Two steps forward, one step back: an opinionated take on NEJM highlights for January 2018

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Playing chess against cancer

Tumors are not intelligent, but, because they have escaped mutational control, they constantly probe for mutations that will allow them to escape chemotherapeutic suppression. The epidermal growth factor receptor (EGFR) is a frequent driver of malignancy in the lung and as such, a target for EGFR inhibitors such as erlotinib (Tarceva, Roche) or gefitinib (Iressa, Astra Zeneca); unfortunately, tumors initially responsive to these agents quickly develop mutations which make them resistant. Osimertinib (Tagrisso, Astra Zeneca) was designed to overcome the most common resistance mutations and has been approved as rescue therapy for cancers that progress under treatment with traditional EGFR inhibitors. Now it has been tested as first line therapy in a large study that showed clear advantage (9 additional months till disease progression). This approach to counter in advance the most likely tumor escape mechanisms is gaining traction, e.g. in the ALK pathway with the advent alcetinib (Alecensa, Roche) which covers mutations that conferred resistance to the previous agent in that category, crizotinib (Xalkori, Pfizer). As in chess, it pays to anticipate and block your opponent’s moves.  Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer; Osimertinib as First-Line Treatment in EGFR-Mutated Non–Small-Cell Lung Cancer (subscriber access)

 

The long march to address Alzheimer’s disease shall continue

A favorite theory for the repeated failures to validate disease modifying therapies for Alzheimer’s is that they are tested in populations too advanced in the disease; this has led to studies in patient populations in ever earlier stages. Sadly, this has not worked, as exemplified with the latest failure of anti-amyloid agent solanezumab which was announced a few months ago, but, for which, the details are only coming out now in the journal. Coincidentally, last week, a trial of pioglitazone (Actos, Takeda) in an even earlier population was stopped due to a futility analysis. Two key takeaways: first, amyloid as a target is probably on its last legs; there is likely only 1-2 additional variant approaches that are legitimate shots on goals such as aducanumab (Biogen) before it will be time to throw in the towel and move on (to tau?). Second this illustrates how confused our understanding of the underlying causes of Alzheimer’s remains, and how that makes R&D so risky in this space.  Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease; Amyloid-Beta Solubility in the Treatment of Alzheimer’s Disease (subscriber access)

 

An unusual drug advertisement in the journal

On the prime real-estate of the back-cover of the Jan 18 issue, one finds an ad for Invokana (canagliflozin, J&J), an SGLT2 inhibitor which is a new but now crowded class of anti-diabetic agents. Interestingly, the top message of the ad is not about great effectiveness or favorable side-effect profile:  it is that Invokana has preferred status with CVS Caremark. This is the first time I see that in an ad targeting physicians; perhaps it is a sign that finally, docs are thinking more about their patients’ wallets.

 

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.