Cancer and mutational complexity
Probably the biggest news in cancer treatment this year is the approval of sotorasib (Lumkras, Amgen) which received accelerated approval in lung cancer with mutated KRAS (G12C) and has potential for use in other cancers (see here). Mirati is hot on the trail with adagrasib, but unusually for a drug in the approval process, their paper in the NEJM is a deep dive into the mechanisms of resistance to KRAS G12C inhibition that lead to treatment failure. They present very detailed in vitro studies in which they systematically studied the effect of every possible additional single point mutation on KRAS G12C with exposure to their drug, and in addition, comprehensive genomic analysis of trial patients who developed resistance and whose tumor began to progress on adagrasib. The picture that emerges is both dauntingly complex and hopeful: complex because the mechanisms of resistance are highly heterogeneous ranging from alteration of the drug binding site to activation of alternative pathways, but also hopeful because many of those could potentially be addressed by judicious treatment choices. But to me the biggest takeaway is that we are quickly getting beyond the range of therapeutic pathways that can fit in a typical human head and decision support tools will increasingly be a key element of progress. Acquired Resistance to KRASG12C Inhibition in Cancer
Non-natural selection in humans
The standard procedure for IVF is collect and fertilize a dozen or more eggs, let embryos progress to multicellularity, and extract a cell from each for genetic testing. The initial goal of this process was to screen out embryos with a clear genetic defect, but once that is done, how do you decide which one to implant? As reported in a special article in the NEJM, companies are increasingly offering scores that purport to characterize likelihood of educational attainment, or long-term health status. At a primary level, it is unclear what the validity of those scores are, given a complex admixture of nurture and nature and lack of transparency on how they were established. But beyond that, it is easy to imagine how a departure from randomly driven evolution in humans will open up societal debates much earlier than expected. Whereas direct gene modification in humans is likely to remain rare for a while given the reaction to the He Jiankui affair, embryo selection is a natural extension of the IVF process, and while uncommon today, it has a lot of room to grow. Problems with Using Polygenic Scores to Select Embryos
Dealing with dementia
Dementia is horrible, but among the most distressing aspects is psychosis: it often makes the patient either terrified, or aggressive towards caretakers, or both. Standard antipsychotics are used with limited efficacy and a clear but poorly understood increase in mortality. Pimavanserin (Nuplazid, Acadia Pharmaceuticals) is a new type of antipsychotic that does not act on the dopamine systems and that was approved in psychosis related to Parkinson’s in 2016. Based on a randomized placebo-controlled trial with 392 patients with psychosis suffering from a broad range of dementias (majority were Alzheimer’s), it appears to have sustained efficacy in more than half the patients and the trial was stopped early for efficacy. Meanwhile, Acadia is in CRL limbo with the FDA for the broader dementia indication, but if/when it eventually comes through, they have an enormous blockbuster in their hands. Trial of Pimavanserin in Dementia-Related Psychosis
The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.