With the American Association for Cancer Research meeting in full swing, Bristol-Myers Squibb let forth a flurry of announcements on its immuno-oncology star Opdivo over the past few days. The upshot? It’s a good news, bad news and wait-and-see story.
Opdivo and its BMS companion Yervoy showed they could together cut the risk of death in melanoma patients better than Yervoy alone. In a phase 1 extension study, an estimated 16% of Opdivo lung cancer patients survived five years, compared with a historical 5%. The FDA put Opdivo on its priority-review track for an expansion into two specific types of colorectal cancer. All good.
The bad news? Opdivo failed a trial in glioblastoma, a hard-to-treat form of brain cancer. The drug, used on its own in this trial, fell short of Roche’s Avastin at helping patients live longer.
As for the wait-and-see, we’re back to the Opdivo-plus-Yervoy combo in melanoma. More on that next. Here we’ll note that, per Evercore ISI analyst Umer Raffat, who analyzed QuintilesIMS prescription numbers, Merck & Co.’s Keytruda surged by 80% in January and February, compared with the same period in 2016, to an estimated $260 million. According to the Financial Times (sub. req.), Opdivo’s sales ticked upward by less than 1% over the same period, though its total still surpassed Keytruda at $448 million.
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Getting back on track, growth-wise, is why the steady stream of data and regulatory moves is so important to Opdivo, and Bristol-Myers itself.
In the melanoma combo trial, overall survival numbers were impressive, compared with Yervoy: On its own, Yervoy extended patients’ lives by 20 months at the median, while the combo and Opdivo alone hadn’t yet reached a median after 28 months in the study.
The combo also delivered a 45% decrease in death risk compared with Yervoy alone; Opdivo monotherapy cut the risk of death by 37%, the company said in a statement. As for two-year survival, 64% of the combo patients were alive at that point, compared with 59% of Opdivo-only patients and 45% of those in the Yervoy monotherapy arm.
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But serious side effects were significantly more common among the combo patients. Some 58% of them suffered severe side effects, and almost 40% stopped treatment because of adverse events. By contrast, only 21% of patients treated only with Opdivo saw Grade 3/4 side effects, and 11.5% dropped out of therapy. The numbers were also lower for Yervoy.
“We suspect the debate will move to the relative risk-reward profile,” Barclays analyst Geoff Meacham wrote in an investor note.
Also part of the calculus going forward: The combo costs more, Credit Suisse analyst Vamil Divan, M.D., pointed out in a Monday note to investors.
“From a commercial perspective, the risk/benefit of the combo over Opdivo alone is more relevant, and on that front the conclusion is less clear,” Divan wrote.
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“Given the combination also has an added financial cost, we assume the majority of melanoma patients will be treated with monotherapy PD-1 (either Opdivo or Merck’s Keytruda)," Divan added, "with the combo used more selectively by thought leaders at leading academic centers that are able to monitor patients closely for signs of potential side effects.”
Meacham was more optimistic on Opdivo's behalf, however. "As physician experience with the regimen increases and the side effect profile becomes better characterized, we anticipate that adoption of the regimen will continue," he said.
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Also on the wait-and-see side were some details about the Checkmate-026 trial, the one big flop for Opdivo in non-small cell lung cancer—and an important one at that, because it gave Merck & Co.’s Keytruda the lead in that key market, one that Opdivo had previously been leading.
The trial had tested Opdivo in previously untreated patients with a PD-L1 expression rate of 5% or more, a broad group, given that patients with higher levels tend to do better on this class of PD-1/PD-L1 inhibitors. The failure had widely been attributed to that risky choice, but subgroup analyses later found that patients with much higher PD-L1 levels didn’t see much benefit with Opdivo monotherapy, either.
Another analysis presented at AACR showed that in patients with a higher tumor mutation burden, Opdivo did beat chemotherapy at keeping cancer at bay. In high-expressing PD-L1 patients with that high tumor burden, the difference was even bigger.
RELATED: An Opdivo setback for Bristol, this time on the combo front, widens Merck's immuno-oncology lead
As Divan noted, this conclusion doesn’t explain why Opdivo fell short in its first-line trial while Keytruda succeeded. What it does show is that “there is still much we do not know about how immuno-oncology agents work,” the analyst said.
And here’s another confounding factor. High PD-L1 expression wasn’t associated with high tumor mutation burden, Raffat said.
Which leads to this: Because we don’t know everything about how immuno-oncology drugs work, we also don’t know which are the best biomarkers to use to sift out patients best matched with particular therapies, Divan said.
Meanwhile, doctors and researchers will work with the biomarkers they have, and Bristol-Myers is using two in colorectal cancer for Opdivo. That priority review granted by the FDA this week covers patients with mismatch repair deficient or microsatellite instability high metastatic colorectal cancer who’ve been previously treated with chemotherapy. Patients with these biomarkers have a poorer prognosis compared with those who don’t, the company said in a release.
And as for the failure in glioblastoma, Bristol-Myers will still move forward with two other Opdivo trials in that disease, both of which pair that therapy with other treatments.