ASCO 2015: Developmental Therapeutics Immunotherapy Poster Discussion

Not surprisingly, this was a very popular topic. I’m not sure why the American Society of Clinical Oncology (ASCO) planners didn’t anticipate this, because I had to wait a few minutes outside the door to even get in. At one point, it was standing room only!

The first discussant summarized pembrolizumab (MK-3475, Keytruda) plus ipilimumab (Yervoy), and nivolumab (Opdivo) plus ipilimumab. The advantage of this regimen is that ipilimumab can be given at much lower doses, thereby hopefully avoiding some of its more difficult side effects. Overall, ipilimumab plus nivolumab was reasonably well-tolerated, but 50% had grade 3/4 toxicities. It was noteworthy that some were asymptomatic (e.g., grade 3 elevated lipase levels), but some were more important, like colitis or pneumonitis.

The next nivolumab trial reported on was the phase IIIb/IV experience in non-small cell lung cancer (NSCLC), which was conducted postapproval and primarily in the community setting. Overall, toxicities and efficacy were similar to the reported experiences. Although nivolumb is generally well tolerated, it is extremely important to remember that toxicities occur in an idiosyncratic fashion, and all providers using this must remain vigilant. Efficacy remained consistent to previously reported data – about 10% to 20%. The famed pseudoprogression occurred in approximately 0.5%, so it warrants mindful consideration, but great caution to not over interpret it in the majority of nonresponders who are simply progressing.

The next series of abstracts went on to summarize the status of biomarkers in PD-L1.

The bottom line: while it's somewhat useful to screen for PD-L1, PD-L1-positivity doesn’t guarantee response, and PD-L1-negativity doesn’t clearly promise a patient will be unresponsive to treatment either. For example, in one abstract, the investigators studied over 2000 NSCLC samples, and concluded that it is not a binary predictor of response. Additionally, it is important to consider that when PD-L1 is high on tumor cells (TC3), this is different than if PD-L1 is high on immune cells (IC3) since they have distinct microenvironments. They have distinct immunophenotypes and biology. In both populations, responses are enriched to anti-PD-L1 (atezolizumab) and PD-L1-positivity can change over time. This evolution from PD-L1-negativity to positivity can be harnessed to improve response to these immune checkpoint inhibitors.

The next study discussed was MEDI4736 in combination with the CTLA4 inhibitor, tremelimumab in NSCLC. This was a 102 patient phase I dose-escalation trial. The investigators reported that the grade 3 and 4 toxicities were generally dose proportional, with up to 78% grade 3 and 4 toxicities at the highest doses of tremelimumab. Significantly, 44% of patients had to discontinue therapy due to toxicity. The combination was much better tolerated at the low dose. The discussant posed the question: "Why is there a lower therapeutic window in NSCLC than melanoma?" I might speculate that there is a difference in the patient population with a higher comorbidity burden in the NSCLC population compared to the melanoma population. Notably, the response was similar throughout both PD-L1-positive and negative patients. Therefore, the addition of tremelimumab to MEDI4736 might be useful in increasing the therapeutic value for patients with PD-L1-negative tumors.

The third speaker started out with an interesting overview of immunotherapy before its current glamour state, starting 35 years ago with the onset of anti-IL-2 therapies in 1979. Additionally, the first tumor infiltrating lymphocytes (TILs) and gene therapies (PD-1, PD-L1) started in 1987!

He discussed a novel CEA-targeted IL-2 variant. The basic premise is that IL-2 therapy is limited by severe side effects, including capillary leak syndrome. If you can couple IL-2 to this CEA-targeted IL-2 variant, you may be able to temporize the severe side effects. In the study at hand, the investigators demonstrated tumor targeting and intratumoral uptake in CEA-positive tumors such as colon cancer. This study also demonstrated an immunotherapy relevant, dose-dependent increase in the CD8:CD4 ratio, and also an increase in PD-L1 from pre-to post-treatment biopsies.

Next he discussed a pegylated recombinant human IL-10 administered in a phase I study of 33 patients. Five patients at the recommended phase II dose achieved disease control for at least 2 months, but only two had partial response(renal cell carcinoma and melanoma), and two stayed on therapy for greater than 14 months.

Intratumoral therapy was tried in the past with limited success, but is back in vogue as demonstrated by the recent publications of herpes virus injections. The study presented was of ipilimumab plus intratumoral IL-2 in unresectable stage III/IV melanoma patients. An abscopal effect (a phenomenon in the treatment of metastatic cancer where localized treatment of a tumor causes not only a shrinking of the treated tumor, but also a shrinking of tumors in different compartments from the treated tumor) was seen in 75% of patients. Overall, the therapy was well-tolerated (with some focal necrosis at the injection site) and generated responses both in the injected and noninjected lesions.

The final presenter, Lillian Siu, MD, FRCPC, reviewed vaccine therapies and dendritic cell therapies. These seemed a little more nebulous in therapeutic outcome. The most interesting to me was the lung cancer vaccine trial in which Yataro Daigo, MD, PhD and his team investigated genome-wide screens to identify multiple genes/antigens. In this phase I trial, they administered a vaccine "cocktail" with three antigens. Patients with response to all three had more pronounced response than those with single response.

In summary, there are a number of exciting fronts being explored in early-phase immuno-oncology. One notable category that was not discussed was CAR-T-cell therapy. I expect there will be more of that next year. Finally, as a quick aside, Leonard Saltz, MD, gave an excellent discussion at the end of the plenary session on Sunday that looked at the exponentially rising costs of therapies, highlighting the enormous monthly cost of the check point inhibitor, pembrolizumab, which costs around $14,000 per month. While the field of immuno-oncology continues to grow, so are drug costs. This will continue to be a topic of discussion as well.