RRs, 6.3, 4.9, and 6.3, respectively): Hodgkin lymphoma survivors had high risk of malignant neoplasms (RR, 3.7).

On average, AYA survivors spent 50% more days in hospitals than did the comparison cohort.

A separate study compared neurocognitive performance of long-term survivors of childhood osteosarcoma with community controls and found lower reading scores (P = .01), more variability in sustained attention (P = .002), poorer short-term memory (P = .01), slower motor processing speed (P less than .001), and poorer cognitive fluency (P = .006), reported Michelle N. Edelmann, Ph.D., of St Jude Children’s Research Hospital, Memphis, Tenn., and colleagues (JAMA Onc. 2015 Nov. 19. doi: 10.1001/jamaoncol.2015.4398).

The St. Jude Lifetime Cohort Study evaluated 80 survivors of childhood osteosarcoma at a mean 24.7 years after diagnosis, and compared their neurocognitive function results with 39 community controls.

All osteosarcoma survivors had undergone treatment with high-dose methotrexate, but neurocognitive outcomes were not related to cumulative dose or pharmacokinetic indices of methotrexate exposure.

Chronic health conditions can affect neurocognitive functions in survivors of childhood cancers, and the study found that osteosarcoma survivors with grade 3 or 4 adverse chronic health conditions showed poorer memory and processing speeds.

Preventing nausea and vomiting from the most emetogenic chemotherapy drugs is best accomplished with a three-drug combination, according to newly updated guidelines from the American Society of Clinical Oncology (ASCO).

The combination should include dexamethasone as well as a 5-hydroxytryptamine-3 (5-HT-3) receptor antagonist and a neurokinin-1 (NK-1) receptor antagonist, said Dr. Paul J. Hesketh and guideline coauthors.

An all-oral regimen that is a treatment option in this setting is the combination of netupitant and palonosetron – NEPA (Akynzeo) – together with dexamethasone, said Dr. Hesketh, an oncologist at Lahey Hospital and Medical Center, Burlington, Mass, and his coauthors.

For this interim update, the guideline committee used clinical trial data to “provide expedited guidance regarding a new agent,” pending a full update of ASCO’s antiemetic guideline (J Clin Oncol. 2015 Nov. 2. doi: 10.1200/JCO.2015.64.3635).

The fixed NEPA combination was approved in October of 2014 by the Food and Drug Administration for treatment of chemotherapy-induced nausea and vomiting (CINV). In clinical trials, NEPA plus dexamethasone was effective for both acute and delayed nausea and vomiting for the majority of individuals receiving moderately or highly emetogenic chemotherapy, and was more effective than just palonosetron combined with dexamethasone.

One phase III trial examined use of NEPA compared with palonosetron alone for individuals with cancer receiving the highly emetogenic combination of anthracycline plus cyclophosphamide. Overall, 74% of the NEPA group vs. 67% of the palonosetron group had a complete response, defined as no vomiting and no need for rescue medications (P less than .001). Another phase III trial found that NEPA’s effectiveness was durable over up to six courses of highly emetogenic chemotherapy, and that the drug was safe over time.

The approved fixed-dose combination of 300 mg of netupitant and 0.5 mg of palonosetron is meant to be taken as a one-capsule dose 1 hour before chemotherapy.

The mechanism of action of NK-1 antagonists, which block substance P from binding to neurokinin, can add a more durable anti-emetic effect and prevent or minimize late-onset CINV. A dose-ranging phase II clinical study of NEPA for CINV in treatment-naive patients receiving cisplatin for solid tumors found that the highest dose of netupitant tested, 300 mg, resulted in the least need for rescue medication, though all doses were significantly more effective in achieving complete response than palonosetron alone, or than ondansetron plus aprepitant.

A real-world consideration for patients and oncologists is that NEPA is an oral medication meant to be taken at home. This means that patients will have to fill – and pay for – NEPA prescriptions. “The out-of-pocket cost will vary by insurance plan, and this point should be discussed with patients,” said Dr. Hesketh and his coauthors.

Full cost analyses are underway; NEPA’s steep cost may be offset, at least in part, by the avoidance of any additional rescue medication for chemotherapy-induced nausea and vomiting.

[email protected]

On Twitter @karioakes

Preventing nausea and vomiting from the most emetogenic chemotherapy drugs is best accomplished with a three-drug combination, according to newly updated guidelines from the American Society of Clinical Oncology (ASCO).

The combination should include dexamethasone as well as a 5-hydroxytryptamine-3 (5-HT-3) receptor antagonist and a neurokinin-1 (NK-1) receptor antagonist, said Dr. Paul J. Hesketh and guideline coauthors.

An all-oral regimen that is a treatment option in this setting is the combination of netupitant and palonosetron – NEPA (Akynzeo) – together with dexamethasone, said Dr. Hesketh, an oncologist at Lahey Hospital and Medical Center, Burlington, Mass, and his coauthors.

For this interim update, the guideline committee used clinical trial data to “provide expedited guidance regarding a new agent,” pending a full update of ASCO’s antiemetic guideline (J Clin Oncol. 2015 Nov. 2. doi: 10.1200/JCO.2015.64.3635).

The fixed NEPA combination was approved in October of 2014 by the Food and Drug Administration for treatment of chemotherapy-induced nausea and vomiting (CINV). In clinical trials, NEPA plus dexamethasone was effective for both acute and delayed nausea and vomiting for the majority of individuals receiving moderately or highly emetogenic chemotherapy, and was more effective than just palonosetron combined with dexamethasone.

One phase III trial examined use of NEPA compared with palonosetron alone for individuals with cancer receiving the highly emetogenic combination of anthracycline plus cyclophosphamide. Overall, 74% of the NEPA group vs. 67% of the palonosetron group had a complete response, defined as no vomiting and no need for rescue medications (P less than .001). Another phase III trial found that NEPA’s effectiveness was durable over up to six courses of highly emetogenic chemotherapy, and that the drug was safe over time.

The approved fixed-dose combination of 300 mg of netupitant and 0.5 mg of palonosetron is meant to be taken as a one-capsule dose 1 hour before chemotherapy.

The mechanism of action of NK-1 antagonists, which block substance P from binding to neurokinin, can add a more durable anti-emetic effect and prevent or minimize late-onset CINV. A dose-ranging phase II clinical study of NEPA for CINV in treatment-naive patients receiving cisplatin for solid tumors found that the highest dose of netupitant tested, 300 mg, resulted in the least need for rescue medication, though all doses were significantly more effective in achieving complete response than palonosetron alone, or than ondansetron plus aprepitant.

A real-world consideration for patients and oncologists is that NEPA is an oral medication meant to be taken at home. This means that patients will have to fill – and pay for – NEPA prescriptions. “The out-of-pocket cost will vary by insurance plan, and this point should be discussed with patients,” said Dr. Hesketh and his coauthors.

Full cost analyses are underway; NEPA’s steep cost may be offset, at least in part, by the avoidance of any additional rescue medication for chemotherapy-induced nausea and vomiting.

[email protected]

On Twitter @karioakes

Preventing nausea and vomiting from the most emetogenic chemotherapy drugs is best accomplished with a three-drug combination, according to newly updated guidelines from the American Society of Clinical Oncology (ASCO).

The combination should include dexamethasone as well as a 5-hydroxytryptamine-3 (5-HT-3) receptor antagonist and a neurokinin-1 (NK-1) receptor antagonist, said Dr. Paul J. Hesketh and guideline coauthors.

An all-oral regimen that is a treatment option in this setting is the combination of netupitant and palonosetron – NEPA (Akynzeo) – together with dexamethasone, said Dr. Hesketh, an oncologist at Lahey Hospital and Medical Center, Burlington, Mass, and his coauthors.

For this interim update, the guideline committee used clinical trial data to “provide expedited guidance regarding a new agent,” pending a full update of ASCO’s antiemetic guideline (J Clin Oncol. 2015 Nov. 2. doi: 10.1200/JCO.2015.64.3635).

The fixed NEPA combination was approved in October of 2014 by the Food and Drug Administration for treatment of chemotherapy-induced nausea and vomiting (CINV). In clinical trials, NEPA plus dexamethasone was effective for both acute and delayed nausea and vomiting for the majority of individuals receiving moderately or highly emetogenic chemotherapy, and was more effective than just palonosetron combined with dexamethasone.

One phase III trial examined use of NEPA compared with palonosetron alone for individuals with cancer receiving the highly emetogenic combination of anthracycline plus cyclophosphamide. Overall, 74% of the NEPA group vs. 67% of the palonosetron group had a complete response, defined as no vomiting and no need for rescue medications (P less than .001). Another phase III trial found that NEPA’s effectiveness was durable over up to six courses of highly emetogenic chemotherapy, and that the drug was safe over time.

The approved fixed-dose combination of 300 mg of netupitant and 0.5 mg of palonosetron is meant to be taken as a one-capsule dose 1 hour before chemotherapy.

The mechanism of action of NK-1 antagonists, which block substance P from binding to neurokinin, can add a more durable anti-emetic effect and prevent or minimize late-onset CINV. A dose-ranging phase II clinical study of NEPA for CINV in treatment-naive patients receiving cisplatin for solid tumors found that the highest dose of netupitant tested, 300 mg, resulted in the least need for rescue medication, though all doses were significantly more effective in achieving complete response than palonosetron alone, or than ondansetron plus aprepitant.

A real-world consideration for patients and oncologists is that NEPA is an oral medication meant to be taken at home. This means that patients will have to fill – and pay for – NEPA prescriptions. “The out-of-pocket cost will vary by insurance plan, and this point should be discussed with patients,” said Dr. Hesketh and his coauthors.

Full cost analyses are underway; NEPA’s steep cost may be offset, at least in part, by the avoidance of any additional rescue medication for chemotherapy-induced nausea and vomiting.

[email protected]

On Twitter @karioakes

BOSTON– Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.

“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.

There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”

Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.

The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.

Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.

He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.

Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.

Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.

As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.

“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.

PD-1 inhibitors

Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.

In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.

The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.

Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.

Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.

In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.

For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.

In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.

A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.

BOSTON– Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.

“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.

There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”

Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.

The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.

Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.

He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.

Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.

Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.

As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.

“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.

PD-1 inhibitors

Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.

In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.

The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.

Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.

Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.

In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.

For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.

In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.

A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.

BOSTON– Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.

“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.

There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”

Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.

The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.

Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.

He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.

Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.

Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.

As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.

“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.

PD-1 inhibitors

Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.

In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.

The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.

Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.

Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.

In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.

For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.

In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.

A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.