Faculty Bibliography

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%-16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%-25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

Background gpNMB is an internalizable transmembrane glycoprotein expressed in multiple tumor types. The ADC GV delivers the potent cytotoxin MMAE to gpNMB+ cells and showed promising activity as monotherapy in advanced melanoma refractory to checkpoint inhibitors (CPI). Preclinical results showed synergistic antitumor activity between ADC with CPI [1, 2], via dendritic cell (DC) activation; ADC-MMAE augmented the immune response induced by V, an agonist monoclonal antibody against the T cell costimulatory molecule CD27. This Phase 2 study was conducted to evaluate the activity and safety of the GV/ V combination in advanced melanoma. Methods Patients with advanced melanoma, progressive after <=1 chemotherapy, >=1 checkpoint inhibitor (CPI), and if BRAF mutation >=1 BRAF or MEK + BRAF inhibitor, were treated with GV (1.9 mg/kg q3w until progression/ intolerance) in combination with V (3.0 mg/kg) on day 1 of weeks 1, 3, 9, 15, 21, and 27. Retrospective analysis on pre-study tumors and skin biopsies include gpNMB expression and infiltrating lymphocytes by immunohistochemistry plus gene expression profiling. Primary objective is to evaluate objective response rate (ORR) (RECIST 1.1). Results Thirty-four patients enrolled: median age of 61 years; 59% male; 18% BRAFV600 mutated; 59% >=3 lines prior therapy; 76% prior anti-CTLA-4; 100% prior anti-PD-1/PD-L1 inhibitor; 97% Stage IV; 71% M1c. Of 30 response evaluable patients, emerging tumor response data shows 2 confirmed partial responses (PR) (ORR = 7%, CI: 0.8, 22.1), and 1 single time point PR before patient withdrew consent. 48% patients had tumor shrinkage. Median PFS = 2.6 months and median OS = 4.4 months; 3 patients remain on treatment and 18 patients in survival follow up. Most common treatment related toxicities include alopecia, rash, fatigue, neuropathy, nausea, and vomiting. Tumor cells in 84% of patients with samples (n=25) tested to date are 100% gpNMB+. Conclusions The GV/V combination was well tolerated without evidence of additive toxicity. There was no apparent enhanced clinical benefit of GV/V over GV alone in this patient population, perhaps because immune checkpoint molecules remained unblocked and/or of a dearth of antigen presenting cells in tumors. Correlative biomarker analyses are ongoing and will be presented. For further insights into the synergy of ADC and immunotherapy, a cohort evaluating GV with anti-PD-1 in CPI-refractory melanoma is enrolling and a cohort investigating GV with the DC growth factor FLT3L (CDX-301) is planned

Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice.

A 60-year-old woman with history of vaginal malignant melanoma and inguinal nodal metastases underwent F-FDG PET/CT for restaging following ipilimumab (Yervoy) immunotherapy, a Food and Drug Administration-approved human monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen 4. PET/CT demonstrated mildly FDG-avid multifocal enlarging bilateral lung opacities. Within each lung lesion, there was circumferential uptake localizing to a high-attenuation rim with a photopenic ground-glass center on CT, consistent with "reversed halo sign." Patient was asymptomatic at the time of imaging. Ipilimumab was discontinued, and 3-month follow-up PET/CT revealed spontaneous complete resolution of the lung lesions, supporting the diagnosis of ipilimumab-induced organizing pneumonia.

Background: There are no predictive biomarkers of ipilimumab (IPI) toxicity. Of metastatic melanoma (MM) patients (pts) receiving IPI (3mg/kg), 35% require systemic therapies to treat immune-related adverse events (irAEs) and 20% must terminate treatment (Horvat et al., JCO 2015). Here we tested the hypothesis that a pre-existing autoantibody (autoAb) profile is predictive of IPI irAEs. Methods: We measured autoAb levels in pre- and post-treatment sera from mm pts who received IPI (3mg/kg) monotherapy on a proteome microarray containing ~20,000 unique full-length human proteins (HuProt array, CDI Laboratories). Clinical data were prospectively collected with protocol-driven follow-up. IrAEs were categorized by CTCAE guidelines as none (grade 0), mild (grade 1-2), or severe (grade 3-4). AutoAb levels were standardized using median quantile normalization and considered positive hits if > 2-SD above the peak array signal and differed by >=2 fold with p < 0.05 between toxicity groups (Non-parametric Analysis/Wilcox test). Results: Seventy-eight sera from 37 mm pts were analyzed. Antibodies against CTLA-4 were significantly elevated post IPI treatment (p < 0.0001), validating the assay. The pre-treatment levels of 190 IgG autoAbs were significantly diferent in pts who experienced irAEs (n = 28) compared to those with no irAEs (n = 9). Comparison of severe irAE (n = 9) and no irAE (n = 9) groups revealed 129 IgG autoAbs that significantly differed in pre-treatment sera. Localization and pathway analysis (UniProt, KEGG, Reactome) showed 81/190 (43%) of the autoAbs targeted nuclear and mitochondrial antigens and were enriched in metabolic pathways (p = 0.015). AutoAbs associated with irAEs did not correlate with treatment response. Conclusions: AutoAbs to antigens enriched in metabolic pathways prior to treatment may predict IPI-induced toxicity in MM. The subcellular localization of targeted antigens could explain the autoimmune toxicities associated with IPI. Studies in larger cohorts and in pts receiving other checkpoint inhibitors and/or combination therapies are essential to determine the validity of the data. If validated, our results would support the discovery of the first toxicity predictor in cancer immunotherapy