Multiple immunotherapy combinations are already duking it out in newly diagnosed kidney cancer. Now, Exelixis is throwing another hat in the ring, hoping a triplet based on two Bristol Myers Squibb checkpoint inhibitors could have a seat at the table. But data so far suggest an uphill battle ahead.
In previously untreated advanced kidney cancer with intermediate or poor risk, adding Exelixis’ Cabometyx to Bristol Myers Squibb’s Opdivo and Yervoy pared down the risk of disease progression or death by 27%. The phase 3 Cosmic-313 trial has therefore hit its primary goal.
Within the current tumor progression data, it appears that only patients with intermediate risk are driving the triplet’s benefit with 37% reduction in the risk of disease worsening of death. As for those with poor risk, investigators found no risk difference between the two treatment arms, according to data presented at the European Society for Medical Oncology congress 2022.
“I think very possibly, this may end up in the intermediate risk [population],” study first author Toni Choueiri at Dana-Farber Cancer Institute said of the potential proper use of the triplet during a press briefing.
SVB Securities analyst Daina Graybosch, Ph.D., also questioned whether the current data are clinically relevant to doctors, because beating Opdivo and Yervoy is an easy task, Graybosch said in an interview before the data were released
In 2018, BMS’ dual-immunotherapy combo of Opdivo and Yervoy got an FDA approval for previously untreated intermediate- and poor-risk kidney cancer based on phase 3 data showing it could extend patients’ lives more than Pfizer’s old standard-of-care, Sutent. But in that CheckMate-214 trial, Opdivo and Yervoy only reduced the risk of disease progression or death by a non-statistically significant 18%.
By comparison, Cabometyx’s combination with Opdivo earned its FDA go-ahead early last year as a first-line treatment for all patients with advanced kidney cancer. Data from the CheckMate-9ER trial showed the combo reduced the risk of disease worsening or death by 49% against Sutent.
In short, Opdivo and Yervoy simply isn’t good at stalling tumor progression, Graybosch said. Therefore, a progression-free survival advantage over that weak comparator isn’t exactly very convincing.
What’s more, with the addition of Cabometyx, a strong tyrosine kinase inhibitor, the triplet didn’t really get much more responders. The tumor response rates were 43% and 36% for the triplet and doublet, respectively. Again, the data were better for the triplet’s comparison against the Opdivo-Yervoy regimen in intermediate risk patients. The overall response rates were 45% and 35%, respectively. In the poor-risk population, the numbers were 37% and 38%, respectively.
To make things worse, piling on Cabometyx apparently comes with additional toxicities. Grade 3 or 4 treatment-related side effects happened in 73% of patients who took the triplet, versus 41% in the Opdivo-Yervoy arm. Side effects also led to discontinuation of all treatment components in 12% of patients on triplet, compared with 5% for doublet.
Having a disease progression benefit is simply not enough also because all other options have shown they can prolong patients’ life expectancy. At this point, the Cabometyx-Opdivo-Yervoy regimen has yet to show a significant improvement in the patient survival department, and the trial will continue.
The Cabometyx-Opdivo combo cut the risk of death by 40% against Sutent. Merck and Eisai’s Keytruda-Lenvima cocktail was approved a year ago after the Keynote-581 trial showed it could reduce the risk of death by 34% versus Sutent.
“The bar is really high,” Graybosch said. “All the doctors are basically like, I need to see survival, and I need to see the lift of the [survival] tail.”
Similarly, Viktor Grünwald from the University Hospital Essen, a genitourinary cancer expert invited by ESMO, also said in a statement that the triplet may try to compete with others, “but mature overall survival data is needed to become a novel standard of care.”
Graybosch doubted Cabometyx would even file for an approval without the overall survival data, even though the tumor progression showing may already be approvable.
“Why waste your resources in your launch and something that’s not clinically meaningful? You only get a chance to launch once,” the SVB analyst said.
But the prospect doesn’t look very promising for Exelixis. As Graybosch noted, based on observations from all the other frontline kidney cancer trials of PD-1/TKI combinations, the death risk reductions typically dwindle over time. Take CheckMate-9ER, the death risk reduction Cabometyx-Opdivo had over Sutent narrowed from the original 40% first to 34% after a longer, 23.5-month follow-up, then to 30% at median 32.9 months.
The current Cosmic-313 trial has followed patients for 17 months for the overall survival analysis, study first author Choueiri told reporters. Previously, Cabometyx-Opdivo reported its trial win after a median follow-up of 18.1 months. In the original CheckMate-214 trial, the Opdivo-Yervoy combo hit its goal after a median 25.2 months.
For now, Exelixis may target some existing Opdivo-Yervoy believers with the triplet because the addition of Cabometyx could trigger tumor shrinkage in potentially more patients while maintaining the dual immunotherapy’s long duration of response, Graybosch said. Among several scenarios she has analyzed before the data release, Exelixis’ current data now fall in the category of a little bit better efficacy but higher toxicity. In that case, Graybosch said she doesn’t expect the triplet regimen to be as competitive as other existing options.