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Adding Merck’s Keytruda to a standard chemotherapy regimen halved the odds that previously untreated patients with advanced non-small cell lung cancer would die, meaning that at the end of 21 months an extra two patients out of every 10 were still alive.
The results set the stage for Keytruda to become a standard treatment for patients with non-small cell lung cancer, and herald another advance for the field of cancer immunotherapy, which uses drugs like Keytruda to harness the immune system to attack tumors.
“I do think that improvement of overall survival is quite striking,” says Alice Shaw, a Harvard professor who has done leading research in lung cancer.
Two more studies may light the path toward future advances in treatment. One combined Opdivo, a drug made by Bristol-Myers Squibb, with Yervoy, another Bristol immunotherapy drug, in lung cancer patients selected with a new type of diagnostic test. Again, cancers on this second combination progressed more slowly, and there’s hope it may prevent death. An independent test hints that giving Opdivo earlier – before surgery to remove tumors – may lead to even more benefits for patients. All three studies are being presented this morning at the annual meeting of the American Association for Cancer Research and published in the New England Journal of Medicine.
“I think the summary there is that when you start looking at combinations, that you do better,” says Drew Pardoll of Johns Hopkins, who led the study on giving immunotherapy earlier. He says the other studies prove that drugs like Keytruda and Opdivo are not “one-hit wonders.” Pardoll says: “You can build on them.”
For investors, these data are the latest volley in a heated race for a giant financial market stoked by the $150,000-a-year price of both Opdivo and Keytruda. Bristol-Myers Squibb pioneered the science behind cancer immunotherapy, and most experts believe Keytruda and Opdivo are extremely similar, if not identical. But Merck has run clinical trials that have proved Keytruda has clear benefits in previously untreated lung cancer patients, giving it and entrée into one of cancer’s biggest markets. Meanwhile, Bristol has stumbled, with one key trial dramatically failing to show a benefit. Wall Street analysts currently forecast that Keytruda will generate sales of $11.3 billion in 2023, up from $3.8 billion today, while Opdivo will have sales of $9.7 billion that year, up from $4.9 billion today.
Apples, Oranges, And Tumors
The data presented on combining Opdivo and Yervoy represent a clever gambit by Bristol to try to regain ground in the lung cancer market while advancing the science. The company and the scientists working with it redesigned two studies that had enlisted 1,700 patients to look at those who benefited from a new diagnostic test.
Opdivo and Keytruda work by targeting a protein called PD-1 (for programmed death receptor). Cancer cells hijack this protein to keep white blood cells from killing them. Up until now, scientists and drug companies have tried to predict which patients would benefit from the PD-1 drugs using tests for PD-L1, but there have been concerns that the tests miss patients and that the ones used by different companies may not agree perfectly. Bristol was attempting to evaluate a different diagnostic, tumor mutation burden or TMB, which uses DNA sequencing to measure how mutated a tumor is.
But researchers were only able to measure TMB in a subset of patients, meaning that the data presented today are for 299 patients. A bigger problem: while the patients with high TMB benefitted from the Opdivo-Yervoy combination, right now the data in this subgroup don’t give this combination obvious advantages over Merck’s chemotherapy combo. At least, not yet. (Warning: It’s impossible to accurately compare results from two different trials, so tread carefully.)
Comparing Opdivo-Yervoy to Keytruda-Chemo
On overall mortality, patients in the Merck trial who got Keytruda and chemo were 51% less likely to die at a given moment than those who just got chemo. (Yes, everyone eventually dies, because the risk of death never goes to zero.) For patients with tumors with high PD-L1 levels, this figure was 58%. For those with moderate PD-L1 levels, it was 45%. Even if no PD-L1 was detected, it the risk of dying at a given moment was reduced 41%.
For the Bristol study, patients were 21% less likely to die, about half the difference for the Merck study. That result is not statistically significant, and could improve dramatically, but for now Opdivo-Yervoy doesn’t look better on the thing that matters most.
It’s unfair to Opdivo-Yervoy to look at survival, because the main goal of the study was to measure progression-free survival, which is basically whether tumors grow significantly. It took a median of 7.2 months for tumors to worsen for patients with high TMB who received Opdivo-Yervoy, compared to 5.4 months on chemo. For the Merck study, the equivalent figures are 8.8 months and 4.4 months. (The Opdivo Yervoy combination also did 25% better better than Opdivo alone, but the result was not statistically significant.)
Concluding that the Opdivo-Yervoy is worse than Merck’s Keytruda-chemo combo from these data would be wrong. There are many differences between the studies, including the exact types of cancer included, that make that impossible. But combining Keytruda with chemo improves survival. And the Opdivo-Yervoy data don’t really make an argument for using it instead.
Hurdles For A New Diagnostic Test
One result of the success of Opdivo and Keytruda has been a wider adoption of using diagnostic tests to pick cancer drugs. Keytruda was initially only approved for previously untreated lung cancer patients if they had high levels of PD-L1. Doctors had to use the test. Merck’s wins were largely seen as a result of the company’s embrace of personalized medicine. Things have changed. Roger Perlmutter, Merck’s research chief, says that based on these data, “It would make sense to think about the combination of Keytruda plus chemotherapy for essentially all non-small cell lung cancer patients,” so long as another study, in patients with a type of cancer called squamous cell cancer, is also positive.
But doctors, though universally excited about the prospect of using TMB, say it’s not practical yet, in part because it takes weeks to get results. “Right now, real world, it takes six weeks if not a little bit longer to get that information back,” says Hopkins’ Pardoll. “If you have metastatic lung cancer and there are other alternatives, you don’t want to wait that long before you get treated.” Foundation Medicine, which makes the current test, says it is working on making the results arrive faster. Illumina, a DNA sequencing firm, partnered with Bristol-Myers on Friday to develop a different TMB test.
Another problem for Bristol: one of they key reasons to use Opdivo-Yervoy is to avoid chemotherapy and its side effects. Bristol’s oncology development head, Fouad Namouni, says the company is “happy” that some patients with high-TMB may in the future be able to be spared chemotherapy. But doctors are afraid of combining Opdivo and Yervoy, too, especially with side effects like fluid in the lungs. “It is not sparing of toxicity,” says Corey Langer, a University of Pennsylvannia oncologist. “The data here soft-pedal the toxicity we have observed clinically.” Another factor: Umer Raffat, an analyst at Evercore/ISI, an investment bank, has noted in communications with investors that doctors tend to like sticking with chemo because of both financial incentives and convenience.
That is not to say that another result couldn’t upend this new, fast-growing market once again. This same Bristol trial could read out survival results of the Opdivo-Yervoy combo based on PD-L1 later this year. Immunotherapy drugs can tend to show their survival benefits later than chemotherapy, as it takes time for the immune system to kick in. And Bristol will also be trying a combination of Opdivo-Yervoy with chemotherapy.
Big Questions Remain
The field is moving so fast that things could shift in an eye blink. Here are some big questions:
- Will these drugs be given earlier? Pardoll, funded in part by the charities Stand Up 2 Cancer and The Cancer Research Institute, found that giving Opdivo before surgery at an earlier stage of the disease resulted in dramatic tumor shrinkage in 9 of 21 patients. Bristol-Myers and Merck are both conducting their own trials to see if the results hold up.
- Will Opdivo-Yervoy in high TMB be approved? Namouni, the Bristol-Myers executive, says that the company has discussed all its changes to the study with regulators. The decision to re-cut the data based on TMB was made before Bristol saw any data. But Roy Herbst, chief of medical oncology at Yale Cancer Center, isn’t so sure. “It’s a subset of a subset of a subset,” Herbst says. “Again, yeah, they asked the question before they unblinded, but that doesn’t necessarily get you regulatory approval. At least, it didn’t in the old days. I think it’s pretty compelling, though.”
- How do we get to the future? Companies and researchers alike tend to see the immunotherapy maket segmenting, with more diagnostic tests and different drugs for different patients. Otis Brawley, the chief medical officer of the American Cancer Society, worries that scientists and regulators aren’t ready for this reality. How do we conduct tests of whether drugs help people live longer in these populations? Another question: do Merck’s results today mean some cancer doctors will back off using these diagnostic tests?
Two things are absolutely certain. The progress shown by these studies is stunning. And there are still too many patients who aren’t helped. In the Merck study, three out of every 10 patients on the Keytruda-chemotherapy arm were dead as the end of two years approached. That’s still three too many.
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