TKI-Immunotherapy Combinations Push the Envelope in Frontline RCC

Eric Jonasch, MD

Convincing data have made the case for the use of immunotherapy in the frontline for advanced renal cell carcinoma (RCC), ushering in a second revolution in slightly more than a decade. In 2007, the anti-VEGF tyrosine kinase inhibitor (TKI) sunitinib (Sutent) elbowed aside interferon alfa in advanced RCC. Now, TKI monotherapy is on the verge of being displaced by immunotherapy combinations.

The National Comprehensive Cancer Network (NCCN) is contemplating a frontline treatment guideline change to include pembrolizumab (Keytruda) plus axitinib (Inlyta), as well as avelumab (Bavencio) plus axitinib, as results of recently completed clinical trials are considered by the FDA, according to Eric Jonasch, MD, vice chair of the NCCN Clinical Practice Guidelines in Oncology Panel for Kidney Cancer.¹

“We have a number of potential approvals over the next 6 months…making this algorithm quite dynamic and quite interesting,” Jonasch said during a presentation at the 2019 NCCN Annual Conference, held March 21 to 23 in Orlando, Florida.¹

Recent results show significantly longer overall survival (OS) with pembrolizumab and axitinib compared with sunitinib, and with FDA approval of the combination anticipated, oncologists are beginning to consider when to give it to patients and when to use ipilimumab (Yervoy) plus nivolumab (Opdivo), which became the standard frontline treatment for intermediate- and poor-risk patients just last year. They are also looking forward to seeing more data on novel combinations and agents that may advance progress in making RCC a chronic or in some cases curable disease.

“With immunotherapy it is possible to have no adverse effects and have cancer control for years,” said Elizabeth Plimack, MD, MS, chief of the Division of Genitourinary Medical Oncology and director of Genitourinary Clinical Research at Fox Chase Cancer Center in Philadelphia, Pennsylvania. “Not everyone achieves that, but the fact that there is that possibility is what drives our enthusiasm for this approach.”

An update to NCCN guidance for advanced RCC risk categories and appropriate agents was introduced this year and could see further adjustment based on anticipated FDA approvals, Jonasch said. Whereas the 2018 version of the guideline considered “good or intermediate risk” as a single category, with “poor risk” as a separate category for designation of preferred treatments, version 3.2019 now considers “good risk” a risk category of its own, combining “intermediate risk and poor risk” into a single category.²

Until the FDA makes a determination on the immunotherapy applications, however, good-risk patients can be considered for sunitinib or pazopanib (Votrient), said Jonasch, who also teaches in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. Cabozantinib (Cabometyx) is also recommended as first-line therapy for favorable-risk patients in the latest NCCN guideline update, as well as for subsequent therapy, for relapse or stage IV RCC.

Accelerated FDA Approval Process

In February, the FDA granted a priority review designation to a supplemental biologics license application (sBLA) for the pembrolizumab/axitinib combination as a frontline treatment for patients with advanced RCC (Figure).³ Under a timetable established by the Prescription Drug User Fee Act, the FDA is expected to make a decision on the sBLA by June 20.

The application is based primarily on data from the phase III KEYNOTE-426 (NCT02853331) study presented at the 2019 Genitourinary Cancers Symposium; results showed that the combination significantly improved progression-free (PFS) and OS.⁴ Pembrolizumab/axitinib led to a 47% reduction in the risk of death versus sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P <.0001). The median OS was not reached in either arm.

At a median follow-up of 12.8 months, the 12- and 18-month OS rates with pembrolizumab/axitinib and sunitinib were 89.9% versus 78.3% and 82.3% versus 72.1%, respectively.

The 12- and 18-month PFS rates were also higher with the dual-agent therapy (59.6% and 41.1%, respectively) compared with sunitinib (46.2% and 32.9%). The median PFS was 15.1 months (range, 12.6-17.7) for pembrolizumab/ axitinib and 11.1 months (range, 8.7-12.5) with sunitinib. The combination provided a 31% reduction in the risk of disease progression (HR, 0.69; 95% CI, 0.57-0.84; P = .0001). The survival benefits were observed irrespective of PD-L1 status or risk group.

The incidence of all-grade, treatment-related adverse events (AEs) was comparable between the 2 arms, at 96.3% with the combination and 97.6% with sunitinib. Grade 3 to 5 AEs were higher with pembrolizumab/axitinib (62.9%) versus sunitinib (58.1%). In the combination arm, 0.9% of AEs led to death versus 1.6% in the sunitinib arm. Among patients treated with pembrolizumab/axitinib, 25.9% discontinued treatment of either drug compared with 10.1% who discontinued sunitinib. A total 8.2% of patients discontinued both pembrolizumab and axitinib.

The sBLA also included data from the phase IB KEYNOTE-035 trial. It showed the combination had a tolerable safety profile and elicited a 73% objective response rate (ORR) in patients with advanced RCC.⁵

“There’s no question that this combination will become a standard of care in the frontline setting,” Plimack said. “I wish I had this now in hand to give patients.”

A Complex Choice

Data emerging from clinical studies of the most advanced combinations in development provide details stratified by risk group and PD-L1 expression level (Table).^6-8 Also presented at the Genitourinary Cancers Symposium were updated data on nivolumab/ ipilimumab from the phase III CheckMate 214 trial (NCT02231749).⁹ They showed a 30-month OS rate of 60% versus 47% with sunitinib in the intermediate- and poor-risk populations (HR, 0.66; 95% CI, 0.54-0.80; P <.0001). The ORR was 42% versus 29% (P = .0001), respectively, including complete response (CR) rates of 11.3% versus 1.2%. Among the responders, 52% of patients receiving nivolumab/ipilimumab had a response duration ≥18 months compared with 28% of patients on the TKI arm.

Among all randomized patients (intentionto- treat [ITT] population), the 30-month OS rate was 64% with the immunotherapy combination versus 56% with sunitinib (HR, 0.71; 95% CI, 0.59-0.86; P = .0003). The ORR in the ITT population was 41% versus 34% (P = .015), respectively, including CR rates of 10.5% versus 1.8%.

In the primary data analysis, nivolumab/ ipilimumab was associated with an ORR of 41.6% (95% CI, 36.9%-46.5%; P <.0001) versus 26.5% for sunitinib (95% CI, 22.4%-31.0%) in the intermediate- and poor-risk patient populations. However, favorable-risk patients had a significantly higher confirmed ORR with sunitinib versus nivolumab/ipilimumab, at 52% versus 29% (P =.0001), and a significantly longer PFS (25.1 vs 15.3 months; P <.001).

The new results confirm the long-term efficacy of nivolumab/ipilimumab in intermediate- and poor-risk patients, but the lack of a head-to-head comparison with pembrolizumab/axitinib has created uncertainty about which immunotherapy combination is preferable.

“We all lament that the trial didn’t randomize those 2 against each other because halfway through the pembrolizumab/axitinib trial, ipiilimumab and nivolumab became the standard of care,” Plimack said.

Deciding between them is “a complex question that we’ll be sorting out over the next few years,” said Brian I. Rini, MD, of Cleveland Clinic Taussig Cancer Institute and principal investigator of the phase III KEYNOTE-426 trial. “The advantage to pembrolizumab/ axitinib is that it includes favorable-risk patients in the benefit. It got a higher response rate [and] a higher progression-free survival rate, and it’s probably easier to give than ipilimumab, which can be a little daunting.

“People who would take the other side of that argument would say that the dual immunotherapy is going to provide more durable responses. We don’t know that yet, but that would at least be the hypothesis,” Rini said.

Figure. Development of Kidney Cancer to the Advanced Stage³

Plimack noted that the incidence of serious immune-mediated AEs was “unquestionably higher” with nivolumab/ipilimumab than with pembrolizumab/axitinib. In the nivolumab/ ipilimumab data, “it jumps out that a third of patients required high-dose steroids to reverse an autoimmune complication. That’s pretty high,” she said. “The flip side is that [axitinib]… has a kind of chronic nagging toxicity, potentially long term. That’s one of the drawbacks.” That said, for many clinicians the hazard ratio for OS in the pembrolizumab/axitinib trial and its effectiveness across risk groups will trump concerns about toxicities, Plimack said.

Table. RCC Combination Study Findings by Risk and PD-L1 Subgroup Status^6-8

Jonasch agreed that those factors will likely make pembrolizumab/axitinib a favored choice for treatment of advanced RCC. At the same time, he noted that the combination had a relatively low CR rate of 5.8%. For intermediate- and poor-risk patients in the nivolumab/ipilimumab trial, the CR was 9%, and in the PD-L1—positive group, the CR was 16%.⁶ The possibility of achieving a treatment- free interval could make nivolumab/ ipilimumab more attractive to some patients despite the toxicities, he said. “That’s obviously something very desirable and actually exciting for individuals with intermediate- and poor-risk features. Previously these were patients [whose] prognosis was poor, and the probability of responding to therapy was also poor,” Jonasch said.

The results of the pembrolizumab/axitinib and nivolumab/ipilimumab trials suggest that use of sunitinib and other single-agent TKI therapies for advanced RCC will steadily decline. Rini predicted sunitinib will have essentially “no role” in treatment of the disease. Jonasch said it could remain an option for favorable-risk patients who are not candidates for immunotherapy, such as those with comorbidities or severe autoimmune disease. Plimack said she stopped giving sunitinib outside clinical trials, preferring the better-tolerated pazopanib, but sunitinib may still appeal to some patients in resource-poor areas.

“There is something nice about being on a pill and coming in every 3 months for scans instead of coming in every 3 or 4 weeks for an infusion,” Plimack said. “Cost might be a driver. If sunitinib ever goes off patent and becomes inexpensive, we’ll have to bring that up in the conversation.”

Unclear Prospects for Avelumab

Another immunotherapy combination with promising trial results is avelumab (Bavencio) with axitinib. Its sBLA also has FDA priority review designation with an expected June decision date, although its prospects for wide uptake are less clear.

The combination doubled ORRs and significantly improved PFS compared with sunitinib in patients with treatment-naïve advanced RCC regardless of PD-L1 expression, according to findings from the phase III JAVELIN RENAL 101 (NCT02684006) trial presented at the European Society for Medical Oncology 2018 Congress.¹⁰

In the PD-L1—positive population, the median PFS was 13.8 months (95% CI, 11.1– not estimable [NE]) with avelumab/axitinib compared with 7.2 months (95% CI, 5.7-9.7) with sunitinib, leading to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95%, 0.475-0.790; P <.0001). The ORR with the combination was 55.2% (95% CI, 49.0- 61.2), which included 12 CRs and 137 partial responses (PRs); the ORR with sunitinib was 25.5% (95% CI, 20.6-30.9). Twenty-seven percent of patients in the combination arm (n = 72) had stable disease (SD), and 11% (n = 30) had progressive disease (PD).

In the overall population, the median PFS with the combination versus sunitinib was 13.8 months (95% CI, 11.1-NE) and 8.4 months (95% CI, 6.9-11.1), respectively (HR, 0.69; 95% CI, 0.563-0.840; P = .0001). The ORR with avelumab/axitinib was 51.4% (95% CI, 46.6%-56.1%) and 25.7% (95% CI, 21.7%-30.0%) with sunitinib. In the combination arm, the ORR included 15 CRs (3.4%) and 212 PRs; 131 patients (29.6%) had SD, and 51 patients (11.5%) had PD.

In the PD-L1—positive and overall population arms, 73% and 70% of patients remained on avelumab/axitinib treatment, respectively, versus 65% and 71% of those on sunitinib. Median duration of response was not yet reached in either treatment arm in either population. OS data are not yet mature.

That lack of OS data left Rini skeptical of the combination’s prospects. “I don’t think it’ll get used much because it doesn’t have a survival benefit. It probably won’t be approved in Europe,” he said. OS “might become positive over time. My opinion is that’s never going to happen.”

Jonasch said the avelumab/axitinib PFS and ORR data were favorable, but he was not sure what to make of the CR rates of 3.4% in the overall population and 4.4% in the PD-L1—positive arm, which are lower than the CR rate in the pembrolizumab/axitinib trial.

In addition, from a practical perspective, patients may prefer receiving infusions of pembrolizumab every 3 weeks rather than avelumab every other week, as was done in the JAVELIN trial, Jonasch said. Depending on the final OS results, the manufacturer could develop a competitive pricing strategy that would stoke interest in the avelumab/axitinib combination among payer groups, he said.

Looking for New Paths

A number of other studies of new combinations and agents are under way for treatment of advanced RCC. At the Genitourinary Cancers Symposium, investigators reported that the combination of pembrolizumab and cabozantinib has antitumor activity and manageable toxicities in patients with previously treated metastatic RCC, according to a phase I study.¹¹ A phase II study has begun.

Jonasch described cabozantinib as a “great” TKI and noted that it is also being studied in combination with nivolumab in the phase III CheckMate 9ER study.¹² Rini said cabozantinib will have a high bar to overcome given the efficacy of pembrolizumab/axitinib and nivolumab/ipilimumab in phase II studies and added that the drug’s toxicities are a concern.

Results from a phase IB/II trial of lenvatinib (Lenvima) plus pembrolizumab showed promising activity and an acceptable safety profile.¹³ Lenvatinib combinations are now being studied in the phase III CLEAR trial, which has 3 arms: lenvatinib plus pembrolizumab, lenvatinib plus everolimus (Afinitor), and sunitinib.¹⁴

Plimack said she is excited about the HIF-2α inhibitor PT2977. She is looking forward to seeing results in the coming months from a phase I/II study (NCT02974738) that is investigating the drug for treatment of RCC and other advanced solid tumors.¹⁵ Other trials are testing PT2977 with cabozantinib and for treatment of RCC associated with Von Hippel— Lindau disease.

“I am hungry for new drugs with new mechanisms of action,” Plimack said. “Even though we’re very excited about how far we’ve come, there are still people who don’t respond to these combinations or immunotherapy and need something else. Finding a way to inhibit their cancer through different paths is critical.”

Immunotherapy combinations are making a huge impact on the treatment of advanced RCC because they offer more durable responses than TKI monotherapy and are potentially curative, the oncologists said. But Plimack noted that additional research is needed not only to uncover even more effective drugs but also to establish how to use a combination like pembrolizumab and axitinib over the long term.

“What happens when you do really well on it? How long do you have to be on them?” Plimack asked. “In the clinical trial, the pembrolizumab stops at 2 years and the axitinib can be continued. Well, do you have to continue it? Can we stop it? Should you really be continuing both? Those are the kinds of answers that aren’t known.”

Plimack said another important area of investigation is the use of immunotherapy after patients have progressed on immunotherapy. The practice of enrolling trial patients who have been on prior immuno-oncology regimens is encouraging, she added.

“Just like one VEGF TKI can work after another one has stopped working, maybe a different immunotherapeutic approach can work after the first one stops working,” Plimack said.

Jonasch said the focus of studies must evolve now that effective treatments are available for many more patients compared with a few years ago.

“We need to keep recalibrating, and the endpoint we need to demand is a higher complete response rate. The more we can actually push complete response rate, the more we’re going to, by definition, push overall survival,” Jonasch said. “We have to start designing clinical trials that are powered to a delta in CR rates, as opposed to progression-free survival or objective response rate.”

References

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