Faculty Bibliography

PURPOSE/OBJECTIVE:Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment. PATIENTS AND METHODS/METHODS:Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS:= 0.0287) with PFS. CONCLUSIONS:With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.

Agonists of the co-stimulatory molecule OX40 (CD134) are in clinical assessment alone and in combination with other immunotherapies. Recent pre-clinical studies have suggested that concurrent administration of OX40 agonists with anti-PD1 therapy is detrimental to the efficacy of such combinations and maximal efficacy may require sequential administration of the OX40 agonist followed by anti-PD1 therapy. In this report, we detail two patients with advanced ovarian carcinoma were treated with INCAGN01949, an agonistic OX40 Ab, as part of a clinical trial until disease progression. Both patients then received the combination of ipilimumab and nivolumab and experienced unusually deep and durable responses. These cases support the hypothesis raised in pre-clinical studies and highlight the potential relevance of sequence in combinational immunotherapy.

OBJECTIVES/OBJECTIVE:To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. METHODS:In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). RESULTS:Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens (N = 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA. CONCLUSIONS:Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combined with results from other anti-PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology.

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempeg-a-ldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8⁺ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

Background: Checkpoint Inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (mNSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for pts with poor prognostic features or negative predictive clinical factors for CPI benefit, including PD-L1 negative (-) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 betagamma receptor. BEMPEG + CPI has demonstrated promising efficacy and can convert PD-L1(-) tumors to PDL1( +) in pts with multiple solid tumors (Diab A, ASCO 2018; Siefker-Radtke A, ASCO-GU 2019). Given the early efficacy data and favorable safety profile of BEMPEG +nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO). Trial Design: This phase I/II multinational trial evaluates BEMPEG +PEMBRO in pts with locally advanced or metastatic solid tumors. There are two key components to the study: 1) Dose optimization: which includes 3+3 and step-up dosing (U.S. enrollment only) and will include ~40 pts with first-and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma, regardless of PD-L1 status; 2) Dose expansion: which includes ~58 first-line mNSCLC pts (enrolling globally). The expansion cohort will evaluate the preliminary anti-tumor activity of BEMPEG, in combination with PEMBRO, in first-line mNSCLC, regardless of PD-L1 status (<1%, 1-49%, and>50%). The primary objectives in the dose optimization cohorts are safety and tolerability of the combination and to determine the maximum tolerated dose, recommended phase II dose and optimal dosing schedule of BEMPEG in combination with PEMBRO in locally advanced or metastatic solid tumors. The primary objective in the dose expansion cohort is objective response rate by RECIST 1.1. Enrollment is ongoing

Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater antitumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design.
Method(s): This is an interim report of a phase I dose escalation study of mRNA-4157 given as monotherapy in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients received up to 9 cycles (Q3W) of mRNA- 4157 by IM injection (0.04 - 1 mg). In combination arm, pembrolizumab (200 mg) was administered for two cycles prior to combination with mRNA-4157 for up to 9 cycles and may continue on pembrolizumab monotherapy for up to 2 years.
Result(s): As of 10- May-2019, 33 patients received mRNA-4157 alone or in combination. No DLTs or related SAEs or AEs >= grade 3 were reported. Of the 13 patients treated with monotherapy (3 melanoma, 8 NSCLC, 2 MSIhigh CRC), 11 patients remain disease free on study, median follow-up of 10 months. Of the 20 patients treated in combination (1 TMB-high metastatic cutaneous squamous cell, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high (CRC, prostate, endometrial), 13 had received prior CPI, 5 PRs (2 in patients previously treated with PD-1/L1 inhibitors), 6 SD, and 8 PD were reported. Neoantigen specific CD8+ T-cell responses have been detected.
Conclusion(s): mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2

Background: INDUCE-1 is a first in human study investigating GSK609 alone (mono) and in combination (combo) with other regimens including pembro. The study consists of dose escalation (DE) and expansion phases. Findings from DE and the PK/PD mono cohort demonstrated that a range of GSK609 doses (>=0.1-1 mg/kg) have biological and clinical activity supporting the mechanism of action of a non-T cell depleting IgG4 ICOS agonist antibody as a clinical target.
Method(s): Eligible patients (pts) for the HNSCC EC had recurrent or metastatic disease, <=5 prior lines of therapy, measurable disease, and no active autoimmune disease. Pts received 1 mg/kg GSK609 in the mono EC and 0.3 mg/kg GSK609 +200 mg pembro in the combo EC until disease progression or unacceptable toxicity, up to 2 years (yrs). Disease assessments were performed every 9 weeks (wks) through wk 54 then every 12 wks. Overall response rate (ORR) was assessed for futility in>=10 pts/EC, analyzed by prior PD-1/L1 treatment status (naive vs. experienced). PD-L1 expression was determined by the 22C3 pharmDx assay.
Result(s): As of 16 April 2019, 12 of 17 PD-1/L1 experienced pts in the mono and 29 of 34 PD-1/L1 naive pts in the combo HNSCC ECs had at least 1 disease assessment (evaluable population). In the mono EC, median age was 56 yrs (range: 27-73); 88% were male; 82% received >=1 prior lines in the metastatic setting. In the combo EC, median age was 61 yrs (range: 33-77); 85% were male; 68% received >=1 prior lines in the metastatic setting. ORR was 8% (95% CI: 0.2%, 38.5%) and 28% (95% CI: 12.7%, 47.2%) in mono (1 of 8 pts) and combo (8 of 29 pts) ECs, respectively. Median PFS in the combo EC was 5.6 months (95% CI: 2.4, NR). Treatment-related adverse events occurring in the overall mono (n=208) and combo populations (n=178) were consistent with that previously reported (Hansen, et al. ESMO, 2018). PD-L1 IHC testing is ongoing.
Conclusion(s): Preliminary data demonstrate GSK609 has single agent activity in PD-1/L1 experienced HNSCC. The combo of GSK609 with pembro shows promising antitumor activity and a manageable safety profile in pts with previously treated, PD-1/L1 naive HNSCC

Cancer cells are known to have distinct metabolic characteristics compared with normal cells, given the catabolic and anabolic demands of increased cell growth and proliferation. This altered metabolism in cancer cells imbues differential dependencies, and substantial effort has been invested in developing therapeutic strategies to exploit these potential vulnerabilities. Parallel to these efforts has been a growing appreciation for the presence of notable intratumoral metabolic heterogeneity. Although many novel agents are showing some promising results in targeting specific metabolic processes, the challenge moving forward will be to develop combination strategies to address the aforementioned metabolic heterogeneity and its interplay with both epigenetic and immune factors in the tumor microenvironment. In this review, we discuss recent developments in targeting tumor catabolism, lipid biosynthesis, glycolysis, and the citric acid cycle as well as efforts to combine these approaches with immunotherapy.