Expanding the Reach of Immunotherapies for Kidney Cancer

David F. McDermott, MD

Newer immunotherapies being used in kidney cancer can help create a dramatic, durable response, but only in a small subset of patients, according to David F. McDermott, MD. Methods of expanding on progress seen in the field of immunotherapy, both in the case of kidney cancer and other tumor types, was the subject of McDermott’s presentation at the PER® European Congress on Immunotherapies in Cancer held in Barcelona.

Researchers have been exploring the PD-1/PD-L1 blockade for many years, as immunotherapy agents of this kind have seen successes in melanoma, lung cancer, and more. McDermott called single-agent therapy targeting the PD-1 pathway blockade the new standard of care for patients with renal cell carcinoma (RCC).

Nivolumab (Opdivo), a PD-1 checkpoint inhibitor, was approved by the FDA for use as a second-line therapy for metastatic RCC in 2015 following the results of the CheckMate-025 trial.¹McDermott, assistant professor of Medicine at Dana-Farber/Harvard Cancer Center, pointed out that the trial, which compared nivolumab to the mTOR inhibitor everolimus (Afinitor), showed both statistically significant and clinically meaningful improvements in overall survival (OS).

The median OS for nivolumab was 25 months (95% CI, 21.8-not estimable) compared with 19.6 months (95% CI, 17.6-23.1) with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93;P= .002). The objective response rate (ORR) with nivolumab was 25% versus 5% with everolimus (P<.001).

&ldquo;This is probably one of the cleanest trials in the history of kidney cancer because not only did we see improvements in overall survival but we also saw improvements in safety and quality of life. And this story has been played out in multiple tumor types,&rdquo; McDermott said.

Many patients also experienced a durable benefit with this immunotherapy treatment. Long-term follow-up for patients treated with nivolumab in the phase I and II trials, in data presented by McDermott at ASCO this year, showed that about one-third of the patients were still alive at &ge;4 years.²

However, McDermott also mentioned that a majority of patients were not retaining the bene t of the treatment or needed to stay on the drug for an extended period of time.

The development of biomarkers is one of the ways that researchers hope to find patients that may benefit most from these treatments and give those patients a more durable remission. Various approaches are being explored to improve predictive biomarkers, McDermott said, including CD-8 T cells and PD-L1 expression at the invasive margin, clonality of T cells in the tumor, mutational frequency, neo-epitope signature, in ammatory gene expression pattern, and tumor histology. Together, McDermott said, they may provide a richer model that will hopefully help researchers select the best treatments for these patients going forward.

PD-L1 does not work as a solitary predictor of outcome in kidney cancer, however, or as a means of selecting patients, especially since when looking at tumor biopsies for PD-L1 expression, one biopsy alone may not provide a good representative sample, McDermott said, which may explain why some PD-L1—negative patients have a prolonged benefit. For example, in the nivolumab phase III trial, patients with negative PD-L1 expression had higher median OS compared with PD-L1&ndash;positive patients on nivolumab (27.4 vs 21.8 months, respectively).

A study of the difference in PD-L1 expression between the primary tumor and metastases sites in RCC showed a 20% discordance in expression between the tumors.³A needle biopsy of the primary tumor is therefore not suf cient for a representation of the patient&rsquo;s predicted outcome.

&ldquo;In the ideal setting, we believe that when you&rsquo;re deciding about immunotherapy for a patient&rsquo;s kidney cancer, you should probably biopsy the metastasis soon before you&rsquo;re starting treatment, and you should be considering an excisional biopsy,&rdquo; said McDermott.

Exploring combination therapies including immunotherapy agents is another way in which researchers are hoping to increase durable responses as additional therapies may help to overcome innate or acquired resistance.

A small trial explored combined VEGF blockade and PD-L1 checkpoint inhibition with bevacizumab (Avastin) and atezolizumab (Tecentriq), and the patients with RCC demonstrated a 40% ORR with partial responses in 4 of the 10 patients. Six patients were still on the combination therapy after 15 months.⁴

The study also found that there were increases in intratumoral CD8+ T cells post treatment with both drugs, as well as decreases in vascular gene signature and upregulation of immune effector gene signatures. Ongoing clinical trials are needed to continue to explore the additional effect of VEGF blockade on these patients.

&ldquo;When you talk about combinations, not every combination is a good one,&rdquo; McDermott cautioned. A phase I/II trial of pazopanib (Votrient) and pembrolizumab (Keytruda) for patients with metastatic RCC encountered considerable hepatotoxicity.⁵Not all combination treatments will perform as well as the combination of nivolumab and ipilimumab in melanoma.

When exploring combination therapies, it needs to be considered whether or not the agents together would perform better than separately in sequence, McDermott suggested, and whether or not the benefits outweigh the costs that come with additional treatments. A complete remission, for example, would outweigh all costs.

References:

1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813.
2. McDermott DF, Motzer RJ, Atkins MB, et al. Long-term overall survival (OS) with nivolumab in previ- ously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. Pre- sented at: the 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 4507.
3. Callea M, Albiges L, Gupta M, et al. Di erential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma. Cancer Immunol Res. 2015;3(10):1158-1164.
4. Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances anti- gen-speci c T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.
5. McDermott DF, Infante JR, Chowdhury S, et al. A Phase I/II study to assess the safety and e cacy of pazopanib (paz) and pembrolizumab (pembro) in patients (pts) with advanced renal cell carcinoma (aRCC). Presented at: the 2015 ESMO Annual Meeting; September 25-29, 2015; Vienna, Austria. Abstract 2622.