The positive trial results for a combination of Bristol-Myers Squibb Co.'s Opdivo and Yervoy should bolster the case for full U.S. approval for use in some melanoma patients, although the data also raised questions about side effects and commercial appeal among Wall Street analysts.
Opdivo and Yervoy together improved overall survival among previously untreated patients with advanced melanoma compared to Yervoy alone, the company said April 3 at the American Association of Cancer Research conference in Washington, D.C. Compared to Yervoy alone, Opdivo reduced the risk of death by a statistically significant 45% when used as a combination therapy and 37% when used with Yervoy alone.
The findings should enable the FDA to grant the status full approval, following conditional accelerated approval in September 2015, Leerink equity analyst Seamus Fernandez wrote in an April 3 note.
Both immunotherapy drugs are so-called checkpoint inhibitors that block naturally occurring pathways that typically restrain the immune system and are thought to have the potential to work synergistically because they inhibit different mechanisms.
Analysts agreed that the more important comparison from a commercial perspective is between combination therapy and Opdivo alone. On this front the data was mixed at best because the trial was not designed to make that comparison, they said. Yervoy was the standard of care for melanoma when the trial was initiated in 2013, but with $3.8 billion in 2016 sales Opdivo has surpassed Yervoy, which last year earned $1.1 billion.
"While the study was not powered to make a comparison between the two groups, there was some evidence of a numerical benefit for the combination," wrote Credit Suisse analyst Vamil Divan in an April 3 note. "However, there was also significantly more toxicity with the combo with 39.6% of patients on the combo discontinuing treatment due to adverse events as compared to only 11.5% of patients on Opdivo alone and 16.1% of patients on Yervoy alone."
Cowen and Co. analyst Steve Scala was more pessimistic, saying the study abstract suggested the differences did not appear statistically significant. Citing an interview with an expert physician, Scala wrote April 4 that "the majority of clinicians will no longer use Opdivo+Yervoy in melanoma." The expert believes clinicians will switch to a PD-1 or PD-L1 monotherapy, such as Opdivo or Merck & Co. Inc.'s Keytruda and use Yervoy if the initial treatment fails.
"This is concerning as combination of Opdivo+Yervoy appears to be used in the majority of melanoma patients today," Scala wrote.
Divan said combination therapy will be "used more selectively by thought leaders at leading academic centers that are able to monitor patients closely for signs of potential side effects."
Levels of the biomarker PDL-1 should be used to stratify who needs the combination therapy given its higher side-effect profile, Jonathan Serody, the head of a lab on tumor immunology at the University of North Carolina School of Medicine, said in an interview. Those with low levels of the biomarker are likely to respond better to the combination therapy, he said.
Bristol-Myers explains prior lung cancer failure
Bristol-Myers has struggled to get its footing in non-small cell lung cancer, where it has approval to use Opdivo as a second-line therapy.
The company said in January that it will not seek accelerated approval for the use of the two drugs as first-line initial therapy against the disease, dealing the company a setback and giving additional momentum to rival inhibitor Keytruda, which has a similar mechanism of action. That followed a bigger blow in August, when Opdivo failed its clinical trial for the first-line non-small cell lung indication, an event that pushed the company's stock down about 20%. The result was a surprise given the success of Keytruda in that setting.
Bristol-Myers presented a retrospective analysis of the study on the patients' level of tumor mutation burden that "at least partially explains" the poor outcome of the trial, according to Leerink's Fernandez. Opdivo outperformed chemotherapy in patients with a high tumor mutational burden, while chemotherapy produced longer progression-free survival among those with tumors that had a medium or low burden, he said.
"There is still much we do not know about how immuno-oncology agents work and the best biomarkers that should be used to select patients for therapy or for inclusion in clinical trials," Credit Suisse's Divan wrote.
Serody said there is an emerging consensus that immunotherapies such as Opdivo, Yervoy and Keytruda work in two situations: high tumor mutational load and virally induced cancers. Smokers are more likely than nonsmokers to have lung cancer tumors with a high tumor mutational load, according to the doctor.
Negative result in brain cancer
The company also presented phase 3 clinical trial data at the conference showing that Opdivo did not significantly improve overall survival compared to Roche Holding Ltd.'s Avastin in patients with recurrent glioblastoma multiforme.
The company said more information will be released in May at a neuro-oncology conference in Zurich.
Studies evaluating Opdivo and radiation therapy with or without chemotherapy as an initial first-line therapy against the form of brain cancer are ongoing.