Empowering the FDA to Require Dose Optimization of All New Oncology Drugs

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The vast majority of drugs used outside of oncology are evaluated in randomized dose-ranging trials to optimize the therapeutic index prior to the pivotal phase III trial. No one would think of dosing a statin or an antibiotic at the highest dose patients could tolerate, especially if that dose resulted in chronic toxicities. In fact, this paradigm is well detailed in global regulatory guidance documents (eg, the U.S. Food and Drug Administration [FDA] Guidance Document entitled “E4 Dose-Response Information to Support Drug Registration1).

Mark J. Ratain, MD, FASCO

Mark J. Ratain, MD, FASCO

Allen S. Lichter, MD, FASCO

Allen S. Lichter, MD, FASCO

However, oncology drugs have historically been given a pass because of the belief that “more is better,” dating back to the genesis of chemotherapy. This belief, although the foundation for the now discarded use of high-dose chemotherapy for breast cancer, is certainly not valid for modern targeted drugs, such as kinase inhibitors and monoclonal antibodies. One should be seeking the optimal dose, the lowest dose that produces the maximum biologic and clinical effect, since once the target is fully inhibited (or the receptor saturated), there is no reason to give a higher dose. Thus, dosing to toxicity is illogical and inconsistent with the principles of clinical pharmacology widely accepted outside of oncology.

We have previously pointed out the multiple opportunities in oncology to reduce prescribing costs—and potentially adverse events as well—through development and implementation of off-label dosing regimens that utilize pharmacologically justified dosing, a concept we have called interventional pharmacoeconomics.2,3 However, there is also an opportunity for the FDA to require that sponsors optimize dosing upfront, either before or soon after approval (ie, as a postmarketing requirement). Although the FDA has done so for several drugs, the vast majority of nonbiologic oncology drugs are developed and approved at their maximally tolerated dose, leading to off-target adverse events that may be fatal (eg, ibrutinib).4,5

Latest Example: Sotorasib in NSCLC

The latest example is sotorasib (previously known as AMG-510), a breakthrough KRAS G12C inhibitor, for which Amgen recently filed a new drug application (NDA) “for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC), as determined by an FDA-approved test, following at least one prior systemic therapy.” 6 This is indeed an exciting drug, as is a similar drug being developed by Mirati Therapeutics, adagrasib.7

Both drugs were developed as selective irreversible inhibitors of KRAS G12C–mutated tumors, as the drugs bind selectively to the cysteine residue that is present in the mutated tumor alone and has no effect on wild-type KRAS (or on other mutated KRAS proteins).8,9 In other words, the drugs’ target is a mutant protein that does not exist in any normal tissue.

Despite the exquisite drug discovery effort and compelling preclinical pharmacology, Amgen pursued an historical phase I design aimed at delivering the maximally tolerated dose to patients with KRAS G12C–mutant tumors (primarily NSCLC and colorectal cancer).10 In fact, the protocol utilized a Bayesian logistic regression model aiming to elicit dose-limiting toxicity in 20% to 33% of patients, despite the fact that the drug may be effective without any toxicity whatsoever, given its mutant target; it presciently stated that the starting dose of 180 mg “is expected to be safe as well as potentially efficacious.”

The phase I trial enrolled 129 patients, 85 of whom were treated at 960 mg daily and 6 of whom were treated at the 180-mg dose. At the 180-mg dose, there were three patients with NSCLC, one of whom had a response (with disease progression after 14 months); the other two patients each had less than a partial response but a time to disease progression of 6 to 8 months. The overall response rate for patients with NSCLC was 32%, and there was no evidence of a dose-response relationship.

Furthermore, the Amgen phase I trial mandated dosing under fasting conditions, without any apparent justification, and demonstrated high variability, a finding commonly observed for drugs whose absorption is increased with food.11 Thus, there is no evidence that the dosing regimen used in the Amgen pivotal trial (960 mg daily fasting) is optimal. In fact, it is likely that a much lower dose of the drug administered with food may have a superior therapeutic index.

“One should be seeking the optimal dose, the lowest dose that produces the maximum biologic and clinical effect….”
— Mark J. Ratain, MD, FASCO, and Allen S. Lichter, MD, FASCO

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Call for Evidence of Dose Optimization

Although the FDA undoubtedly has much more data than are currently publicly available, we urge the FDA to require Amgen to optimize the dose as a condition of the likely accelerated approval. We also urge the FDA to require all sponsors submitting an NDA to provide evidence of dose optimization in accordance with its own Guidance document,1 with the exception of breakthrough drugs, for which optimizing the dosing regimen after approval (as a postmarketing requirement) would be permitted.

Once a targeted oncology drug is labeled and approved by the FDA at an excessive dose, it is expensive and time-consuming to go back and redo a dose-optimization strategy. It is far more sensible to do this work upfront or, alternatively, for the FDA to negotiate an appropriate bridging strategy that would permit rapid approval while also achieving the goal of minimizing adverse events. It is high time for the FDA to discard the obsolete maximally tolerated dose concept for modern targeted oncology drugs. 

Dr. Ratain is Leon O. Jacobson Professor of Medicine and Director of the Center for Personalized Therapeutics, and Associate Director for Clinical Sciences at the Comprehensive Cancer Center at the University of Chicago Medicine. Dr. Lichter is Chair of the Value in Cancer Care Consortium, Ann Arbor, Michigan.

DISCLOSURE: Dr. Ratain has provided expert testimony and patent litigation consulting on behalf of multiple generic pharmaceutical companies; has served as a consultant to Aptevo Therapeutics, Arvinas, Ayala Pharmaceuticals, Genentech, Oncovalent Therapeutics, and Pneuma Respiratory; has been a principal investigator for AbbVie, Genentech/Roche, Xencor, Corvus Pharmaceuticals, Bristol Myers Squibb, Boston Biomedical, and Incyte; has received meeting support from BeiGene; has received royalties from The University of Chicago related to UGT1A1 genotyping for irinotecan; and is co-inventor on a provisional patent application for low-dose tocilizumab to treat viral pneumonitis (including COVID-19). In addition, Dr. Ratain is a Director and Treasurer of the Value in Cancer Care Consortium. Dr. Lichter has a leadership role in LifeLink and Cellworks; is a consultant/advisor for Ascentage Pharma and L-Nutra; and has received reimbursement for travel, accommodations, and expenses from Cellworks. He is also Chair of the Board of Directors at the Value in Cancer Care Consortium.


1. U.S. Food and Drug Administration: E4 Dose-Response Information to Support Drug Registration. July 1996. Available at­response-information-support-drug-registration. Accessed January 5, 2021.

2. Ratain MJ, Goldstein DA, Lichter AS: Interventional pharmacoeconomics—a new discipline for a cost-constrained environment. JAMA Oncol 5:1097-1098, 2019.

3. Serritella AV, Strohbehn GW, Goldstein DA, et al: Interventional pharmacoeconomics. Clin Pharmacol Ther 108:487-493, 2020.

4. Salem JE, Manouchehri A, Bretagne M, et al: Cardiovascular toxicities associated with ibrutinib. J Am Coll Cardiol 74:1667-1678, 2019.

5. Ratain MJ, Moslehi JJ, Lichter AS: Ibrutinib’s cardiotoxicity—an opportunity for postmarketing regulation. JAMA Oncol. November 25, 2020 (early release online).

6. Amgen Submits Sotorasib New Drug Application to U.S. FDA for Advanced or Metastatic Non-Small Cell Lung Cancer With KRAS G12C Mutation. December 16, 2020. Available at Accessed January 5, 2021.

7. Jänne PA, Rybkin II, Spira AI, et al: KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer harboring KRAS G12C mutation. Eur J Cancer 138:S1-S2, 2020.

8. Lanman BA, Allen JR, Allen JG, et al: Discovery of a covalent inhibitor of KRAS G12C (AMG 510) for the treatment of solid tumors. J Med Chem 63:52-65, 2020.

9. Fell JB, Fischer JP, Baer BR, et al: Identification of the clinical development candidate MRTX849, a covalent KRAS G12C inhibitor for the treatment of cancer. J Med Chem 63:6679-6693, 2020.

10. Hong DS, Fakih MG, Strickler JH, et al: KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.

11. Kang SP, Ratain MJ: Inconsistent labeling of food effect for oral agents across therapeutic areas. Clin Cancer Res 16:4446-4451, 2010.