Bill Slichenmyer, Alacrita Partner, reflects on SITC 2016 conference

Reflections on SITC 2016

Part 1:  New Drugs in Clinical Trials

 

The Society for Immunotherapy of Cancer (SITC) recently convened its 31st Annual Meeting in National Harbor, Md.  As a member of the audience I saw several interesting presentations.  In this post my goal is to share some of the highlights that caught my eye, with a focus on clinical trial data with new anti-cancer agents.  I intend to summarize additional thoughts pertaining to tumor biology and biomarker data from SITC in a subsequent post.

Progress in bladder cancer

A few presentations focused on new clinical trial results with anti-PD-1 checkpoint inhibitors (CPI) that are already marketed in the U.S.  For example, late-breaking data were presented on two studies in bladder cancer.  One was from a phase 3 trial  in previously treated patients with bladder cancer comparing pembrolizumab (Merck) vs. chemotherapy.  The study was halted at a planned interim analysis due to positive results.  The study showed a significant improvement in Overall Survival (HR = 0.73, p-value = 0.002) and is the first such demonstration of an OS benefit in this setting using a checkpoint inhibitor.  Results from a phase 1-2 trial in patients with previously treated bladder cancer using the combination of ipilimumab plus nivolumab (BMS)  also looked interesting.  Currently the only immune checkpoint inhibitor approved for use in bladder cancer in the U.S. is atezolizumab (Genentech).  It appears likely that pembrolizumab will gain such an indication before long.

Anti-KIR antibody lirilumab in HNSCC

While it’s great to see continued expansion of approved immunotherapy agents into more and more tumor types, what is even more interesting to me are data on new agents directed against novel targets.  One such agent is the antibody lirilumab (Innate Pharma and BMS), which inhibits the anti-killer-cell immunoglobulin-like receptors (KIR).  Late-breaking preliminary data were presented from a phase 1-2 study of lirilumab in combination with nivolumab in a cohort of patients with advanced platinum refractory squamous cell carcinoma of the head and neck (HNSCC).  It’s worth noting that both HPV-positive and -negative HNSCC have been shown in a recent publication to have the highest level of infiltration by NK cells relative to 9 other tumor types.  This provides a rationale to study an NK-cell activating agent in this disease.  The new data presented at SITC showed a 24% overall response rate, including 10% complete responses.  While the sample size was relatively small (N=26 evaluable patients) the signal of activity looks interesting and worthy of further exploration.  Nivolumab and pembrolizumab are currently approved in the U.S. for use in patients with metastatic or recurrent HNSCC.

Complete response in Merkel Cell Carcinoma with allogeneic activated NK cells

Allogeneic activated NK cells (Nantkwest) used as adoptive cellular therapy in patients with Merkel Cell Carcinoma (MCC) were the subject of another interesting presentation.  MCC is a relatively rare and aggressive skin cancer, which has previously been shown to be responsive to anti-PD-1 checkpoint therapy.   In the study presented at SITC, results for the first three patients on the NK-cell study were presented.  The treatment was relatively well tolerated.  One patient who had failed numerous prior therapies including radiation, interferon, imiquimod, pembrolizumab, somatostatin analogues and neutron beam therapy had a complete response while on treatment with the activated NK cells.  This response looked impressive to me and is reminiscent of what has been reported for other adoptive cellular therapies such as CAR-T cells in CD19 positive leukemias.  In this case the NK cells are allogeneic and the response is in a patient with a solid tumor.  This is a very interesting, albeit anecdotal, proof of principle for allogeneic NK cell therapy.

CA170 – a small molecule checkpoint inhibitor

Another intriguing new agent is CA-170 (Curis), an orally administered small-molecule inhibitor of the PD-1 and VISTA checkpoints.  In contrast with currently available checkpoint inhibitor antibodies that have a long half-life, a small molecule with a shorter half-life has the potential advantage of allowing for quicker resolution of immune-mediated adverse events, which have been seen with current CPIs.   CA-170 is being studied in a phase 1 trial in patients with refractory solid tumors.  Preliminary clinical results for pharmacokinetic and pharmacodynamic measures were presented.  The systemic drug concentrations observed even at low dose levels in patients are within the biologically active range.  CA-170 dosing was associated with increases in the proportion of circulating CD8+ T cells expressing the activation markers CD69, CD134 and Granzyme B.  This agent is still quite early in clinical development but bears watching as it progresses.

4-1BB antibody urelumab ± nivolumab

Clinical data were presented on urelumab (BMS), an anti-CD137 (aka 4-1BB) antibody that was studied as monotherapy (N = 123 patients) and in a phase 1-2 combination with nivolumab (N = 138 patients).  Although some neutropenia and elevations of hepatic enzymes were observed, urelumab overall was well tolerated.  Monotherapy was associated with a 10% ORR in patients with B-cell NHL but not active in other tumor types.  The combination of urelumab plus nivolumab was associated with a 50% ORR in patients with treatment-naïve melanoma but relatively low activity in NSCLC and SCCHN.  While the activity of the combination in melanoma may be modestly higher than expected for nivolumab monotherapy, it is probably no better than the combination of ipilimumab + nivolumab.  Could there be a role for urelumab in triple combination therapy in the future?  Hard to say.

These are just a portion of the clinical data with new agents presented at the SITC 2016 annual meeting.  The 2017 meeting should have even more.

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