Rate Of Immune-related Adverse Events Research Articles

Updates on Immunotherapy for the Treatment of Skin Cancer

Skin cancer is the most common malignancy in the USA, arising when mutated cells escape the host’s natural immune surveillance. Immunotherapy helps boost the host’s immune system, augmenting the antitumor response. Given the ability of the immune system to evolve with a tumor’s evasive maneuvers, it is not surprising that immunotherapy has demonstrated durable clinical benefit in patients with cancer, including certain types of skin cancers. Significant progress has been made with the recent development of immunotherapy for skin cancers. Here, we review the literature on immunotherapies used in the treatment of skin cancer, including immune checkpoint inhibitors, interferon, interleukin-2, BCG, talimogene laherparepvec, and imiquimod. Immune checkpoint inhibitors, which block CTLA-4 and PD-1 signaling pathways, have improved overall survival in patients with metastatic melanoma. The combination of nivolumab and ipilimumab has yielded higher overall survival rates than either agent alone, but at the price of higher rates of immune-related adverse events. In 2017, a PD-L1 inhibitor, avelumab, became the first FDA-approved treatment for patients with metastatic Merkel cell carcinoma. Since 2011, new immunotherapy treatments, including CTLA-4, PD-1, and PD-L1 inhibitors, have become the mainstay of treatment for many advanced skin cancers, supplanting chemotherapy for first-line treatment of metastatic melanoma and Merkel cell carcinoma.

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma

Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.

Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma

To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs). We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab).Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI.Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs. A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9months, 14.5months, and 24.7months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64). Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.

PD-L1 expression profile and immunotherapy (IO) experience in African American (AA) and Hispanic (H) lung cancer (LC) patients: Addressing disparities at a minority-based academic cancer center.

e18073 Background: Immune checkpoint inhibitors have changed the treatment paradigm for metastatic LC. Minority populations are under-represented in large IO clinical trials. Among 989 pts with newly diagnosed LC at Montefiore Medical Center - a community-based academic center from 2014-2015, 330 (33%) were AA and 195 (20%) were H. In line with practice-changing clinical studies, PD-L1 expression testing and IO have been incorporated into LC treatment. Methods: Pts receiving IO and/or had PD-L1 testing between 1/1/14-12/31/16 were identified from records obtained from pathology, pharmacy, oncology clinics and Clinical Looking Glass. Retrospective chart review was conducted. PD-L1 testing was performed using 22C3pharmDx IHC. Results: We identified 111 pts with LC who received IO and/or had PD-L1 testing, with a median age of 66. 55% were female. Based on race, 52 (47%) were AA, 24 (22%) were White, 26 (24%) were Other, and 9 (8%) were race unknown. Based on ethnicity, 30 (27%) were H, 73 (66%) were non-H and 8 (7%) were ethnicity unknown. 82% were former/current smokers. Adenocarcinoma was the dominant histology (60%). The majority were EGFR WT (91%) and ALK neg (98%). PD-L1 testing was performed in 67 (60%), including 32 (29%) AAs and 20 (18%) Hs. Archival tissue was used in 63%. PD-L1 TPS > 50% was found in 30%, 1-49% in 24%, < 1% in 37%. 62 pts received IO, including 26 (42%) AAs and 18 (29%) Hs. Nivolumab was the most commonly used agent (77%). In AAs, 8 (31%) received IO as 1st line, 13 (50%) as 2nd line, 5 (19%) as 3rd line and above. In Hs, 1 (5%) received IO as 1st line, 10 (56%) as 2nd line, 7 (39%) as 3rd line and above. Immune-related adverse events (IRAEs) were reported in 31% of AAs and 39% of Hs. Data analysis on survival is ongoing. Conclusions: Unlike the low numbers of minority pts in large clinical trials, we found no significant difference in PD-L1 testing and IO across racial and ethnic groups treated at our center. Compared to large clinical trials, we observed lower rates of IRAEs in our cohort. Our current and ongoing observations in these populations may have future implications in narrowing health disparities based on race/ethnicity.

Effects of commonly used chronic medications on the outcomes of ipilimumab therapy in patients with metastatic melanoma.

e21038Background: Ipilimumab can induce long-term survival in up to 20% of patients with metastatic melanoma, however response comes with high rates of immune-related adverse events (irAEs). Concur...

Dose effect of ipilimumab in patients with advanced melanoma: Results from a phase II, randomized, dose-ranging study

9025 Background: Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Data from a phase II study showed that patients with previously treated advanced melanoma had proportionately more complete/partial responses (CR/PR) and stable disease (SD) with ipilimumab induction 10 mg/kg every 3 weeks (Q3W) X 4 compared with lower doses using the same schedule. Methods: In this randomized, double-blind, multicenter, phase II trial, patients with unresectable stage III/IV melanoma who had progressive disease (PD) on or were intolerant to prior therapies received ipilimumab induction dosing at 0.3, 3, or 10 mg/kg Q3W X 4. Eligible patients received maintenance therapy Q12W starting at Week 24 at their assigned blinded dose. Patients with PD could cross over to open-label ipilimumab 10 mg/kg induction plus maintenance in another study. The primary endpoint was the best overall response rate (BORR [CR or PR]). Efficacy was measured with modified World Health Organization (mWHO) criteria. Per protocol, tumor evaluation after PD by mWHO (ie, an overall > 25% increase in measurable tumor burden) before treatment with non-ipilimumab neoplastic therapy was permitted. Results: There were 217 patients treated. There was a statistically significant trend indicating an increase in BORR with increasing dose (p = 0.0015). The difference in BORR between 10 and 0.3 mg/kg was 11.2% [95% CI, 3.9 - 18.5]. Rates of immune-related adverse events (irAEs) increased with increasing dose. Conclusions: These data favor 10 mg/kg as the optimal dose. 0.3 mg/kg appears to be clinically ineffective. Follow-up for patients is ongoing. Ipilimumab dose (mg/kg) 10 (n = 72) 3 (n = 72) 0.3 (n = 73) BORR - % [95% CI] CR - n 11.1 [4.9 - 20.7] 2 4.2 [0.9 - 11.7] 0 0 [0.0 - 4.9] 0 Disease control rate (DCR = PR + CR + SD) - % [95% CI] 29.2 [19.0 - 41.1] 26.4 [16.7 - 38.1] 13.7 [6.8 - 23.8] Any irAE - % 70.4 64.8 26.4 Grade 3/4 irAE - % Any 25.4 7.0 Gastrointestinal 15.5 2.8 0 Hepatobiliary 2.8 0 0 Endocrine 1.4 2.8 0 Skin 4.2 1.4 0 Bowel perforations - % 0 0 0 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb