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Axitinib/pembrolizumab combo safe, effective against mRCC

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‘Very promising’ combination

This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.

Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.

Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.

In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.

Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).



A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.

Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.

“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.

Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.

The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).

“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.

As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.

There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.

Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.

Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.

Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.

The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.

At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.

Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.

SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.

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