IMMUNOTHERAPY+TKI COMBINATION IN RENAL CANCER

Two new combination regimens are set to become new standards of care for the treatment of metastatic renal cell carcinoma (mRCC).

The new combinations contain an immunotherapy and a targeted agent.

New results with these combinations were presented here at the Genitourinary Cancers Symposium (GUCS) 2019 and were simultaneously published in the New England Journal of Medicine.

One combination is the immunotherapy pembrolizumab (Keytruda, Merck) and the vascular endothelial growth factor (VEGF)–targeted tyrosine-kinase inhibitor (TKI) axitinib (Inlyta, Pfizer). In the KEYNOTE-426 trial, the combination therapy yielded superior outcomes to the current standard of care, sunitinib (Sutent, Pfizer). As reported by Medscape Medical News, these results showed a significantly extendesd overall and progression-free survival for patients with previously untreated mRCC.

The other combination is the immunotherapy avelumab (Bavencio, Merck KGaA and Pfizer) and axitinib. Previously reported results from the JAVELIN Renal 101 trial showed that the combination significantly extended progression-free survival in the first-line setting in patients with advanced RCC, as compared to sunitinib. Updated results now show superior overall survival, with a 12-month rate of 89.9% vs 78.3% with sunitinib.

"These are exciting times" in the treatment of kidney cancer, commented Lori Wood, MD, associate professor in the Division of Medical Oncology at Dalhousie University and senior scientist at the Beatrice Hunter Cancer Research Institute, both in Halifax, Nova Scotia, Canada.

At the meeting, while discussing the new data with the immunotherapy and axitinib combinations, she said, "The results speak for themselves, and these are practice changing studies.

"A new standard of care in 2019 is present, and the majority of patients will be eligible to receive combination therapy, and it should be checkpoint inhibitors with axitinib," she said.

A new standard of care in 2019 is present...checkpoint inhibitors with axitinib. Dr Lori Wood

"Both combinations are expected to become new standards of care and to be incorporated into future guidelines," writes Bernard Escudier MD, from the Gustave Roussy Cancer Campus, Villejuif, France, in an NEJM editorial published alongside the studies.

However, both commentators noted that several questions still need to be answered about these new data.

Immunotherapy in Kidney Care

In his editorial, Escudier points out that sunitinib became the standard of care in the first-line setting in 2007 after showing superiority to interferon alfa, the original immunotherapy used in the treatment of kidney cancer.

However, disease progression was observed in 51.1% of patients in cohort 1 and 44.4% in cohort 2.

Median radiographic progression-free survival was 5.5 months in cohort 1 and 3.8 months in cohort 2, and overall survival was 19.0 and 15.2 months, respectively.

Mutational Tumor Burden and Outcomes

When looking at exploratory endpoints, the authors noted that a PSA response was observed in 17.6% of patients in cohort 1 and 10.0% of those in cohort 2. In the first cohort, five patients demonstrated a PSA < 0.2 ng/mL, as did two patients in the second cohort.

Of this patient subset, four from the first cohort and one from the second cohort also had an ongoing objective response, Sharma pointed out.

A biomarker analysis was conducted and results showed that higher tumor mutational burden was associated with response, and there was a significant association between higher tumor mutational burden and improved outcomes. High tumor mutational burden was associated with significantly longer radiographic progression-free survival  (7.4 vs 2.4 months; P < .0001).

A relationship was also observed between tumor mutational burden and PSA response. High versus low tumor mutational burden was associated with a higher PSA response (38.5% vs 0%) and achieving PSA < 0.2 ng/mL (30.8% vs 0%) in cohort 1, but the difference was less pronounced in cohort 2, at 14.3% vs 11.1% and 14.3% vs 0%, respectively.

When progression-free survival was evaluated by PD-L1 status, the median was 5.6 months for those with PD-L1 ≥ 1% and 3.9 months for those with PD-L1 < 1%.

High Discontinuation Rate

However, a drawback to combination ipilimumab and nivolumab is toxicity, which appears to affect patients with prostate cancer more than those with other cancer types.

In this study, almost all patients experienced treatment-related adverse events of any grade. Grade 3-5 events were experienced by 42.2% of patients in cohort 1 and 53.3% of patients in cohort 2. Adverse events also caused about a third of patients in cohort 1 and 2 to stop therapy (33.3% vs 35.6%, respectively).

The most common adverse events were diarrhea, fatigue, skin rash, nausea, and hypothyroidism, and there were four treatment-related deaths (two in each cohort).

Sharma commented that although the safety profile of both drugs was generally consistent with prior studies, the "dose/schedule optimization will be important for patients with mCRPC given the number of patients not completing all four combination doses and discontinuing study treatment due to toxicity."

During a discussion of the study, William Kevin Kelly, DO, professor of medical oncology at the Sidney Kimmel Cancer Center and Jefferson Health in Philadelphia, Pennsylvania, pointed out that the median duration of therapy didn't exceed 2.1 months.

"The thing that's dramatic about this is whether the drug was tolerable or not in this population," he said, as only a small percentage of patients in both cohorts actually received the four planned treatment cycles.

"Only a third of patients got to maintenance dose," he pointed out. "It was discontinued for toxicity by 50% in cohort 1 and 44% in cohort 2."

Kelly commented that other studies of this combination in patients with other types of cancer suggested better tolerability of the regimen. For example, in a renal cell carcinoma study, 79% of patients received all four treatments, and in a melanoma study, 50% of patients were able to tolerate the full regimen.

In contrast, only 33% of mCRPC patients in cohort 1 and 24% of those in cohort 2 received the planned four treatments.

"For some reason, prostate cancer patients are not tolerating therapy as well as the other populations," he said. "As I teach all my fellows, if we can't get the drug in, patients don't respond," he added.

The study was sponsored by Bristol-Myers Squibb. Sharma has reported financial relationships with Amgen, Astellas Pharma, AstraZeneca, BioAtla, Bristol-Myers Squibb, Constellation Pharmaceuticals, EMD Serono, Evelo, GlaxoSmithKline, Jounce Therapeutics, Kite Pharma, MSD, Neon Therapeutics, Oncolytics, and Pieris Pharmaceuticals. Several coauthors have also disclosed relationships with industry.

Genitourinary Cancers Symposium 2019. Presented February 14, 2019. Abstract 142