Safety of sequential immune checkpoint inhibitors after prior immune therapy.

BACKGROUND: The use of immune checkpoint inhibitors (ICI) has transformed cancer treatment. Subsequent ICI use has become increasingly common following disease progression. We aim to evaluate the safety and tolerability of the sequential ICI treatment modality. METHODS: Retrospective review of confirmed carcinoma from January 2014 to December 2018. Patients were categorized into "initial ICI arm" and "sequential ICI arm" defined as patients receiving single, dual or chemo-immunotherapy ICI following an initial ICI regimen. Primary outcome was the development of a new or recurrent immune related adverse event (irAE) during sequential therapy. Secondary outcomes were the number of cycles prior to the development of irAE and grade of irAE. RESULTS: A total of 483 patients received ICI during the timeframe. Of those, 22 patients received sequential ICI. The diagnoses included ten lung cancer, seven melanoma, four renal cell carcinoma and one bladder cancer. 16 patients received single agent ICI following the initial ICI, three patients received dual ICI following the initial ICI, one patient received chemotherapy-immunotherapy following initial ICI, and two patients received chemo-immunotherapy after dual ICI. Four patients developed new irAE and one patient developed the same irAE on sequential treatment. A higher proportion of patients experienced grade 3 irAE in the sequential arm compared to the initial ICI arm (p = 0.03). No statistical difference was found between the development of irAE and the number of cycles prior to development of irAE in either treatment groups (p = 0.5). CONCLUSION: Our data shows overall safety of sequencing ICI when close monitoring was employed.

Immune checkpoint inhibitors: immune-related adverse events, healthcare utilization, and costs among commercial and Medicare Advantage patients.

BACKGROUND: Immune checkpoint inhibitors (ICI) are increasingly used across multiple cancer types and stages and little is known about real-world outcomes. This study sought to determine healthcare utilization, costs, immune-related adverse events (irAEs), and all-cause mortality of single-agent versus combination ICI in the USA. MATERIALS AND METHODS: This is a retrospective study conducted with 2016-2018 data from the HealthCore Integrated Research Database, consisting of commercial and Medicare-insured adult patients with a cancer diagnosis using ICI in the USA. Outcomes were healthcare utilization, costs, and irAEs (FDA-recognized and others) up to 1-year post-index between patients using ICI monotherapy (mono, PD-1/PD-L1 inhibitor) and combination therapy (combo, PD-1/PD-L1 with CTLA-4 inhibitors). RESULTS: In total, 9084 patients received monotherapy and 904 patients received combo therapy. Mean age 65 years for mono and 58 years for combo. Overall, the combo arm had higher rates of FDA-recognized irAEs (67.4% vs. 45.9%), especially endocrinopathies (27.7% vs 14.7%) and dermatitis (25.9% vs. 12.4%). All-cause mortality over 1-year follow-up was similar, 30.7% in mono vs 30.8% in combo arms. The combo group had higher rates of all-cause inpatient hospitalizations (55.4% mono vs 65.6% combo) and emergency department (ED) visits (33.7% mono vs 41.4% combo). IrAE-related hospitalizations were higher in combo (55.2% vs 42.1%). IrAE-related ED visits were 15.7% mono vs 22.7% combo. This increased toxicity and health care utilization was reflected in significant differences in healthcare costs. Stark differences were seen in all-cause medical costs as well as costs related to inpatient and ED utilization and costs attributed to irAEs. CONCLUSIONS: Higher rates of irAEs, healthcare utilization, and costs occur with combination immunotherapy. As further indications are approved for combination ICI, our study highlights the real-world tradeoffs involved with combination therapy regarding burdens of toxicity and increased healthcare utilization.

Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. SIGNIFICANCE: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587.

Cardiotoxicity of Immune Checkpoint Inhibitors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) have improved the survival of several cancers. However, they may cause a wide range of immune-related adverse events (irAEs). While most irAEs are manageable with temporary cessation of ICI and immunosuppression, cardiovascular toxicity can be associated with high rates of morbidity and mortality. As ICIs evolve to include high-risk patients with preexisting cardiovascular risk factors and disease, the risk and relevance of ICI-associated cardiotoxicity may be even higher. RECENT FINDINGS: Several cardiovascular toxicities such as myocarditis, stress cardiomyopathy, and pericardial disease have been reported in association with ICIs. Recent findings also suggest an increased risk of atherosclerosis with ICI use. ICI-associated myocarditis usually occurs early after initiation and can be fulminant. A high index of suspicion is required for timely diagnosis. Prompt treatment with high-dose corticosteroids is shown to improve outcomes. Although the overall incidence is rare, ICI cardiotoxicity, particularly myocarditis, is associated with significant morbidity and mortality, making it a major therapy-limiting adverse event. Early recognition and prompt treatment with the cessation of ICI therapy and initiation of high-dose corticosteroids are crucial to improve outcomes. Cardio-oncologists will need to play an important role not just in the management of acute cardiotoxicity but also to reduce the risk of long-term sequelae.

Outcomes of COVID-19 in Patients With a History of Cancer and Comorbid Cardiovascular Disease.

BACKGROUND: Cancer and cardiovascular disease (CVD) are independently associated with adverse outcomes in patients with COVID-19. However, outcomes in patients with COVID-19 with both cancer and comorbid CVD are unknown. METHODS: This retrospective study included 2,476 patients who tested positive for SARS-CoV-2 at 4 Massachusetts hospitals between March 11 and May 21, 2020. Patients were stratified by a history of either cancer (n=195) or CVD (n=414) and subsequently by the presence of both cancer and CVD (n=82). We compared outcomes between patients with and without cancer and patients with both cancer and CVD compared with patients with either condition alone. The primary endpoint was COVID-19-associated severe disease, defined as a composite of the need for mechanical ventilation, shock, or death. Secondary endpoints included death, shock, need for mechanical ventilation, need for supplemental oxygen, arrhythmia, venous thromboembolism, encephalopathy, abnormal troponin level, and length of stay. RESULTS: Multivariable analysis identified cancer as an independent predictor of COVID-19-associated severe disease among all infected patients. Patients with cancer were more likely to develop COVID-19-associated severe disease than were those without cancer (hazard ratio [HR], 2.02; 95% CI, 1.53-2.68; P<.001). Furthermore, patients with both cancer and CVD had a higher likelihood of COVID-19-associated severe disease compared with those with either cancer (HR, 1.86; 95% CI, 1.11-3.10; P=.02) or CVD (HR, 1.79; 95% CI, 1.21-2.66; P=.004) alone. Patients died more frequently if they had both cancer and CVD compared with either cancer (35% vs 17%; P=.004) or CVD (35% vs 21%; P=.009) alone. Arrhythmias and encephalopathy were also more frequent in patients with both cancer and CVD compared with those with cancer alone. CONCLUSIONS: Patients with a history of both cancer and CVD are at significantly higher risk of experiencing COVID-19-associated adverse outcomes. Aggressive public health measures are needed to mitigate the risks of COVID-19 infection in this vulnerable patient population.

Diagnosis and management of tumor lysis syndrome.

Tumor lysis syndrome (TLS) is an oncological emergency characterized by a classic tetrad of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Risk assessment and prophylactic therapy is critical in preventing this oncological emergency. Treatment of established TLS involves aggressive hydration, electrolyte management, and the use of hypouricemic agents.

Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: Case report and review of literature.

We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of pre-existing anti-Hu antibody associated sensory neuronopathy after treatment with programmed cell death-1 (PD-1) inhibitor, nivolumab. We review the literature and identify 6 reported cases to understand the clinical outcomes of patients with anti-Hu paraneoplastic neurologic syndrome (PNS) treated with anti-PD-1 treatment. The PNS clinical spectrum comprised of encephalitis, a combination of sensory neuronopathy and anti-NMDAR encephalitis, isolated sensory neuronopathy, and encephalomyelitis. Immune checkpoint inhibitor have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS.

Incidence and management of ZIv-aflibercept related toxicities in colorectal cancer.

Ziv-afilbercept (Zaltrap, Ziv) is a humanized fusion protein constructed by joining the vascular endothelial growth factor (VEGF) binding portions of human VEGF receptors 1 and 2 to the Fc portion of human immunoglobulin IgG1. Recently, a randomized, open-label, phase III study compared 5-fluorouracil, leucovorin, irinotecan (FOLFIRI)/Ziv with FOLFIRI/placebo in patients who had been previously treated with oxaliplatin based chemotherapy for metastatic colon cancer (mCRC). Patients who had received prior bevacizumab therapy were also eligible. This study showed that the addition of Ziv improved overall survival with median survival time of 13.5 mo vs 12.06 mo in ziv vs placebo arm. Ziv also improved progression free survival from 4.67 mo to 6.9 mo with a response rate of 19.8% in the Ziv/FOLFIRI group vs 11.1% in FOLFIRI alone group. This led to the approval of Ziv in combination with FOLFIRI in metastatic colon cancer patients treated with prior oxaliplatin regimens. The most common side effects were diarrhea, stomatitis, fatigue, hypertension, weight loss, loss of appetite, abdominal pain, and headache. As the use of Ziv has become more widespread in oncology practices, familiarity with the toxicity profile of the drug and the use of practice guidelines for their treatment has become increasing important. This review will address the toxicities noted in trials using Ziv for the treatment of mCRC, and will provide recommendations for toxicity management.

Gastric cancer and trastuzumab: first biologic therapy in gastric cancer.

Gastric cancer remains difficult to cure and has a poor overall prognosis. Chemotherapy and multimodality therapy has shown some benefit in the treatment of gastric cancer. Current therapies for gastric cancer have their limitations; thus, we are in need of newer treatment options including targeted therapies. Here, we review the biologic therapy with trastuzumab in human epidermal growth factor receptor 2 (HER2)+ gastric cancer.

FOLFIRINOX for locally advanced and metastatic pancreatic cancer: single institution retrospective review of efficacy and toxicity.

Although FOLFIRINOX significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine (Conroy et al. N Engl J Med 364:1817-1825, 2011), toxicities have tempered enthusiasm for its use in full doses. To assess the impact of dose attenuations on toxicity and efficacy, we reviewed our institution's experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC) and MPC. We performed a retrospective review of dose, toxicity, and efficacy of FOLFIRINOX in all patients with LAPC and MPC treated between June 2010 and July 2011 at Yale. Toxicities in all patients and response rate (RR) and survival in previously untreated MPC were compared to data reported by Conroy. Overall survival (OS) and progression-free survival were estimated by Kaplan-Meier method. Thirty-five patients were treated (16 LAPC; 19 MPC). Twenty-nine patients received dose attenuations with the first cycle. Median relative doses of irinotecan and bolus fluorouracil were less than those reported by Conroy (64 vs. 81 % and 66 vs. 82 %, respectively). RR was 50 % in LAPC and 47 % in MPC, and the latter did not differ significantly from the RR reported by Conroy (p = 0.19). OS at 6 and 12 months in MPC was comparable to OS reported by Conroy. Grade 3/4 toxicities were less than reported by Conroy, including fatigue (p = 0.009) and neutropenia (p < 0.0001). Nine patients experienced transient dysarthria during irinotecan administration. Our findings validate the efficacy and tolerability of FOLFIRINOX in LAPC and MPC and suggest that dose attenuations of irinotecan and bolus fluorouracil improve tolerability without compromising efficacy.

Highlights on the first line treatment of metastatic pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer deaths in men and women. The estimated deaths from pancreatic cancer in 2012 in the United States are 37,390, and the five-year survival for all patients with pancreatic adenocarcinoma is less than 5%. Majority of patients present with incurable metastatic pancreatic cancer. The 2012 American Society of Oncology (ASCO) Annual Meeting offered new insights into metastatic pancreatic cancer and we discuss Abstracts #4018, #4019, #4022, #4042, #4043, #4048, #4050 and comment on them in this paper.

Primary peritoneal carcinoma in complete remission: a case report.

Primary peritoneal carcinoma (PPCa) is a relatively uncommonly diagnosed tumor. It has a similar presentation to ovarian cancer. PPCa has a poor prognosis with survival ranging from 12-18 months. PPCa spreads mainly transperitoneally, but lymphatic and hematological metastases have also been reported. It is a diagnosis of exclusion made after pathological report. Here, a case of a 71-year-old female who presented with early satiety, fatigue, weight loss and left cervical lymphadenopathy and was diagnosed with metastatic PPCa, is reported. The patient was treated with chemotherapy and achieved a complete remission. The management of this rare tumor is discussed herein.

Ayurvedic herbal medicine and lead poisoning.

Although the majority of published cases of lead poisoning come from occupational exposures, some traditional remedies may also contain toxic amounts of lead. Ayurveda is a system of traditional medicine that is native to India and is used in many parts of world as an alternative to standard treatment regimens. Here, we report the case of a 58-year-old woman who presented with abdominal pain, anemia, liver function abnormalities, and an elevated blood lead level. The patient was found to have been taking the Ayurvedic medicine Jambrulin prior to presentation. Chemical analysis of the medication showed high levels of lead. Following treatment with an oral chelating agent, the patient's symptoms resolved and laboratory abnormalities normalized. This case highlights the need for increased awareness that some Ayurvedic medicines may contain potentially harmful levels of heavy metals and people who use them are at risk of developing associated toxicities.

Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery.

PURPOSE: Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. PATIENTS AND METHODS: This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. CONCLUSION: Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.