Mark J. Ratain, MD

In 1962, President John F. Kennedy stood in Houston and challenged the nation to undertake bold and drastic technological advancement to achieve the goal of reaching the moon. The speech he gave that day was considered the original moonshot address.

The release of FDA’s draft guidance, “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases,” has been greatly anticipated since June 2021, when FDA announced in its accelerated approval of the KRASG12C inhibitor sotorasib that it would require a randomized, controlled trial comparing the efficacy of the labeled dose (960 mg once daily) to a 75% lower dose (240 mg once daily) as a condition of full regulatory approval (The Cancer Letter, June 11, 2021; April 29, 2022).

On May 28, 2021, the FDA granted an accelerated approval for sotorasib (which had previously received Breakthrough designation) for previously treated KRAS G12C non-small cell lung cancer (NSCLC) at a dose of 960 mg daily.

“We are going to start making this a requirement”, stated Richard Pazdur, MD during STAT’s ASCO Recap on June 9, 2021.

The global pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to expectations of global deaths numbering in the hundreds of thousands. Promising therapeutic strategies have emerged slower than society would prefer. COVID-related deaths in the United States exceed 86,000 as of this writing, with projections as high as 134,000.

The ever-rising cost of oncology drugs is doing damage to cancer care on many levels.

Historically, oncology drug development has evolved on what may seem to be a different planet, at least relative to mainstream clinical pharmacology.

Ibrutinib is a selective and irreversible inhibitor of Bruton's tyrosine kinase (BTK) that entered phase 1 clinical trials in 2009 based on preclinical efficacy in models of B-cell malignancy and autoimmune disease.[1, 2] The initial phase 1 trial showed clear efficacy in a number of lymphoid malignancies at doses as low as 1.25 mg/kg/d. Furthermore, full receptor occupancy was demonstrated at 2.5 mg/kg/d. Despite these pharmacological and early clinical findings, development of ibrutinib continued at doses of 420 mg qd and 560 mg qd, levels 3-4 fold higher than suggested by the pharmacological data. In addition, the absorption of ibrutinib is enhanced by administration of food, which may explain why even the lowest dose showed efficacy in some patients.