Faculty Bibliography

Immune checkpoint inhibitors, particularly anti-PD-1-based immune checkpoint inhibitors, have dramatically improved outcomes for patients with advanced melanoma and are currently deemed a standard of care. Ipilimumab/nivolumab is the first combination of immune checkpoint inhibitors to improve progression-free survival and overall survival in the first-line setting, with durable responses and the longest median overall survival, 72.1 months, of any drug therapy approved for advanced melanoma. However, its use is limited by the high rate of severe (grade 3-4) treatment-related adverse events. More recently, the novel immune checkpoint inhibitor combination of nivolumab/relatlimab (anti-PD-1/anti-LAG3) showed improved progression-free survival compared with nivolumab alone in the first-line setting and was well tolerated; thus, it is likely this combination will be added to the armamentarium as a first-line treatment for advanced melanoma. These changes in the treatment landscape have several treatment implications for decision-making. The choice of first-line systemic drug therapy, and the decision between immune checkpoint inhibitor monotherapy or combination therapy, requires a comprehensive assessment of disease-related factors and patient characteristics. Despite this striking progress, many patients' disease still progresses. Several new agents and therapeutic approaches are under investigation in clinical trials. Intralesional treatments hold promise for accessible metastases, although their broad application in the clinic will be limited. Prognostic and predictive biomarkers, as well as strategies to reduce treatment-related toxicities and overcome resistance, are required and are now the focus of clinical and translational research.

PURPOSE/OBJECTIVE:Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg bid and trametenib 2 mg qd (D+T). PATIENTS AND METHODS/METHODS:melanoma patients. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%. RESULTS:34 were evaluable for one-year PFS rate. Patient demographics: elevated LDH: 47%; Stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose limiting toxicity. HCQ 600 mg po bid with D+T was the RP2D. The one-year PFS rate was 48.2% (95% CI = 31.0-65.5%), median PFS was 11.2 months (95% CI = 5.4-16.9 months), and response rate (RR) was 85% (95% CI=64-95%). The complete response rate was 41% and median overall survival (OS) was 26.5 months. In patient with elevated LDH (n=16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively. CONCLUSION/CONCLUSIONS:melanoma patients with elevated LDH and previous immunotherapy is being conducted.

PURPOSE/OBJECTIVE:Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS:) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS:Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION/CONCLUSIONS:V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

INTRODUCTION/BACKGROUND:Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker. METHODS:Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded. RESULTS:MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy. CONCLUSION/CONCLUSIONS:This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.

PURPOSE/UNASSIGNED:The recruitment of underserved patients into therapeutic oncology trials is imperative. The National Institutes of Health mandates the inclusion of minorities in clinical research, although their participation remains under-represented. Institutions have used data mining to match patients to clinical trials. In a public health care system, such expensive tools are unavailable. METHODS/UNASSIGNED:The NYU Clinical Trials Office implemented a quality improvement program at Bellevue Hospital Cancer Center to increase therapeutic trial enrollment. Patients are screened through the electronic medical record, tumor board conferences, and the cancer registry. Our analysis evaluated two variables: number of patients identified and those enrolled into clinical trials. RESULTS/UNASSIGNED:Two years before the program, there were 31 patients enrolled. For a period of 24 months (July 2017 to July 2019), we identified 255 patients, of whom 143 (56.1%) were enrolled. Of those enrolled, 121 (84.6%) received treatment, and 22 (15%) were screen failures. Fifty-five (38.5%) were referred to NYU Perlmutter Cancer Center for therapy. Of the total enrollees, 64% were female, 56% were non-White, and overall median age was 55 years (range: 33-88 years). Our participants spoke 16 different languages, and 57% were non-English-speaking. We enrolled patients into eight different disease categories, with 38% recruited to breast cancer trials. Eighty-three percent of our patients reside in low-income areas, with 62% in both low-income and Health Professional Shortage Areas. CONCLUSION/UNASSIGNED:Prescreening at Bellevue has led to a 4.6-fold increase in patient enrollment to clinical trials. Future research into using prescreening programs at public institutions may improve access to clinical trials for underserved populations.

BACKGROUND:Immune-related adverse events (irAEs) are common, clinically significant autoinflammatory toxicities observed with immune checkpoint inhibitors (ICI). Preexisting immune-mediated inflammatory disease (pre-IMID) is considered a relative contraindication to ICI due to the risk of inciting flares. Improved understanding of the risks and benefits of treating pre-IMID patients with ICI is needed. METHODS:We studied melanoma patients treated with ICI and enrolled in a prospective clinicopathological database. We compiled a list of 23 immune-mediated inflammatory diseases and evaluated their presence prior to ICI. We tested the associations between pre-IMID and progression-free survival (PFS), overall survival (OS), and irAEs. RESULTS:In total, 483 melanoma patients were included in the study; 74 had pre-IMID and 409 did not. In patients receiving ICI as a standard of care (SoC), pre-IMID was significantly associated with irAEs (p = 0.04) as well as improved PFS (p = 0.024) and OS (p = 0.007). There was no significant association between pre-IMID and irAEs (p = 0.54), PFS (p = 0.197), or OS (p = 0.746) in patients treated through a clinical trial. Pre-IMID was significantly associated with improved OS in females (p = 0.012), but not in males (p = 0.35). CONCLUSIONS:The dichotomy of the impact of pre-IMID on survival and irAEs in SoC versus clinical trial patients may reflect the inherit selection bias in patients accrued in clinical trials. Future mechanistic work is required to better understand the differences in outcomes between female and male pre-IMID patients. Our data challenge the notion that clinicians should avoid ICI in pre-IMID patients, although close monitoring and prospective clinical trials evaluating ICI in this population are warranted.

Purpose/objective(s) Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neoplasm traditionally managed with surgical resection followed by radiotherapy (RT). With the recent approval of checkpoint inhibitors, chemotherapy is less commonly utilized. We analyzed the impact of RT and chemotherapy on overall survival (OS) in patients with MCC using Surveillance, Epidemiology, and End Results (SEER), a population-level database. Materials and methods We performed retrospective analyses on SEER 18 Custom Data registries for MCC (ICD-0-3 8247). Data from 1980 to 2016 was queried for analysis, and an initial list of 9,792 patients was populated (ICD: C00, C07.9, C44, C80.9). Selection for cases with chemotherapy and RT status, single primary tumor, primary tumor location and surgery treatment type yielded 5,002 cases for analysis. Baseline characteristics were compared with Chi-square or Mann-Whitney U test. Univariate and multivariable analysis using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias. Results Median follow-up time was 178 months (68 to 217 months). Independent prognostic factors positively correlated with increased OS, for both unadjusted Multivariate analysis and IPTW adjusted MVA were age, male sex, year of diagnosis, stage, RT status, and chemotherapy status. On adjusted MVA, use of chemotherapy was associated with worse OS (hazard ratio: 1.22 [95% CI 1.1-1.35], p<0.001), whereas RT was associated with improved OS (HR:0.9 [95% CI, 0.83-0.97], p=0.008). Conclusions The current study demonstrates that RT is associated with improved survival for patients with MCC. Chemotherapy was associated with worse OS. This supports the recent clinical shift towards immune checkpoints inhibitors as standard of care in the metastatic setting, and promising trials in the adjuvant and advanced settings.

Metastatic melanoma is often accompanied by the development of brain metastases, at presentation or during the course of therapy. Local therapies such as surgery and radiation have been considered standard treatments for intracranial disease. However, the emergence of systemic therapies has been changing the treatment paradigm for the management of brain metastases. In patients with BRAF-mutated melanoma, combined BRAF and MEK inhibition has been found to elicit significant clinical responses. Patients who develop resistance to MAP kinase (MAPK) targeted therapy can achieve significant responses upon rechallenge. In this case, a 68-year-old woman with metastatic melanoma who had received multiple treatment courses including combination immunotherapy and combination MAPK-targeted therapy presented with a brainstem metastasis and demonstrated a complete response upon initiation of encorafenib and binimetinib, thereby obviating the need for stereotactic radiosurgery.