Smackdown: Immune vs Targeted Tx in Rare Kidney Cancers

MIAMI -- If you're treating a patient with advanced non-clear cell renal cell carcinoma (RCC) on Monday and grappling with whether to grab an immunotherapy or choose a targeted agent, look no further.

During the opening session of the International Kidney Cancer Symposium, Primo N. Lara Jr., MD, of the UC Davis Comprehensive Cancer Center in Sacramento, took on Matthew Campbell, MD, of MD Anderson Cancer Center in Houston, in a spirited debate that called upon battle techniques from ancient China, and resorted to spreading fake news and Texas-style wrasslin'.

A Win for ICI

"I was the debate team president when I was in high school, so I intend to win this one," Lara told attendees at the Trump National Doral hotel, speaking in favor of immune checkpoint inhibition as the strategy of choice.

His first evidence was that one of the primary targets for nivolumab (Opdivo), pembrolizumab (Keytruda), and other immunotherapies is PD-L1, which in retrospective series has been shown to be expressed in a smattering of non-clear cell RCC subtypes.

More importantly, he said, recently presented data from the CheckMate 374 study, which included 44 advanced non-clear cell RCC patients treated with nivolumab, reported a 13.6% response rate and median overall survival (OS) of 16.3 months, though responses were regardless of PD-L1 expression. One patient with chromophobe subtype achieved a complete response and five others among the group of patients with papillary, unclassified, and other subtypes had partial responses.

Lara said he needed to prep for his showdown with Campbell, whom he called a tough opponent.

"He's a rising star in oncology -- smart, precocious, very productive, and he has a winning smile," said Lara. "How can I possibly prevail in a 7-minute debate? So I reached for the classics, and I reached for Sun Tzu, who wrote The Art of War."

Further support for Lara's approach came from KEYNOTE-427, a 165-patient trial of non-clear cell RCC patients treated with single-agent pembrolizumab. Here, researchers reported an overall response rate of 26% and a disease control rate of 41%. At 11.1 months follow-up, median OS was not reached, and 72% patients were alive at 1 year. In this study, PD-L1- positive patients derived even further benefit, with response and disease control rates of 35% and 49%, respectively.

During his turn, Campbell took shots at both these trials for their low rates of disease control and high rates of progressive disease as best response -- 51% in the CheckMate trial and 37% in the KEYNOTE trial. "It's a major roll of the dice," he said, with patients either responding or "blowing through therapy" when they don't. He also reminded the audience that pseudoprogression with single-agent immunotherapy is very uncommon in RCC.

Speaking on the response rate breakdown among subtypes in the pembrolizumab study, he noted an "enhanced response" for the papillary subtype (28% of the 118 patients) and said chromophobe was left behind (10% in the 21 patients) -- 31% of the 26 patients with unclassified subtype had responses.

'A Reasonable Option'

Lara also rolled out anti-PD-L1 immunotherapy-based combinations in this setting to bolster his case, including a study on atezolizumab (Tecentriq) plus bevacizumab (Avastin) and the CALYPSO trial of durvalumab (Imfinzi) plus the investigational MET inhibitor savolitinib.

"My closing argument is that in the absence of compelling level 1 evidence that says otherwise, immunotherapy is a reasonable option for the treatment of people with advanced non-clear cell cancer," he said.

In channeling the lessons of The Art of War, Lara had already declared his victory from the start, as "victorious warriors win first, and then go to war," but he saved his most ruthless tactic for last.

"When all else fails, according to Sun Tzu, spread fake news," he said. When Lara's final slide arrived, a doctored front-page story on the Houston Chronicle splashed on all the projector screens in the Ivanka Ballroom, reading: "MD Anderson Oncologist Matthew Campbell Offered Immunotherapy to Patient With Papillary Kidney Cancer."

"I rest my case," said Lara.

Texas-Style Tx

In support of targeted agents, Campbell, pulled the bulk of his evidence from a recent retrospective study of cabozantinib (Cabometyx) in non-clear cell RCC and from two randomized phase II trials involving sunitinib (Sutent) -- ASPEN and ESPN -- which set the stage for the tyrosine kinase inhibitor (TKI) to be the recommended approach for non-clear cell RCC in the current National Comprehensive Cancer Center guidelines.

In ASPEN, 18% of patients responded to sunitinib, with response rates higher in the papillary subtype and somewhat lower in the chromophobe subtype. And only 20% of patients overall had progressive disease as their best response. In ESPN, this rate was 27%, still lower than the experience with immunotherapy.

Campbell noted that chromophobe patients do reasonably well with targeted agents as they tend to be slower growing cancers.

For cabozantinib, the multi-institution retrospective series reported a response rate of 27% (with one complete response in a papillary patient), a clinical benefit rate of 74%, and a median OS of 12 months, and "many of these patients had been previously treated with immunotherapy, TKI, or even both," he noted.

Objective responses were seen across all histologic subtypes:

• Papillary: 18 of 66 patients (27%)
• Xp11.2 translocation: 5 of 17 (29%)
• Unclassified, 2 of 15 (13%)
• Chromophobe: 3 of 10 (30%)
• Collecting duct: 2 of 4 (50%)

Moreover, a retrospective series from Campbell and colleagues demonstrated activity with cabozantinib across the spectrum of non-clear cell RCC subtypes, with durable and stable disease seen in both papillary and chromophobe disease. Also, when patients progress on a targeted agent, he said, they don't necessarily progress in such a way that requires them to discontinue therapy. And though median progression-free survival was 8.6 months in his series, half of the patients stayed on therapy for over a year.

"There's a higher rate of disease control if you lead in with targeted therapy," he concluded. "I think there's significant promise with cabozantinib and there's going to be more data to follow."

For his last slide, Campbell flashed a picture of a tattoo of one of his patients: the word "#wrasslin" atop an orange kidney-cancer awareness ribbon.

"This is how I thought of my debate today," he said. "In Texas we do a lot of wrasslin'."

Then an image of two professional wrestlers appeared on the screen.

"What I think we really need to do is combine forces," he told Lara, suggesting perhaps the discussion shouldn't be an either or in the first place. "Brother, I think it's time for us to wrassle together."

Prior to the debate, 56% of attendees voted that these patients should be treated with immunotherapy plus a VEGF inhibitor, while 24% voted for dual immunotherapy, 16% voted for VEGF alone, and 4% voted for immunotherapy alone. So it seems most would agree it's time.

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