This is unpleasant: a paper published in Clinical Cancer Research described a pattern of “hyperprogression” identified in patients treated with PD-1/PD-L1 inhibitors in clinical trials at Gustave Roussy. The investigators compared tumor growth rate (TGR) prior to treatment with PD-1/PD-L1 agents with the TGR after, defining hyperprogression as greater than or equal to a two-fold increase of the TGR between the reference and post-treatment periods (and here I thought the worst thing that could happen was toxic epidermal necrolysis; see Google Images for more on that one). In the evaluable population of 131 patients, 9% met the definition of hyper-progressive disease, which was associated with older age and shorter OS.
While time to progression generally decreases with lines of treatment, a 2x+ increase in rate of growth seems particularly dramatic, and it’s another blemish on what was considered for a while a unicorn of cancer therapy.
Hyper-PD aside, checkpoint inhibitors are intimidating because the side effects are so unpredictable. When you give a patient chemo, everyone reacts the same. Bone marrow suppression, nausea, whatever. In the absence of the rare allergy, no one dies from chemo. But checkpoint inhibitors can trigger all sorts of inflammatory reactions, particularly if they’re working, and the immune system can attack any organ system. The NYT wrote last week about the risk of heart damage from the drugs. Colitis and skin and liver toxicities are pretty common. And while the standard treatment for these inflammatory reactions are steroids and dose reductions, sometimes the steroids don’t work, and patients can die. There’s no way to tell who will have these reactions.
Naturally, systemic inflammatory responses are associated with efficacy. There was a poster presented as ASCO this year that found similar OS among patients on nivo/ipi combo therapy who discontinued treatment due to toxicity as patients who stayed on therapy. This should provide a bit of comfort that all that really matters is triggering the immune response, not the duration of treatment or total dose. Unlike chemo, where there’s a fear that reducing dose as a result of toxicity will result in an attendant decline in efficacy, there’s little risk of that with checkpoint inhibitors.
It’s not just bad first-line data (the design of that study itself represented a more optimistic time for PD-L1 agents) and newly-observed, unnerving progression patterns and toxicities; the blush has been off the checkpoint inhibitor rose for a while. We just don’t know how to prevent hyper-reactions, and we don’t have better therapy options, to the point that the risks actually matter. Of course you treat with a PD-1/PD-L1. Who are we kidding? We’re talking about melanoma and lung. There’s no comparable alternative, nor is there an “easy” version of a checkpoint inhibitor (with chemo, you can always dial back to Xeloda or something). The Gustave Roussy paper concludes that their hyperprogression observation “raises potentially some concerns about treating elderly patients (>65) with anti-PD-1/PD-L1 monotherapy”. Helpful, especially considering that the average age at diagnosis of lung cancer, where nivo and pembro are on-label and have demonstrated efficacy, is 70.