There’s an op-ed in the New York Times that makes tough reading, and it’s something that we’re going to be seeing more of. The author, Matt Jablow, lost his wife Ronna to non-small cell lung cancer, undiagnosed until a late stage, which is bad enough. Worse, they got to find out about it during a family vacation to Italy, and she was dead within two years of rapidly progressing disease. She was given Opdivo (nivolumab), the anti PD-1 therapy which has been much in the news, but this did nothing for her at all.
And now, as Jablow says, he gets to watch commercials for Opdivo talking about how it can extend lives, ask your doctor, and so on, and he’s (understandably) not happy about it. I’d find it painful, too – who wouldn’t?
It would be incredibly uplifting if it weren’t so utterly misleading and exploitive. To date, only about one in five patients with Stage 4 non-small cell lung cancer has seen any measurable response to Opdivo; and, in those patients who do respond, the median increase in life expectancy is only about three months compared with standard chemotherapy.
The overall five-year survival rate for people with Stage 4 lung cancer is between 1 and 5 percent. Instead of a “chance of living longer,” a more truthful narrator would have said, “Opdivo provides an outside chance for people with advanced lung cancer to live just a few months longer.”
Hmm. With all respect to Mr. Jablow, and to the memory of his wife, his statements aren’t completely correct. The response rate he cites is not in all Stage IV NSCLC patients, but just in those who have failed other therapies. His response rates need some clarification, too: as that NEJM article he links to shows, patients in this category have a survival rate of 22% at one year and 5% at two years. That Bristol-Myers Squibb trial demonstrated that Opdivo/nivolumab changes this to 41% at one year and 19% at three years. We don’t have five-year survival rates yet, because it hasn’t been around that long.
Another key factor (as the recent failed trial for this drug showed) is whether or not a given patient has a form of NSCLC that’s driven by the PD-1 signaling pathway. If so, the response rate seems far better. This is tied up as well in a fight between Bristol-Myers Squibb and Merck, makers of a competing antibody, Keytruda. Keytruda’s clinical trials were set up in patients who strongly expressed PD-1 L1 protein, and their FDA approval thus requires testing for it. Opdivo’s trials were not set up in that way – they did look at PD1-L1 expression, but have been going for a broader patient population. Merck, on the other hand, can well argue that that approach isn’t as relevant, because it’s really the high PD-1 L1 population that should be getting a drug like this anyway, and so on.
It would seem clear the Ronna Jablow was not in that category, because Opdivo (or Keytruda) would very likely have shown a much more pronounced effect if that had been the case. It’s important to note that the survival rates quoted above were enough to blast this drug through the FDA approval process, because, frankly, they’re so damn impressive. This is what “impressive” looks like in oncology. We’ve been redefining that over the years, and that redefinition is still going on (fortunately), but the PD-1 antibodies are indeed a real advance. The op-ed goes on to note the recent failed trial as dashing “the highest of hopes”, but those were the highest of hopes for people who haven’t been following the biology closely (which includes many investors as well). The data were already clear that these drugs work best in specific patients, not in the broad population, and Bristol-Myers Squibb’s attempts to work around that are not coming through for them.
All this is of little consequence to someone who’s lost someone close to them after such a drug has done nothing to help, though. I understand that – I am, in fact, for some years now the only one left standing out of my own birth family, so I understand it pretty well. I can see how Mr. Jablow is offended and distressed by the ads for Opdivo, and for my part I would rather that they mention getting tested for PD-1 L1, or at least say something like “for some patients” rather than giving an impression that this is going to help everyone. (But to be fair in that direction, in combination therapy with other agents, adding Keytruda, Opdivo or similar agents may well extend the lives of patients in the lower-expressing categories as well; we don’t really know yet). At the same time, though, there are people who are indeed going to be helped by these drugs, helped a great deal, and a great deal more than Mr. Jablow’s op-ed would suggest. I’m sorry that his wife wasn’t one of them.
As better therapies come along (and they’re coming along faster than usual these days), this problem is going to occur more often. It’s going to be increasingly painful to lose people to cancer when there are more treatments and better treatments than in years past. Immuno-oncology, in its various forms, has pulled some people practically out of the grave by current treatment standards, and we’re going to see more of that in the years to come. But we’re also going to see people who aren’t helped by it, not yet, and losing them will be harder than ever. I have no good advice for those affected in this way, and no consolation for them. We’re trying.