Hunt for immunotherapy combinations turns up success in kidney cancer
Pairing cancer immunotherapy with a type of targeted drug could soon become standard practice in treating metastatic kidney cancer following positive results from two major late-stage studies.
The trials, conducted respectively by Merck & Co. and Pfizer, are notable for another reason, too. Despite a wave of drugmaker investment, examples of successful combination treatments involving cancer immunotherapy are limited — a reminder of the still-emerging science underpinning immuno-oncology.
Data from the studies, which were presented in full Saturday at this year's Genitourinary Cancers Symposium, provide evidence that giving checkpoint inhibitors like Merck's Keytruda and Pfizer's Bavencio together with a drug called Inlyta is more effective than using Sutent, a common treatment. Pfizer makes both Inlyta and Sutent, which work in part by inhibiting the formation of new blood vessels supplying tumors.
"Both combinations are expected to become new standards of care and to be incorporated into future guidelines," wrote Bernard Escudier of the Gustave Roussy Cancer Campus in Villejuif, France, in an editorial published Saturday in the New England Journal of Medicine.
The two trials enrolled previously untreated patients with metastatic renal cell carcinoma, the most prevalent form of kidney cancer. Renal cell carcinoma is considered the third largest market for immuno-oncology drugs, behind only lung cancer and melanoma.
To date, however, only Bristol-Myers Squibb holds an approval for a cancer immunotherapy in the tumor type. The pharma won U.S. OKs for its checkpoint inhibitor Opdivo as a monotherapy in 2015 and paired with its other immunotherapy Yervoy last April.
Merck and Pfizer could soon challenge Bristol-Myers for that distinction. The Food and Drug Administration has granted each company's combination priority review, setting up a decision on approval by this June.
Merck's study, in particular, impressed. Patients who received Keytruda and Inlyta were 47% less likely to die than those on Sutent, and nearly 90% of study participants in the combination arm remained alive after one year.
The results exceeded expectations set last October, when the pharma announced the trial had met its primary goal. An abstract released earlier this week revealed topline numbers from the study, but full data weren't available until Saturday.
Immunotherapy trial results in metastatic renal cell carcinoma
|Keytruda + Inlyta vs. Sutent (n=861)||Bavencio + Inlyta vs. Sutent (n=886)||Opdivo + Yervoy vs. Sutent (n=1096)|
|Relative risk reduction for death (ITT)||47%||22%*||32%|
|Median progression free survival||15.1 months vs. 11.1 months||13.8 months vs. 8.4 months||12.4 months vs. 12.3 months|
|Response rate in combination-therapy group||59%||51%||39%|
|Median follow-up||12.8 months||11.6 months||25.2 months|
*Result not statistically significant. ITT = Intent-to-treat population SOURCE: New England Journal of Medicine
While anti-angiogenic drugs like Sutent were previously the standard of care in metastatic kidney cancer, Opdivo plus Yervoy has increasingly been used for frontline treatment for intermediate and low-risk patients.
Data from Merck's and Pfizer's studies, however, show longer median progression-free survival and higher response rates. More patients in Bristol-Myers' earlier trial achieved a complete response, and the pharma now has survival data going out 30 months.
Results on survival for Pfizer's combination of Bavencio plus Inlyta is not yet mature and doesn't show a statistical advantage over Sutent.
How checkpoint inhibitors exactly complement Inlyta, a tyrosine kinase blocker, is still not entirely clear. Still, Merck's data — and to a lesser extent, Pfizer's — supports giving the drugs together.
"I think the highest level of evidence is the survival benefit," said Brian Rini, a professor of medicine at the Cleveland Clinic and a study author on Merck's trial. Rini has received consulting and research funding from Merck.
"Neither drug by itself has proved that; these drugs must be doing something together, whether it's additive or synergistic. There's some effect of giving these drugs together that clearly is making people live longer."
That benefit was observed in all patient groups included in Merck's study, regardless of risk status and expression levels of PD-L1, a biomarker associated with response to immunotherapy.
Interestingly, the earlier results supporting approval of Opdivo and Yervoy in first-line kidney cancer showed a sizable difference in risk reduction between those patients expressing PD-L1 and those who did not.
Analysts had previously speculated that Merck's study enrolled a higher proportion of PD-L1 positive patients, theorizing that would drive a greater benefit. Although the first part of that hypothesis proved true — many more patients in Merck's trial were PD-L1 positive than in Bristol's — statistical analysis showed the survival benefit to Keytruda plus Inlyta to be similar in PD-L1 positive and PD-L1 negative groups. (The studies used a different method for testing expression.)
As with most combinations, treatment with both Merck's and Pfizer's combinations came with significant side effects. Roughly three quarters of patients in the treatment arms of both studies experienced adverse events rated grade 3 or higher. About 11% of participants in Merck's trial discontinued both drugs due to safety, while about 8% in Pfizer's did.
Cancer immunotherapy's recent emergence began in advanced melanoma, before spreading to a wide range of tumor types. Keytruda is now approved to treat 11 different cancers and Opdivo, eight.
Many patients still don't see a benefit to immunotherapy, however, and the drugs are still frequently used after other, older treatments depending on the cancer.
That reality has spurred drugmakers to test hundreds of combinations, trying out other immunotherapies, targeted treatments, chemo and radiation as potential partners. For all that effort, only a handful have proved significantly more effective together, including Opdivo plus Yervoy and Merck's pairings of Keytruda and chemo in lung cancer.
Combining checkpoint inhibition with the tyrosine kinase blockade is now firmly on that list as well.
"I think you're going to see a continued progression as we understand the underlying biology a little bit more," said Jill O’Donnell Tormey, head of the non-profit Cancer Research Institute, in an interview.
Teasing out the factors driving immune activity and suppression in tumors, Tormey added, will help "reverse-engineer" treatment combinations that make sense.
Drugmakers aren't reluctant to test new hypotheses, either. Data compiled by the Cancer Research Institute show 145 active clinical studies testing immunotherapy in renal cell carcinoma as of Feb. 10. One hundred and three are combination trials.
And while Merck and Pfizer might now compete in kidney cancer, Bristol-Myers holds a sizable lead in a number of clinical studies underway, with 10 in late-stage and 26 in Phase 2 by CRI's count. One, testing Opdivo with another tyrosine kinase inhibitor called Cabometyx, is due to read out results later this year.
- New England Journal of Medicine Combination Therapy as First-Line Treatment in Metastatic Renal-Cell Carcinoma
- BioPharma Dive Merck kidney cancer data impresses, putting pressure on Bristol-Myers
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