Tilting the Balance of Dose Modification for Oral Anticancer Drugs?
Authors: Philippe L. Bedard, Lillian L. Siu
Journal: Journal of Clinical Oncology (2014)

Oral anticancer drugs account for more than one quarter of annual global oncology drug sales and nearly one half of new oncology drug approvals. In the article that accompanies this editorial, Prasad et al argue that unequal dose modification in comparative trials of oral anticancer drugs, due to the constraints of manufactured oral dosing formulations and unbalanced trial design, are a potential source of bias. Examples of inconsistent dose-modification criteria in trials where a new drug was compared against an existing standard are provided, such as the thresholds for dose reduction with elevated blood pressure in the randomized phase III AXIS (Axitinib Versus Sorafenib As Second-Line Treatment for Advanced Renal Cell Carcinoma) and TIVO-1 (Tivozanib Versus Sorafenib As Initial Targeted Therapy for Patients With Advanced Renal Cell Carcinoma) trials that respectively compared axitinib and tivozanib to sorafenib in metastatic renal cell cancer. The effects of such unequal dosing may be compounded in routine clinical practice, where a greater proportion of patients require large reductions from the approved dose of an oral anticancer drug because of poor tolerability or cumulative toxicity. However, the analysis of Prasad et al does not address the most clinically relevant question: do reductions from the recommended starting dose of oral anticancer drugs impact clinical outcome? It should be noted that Prasad et al did not perform a comprehensive systematic review of all oral anticancer agents, notwithstanding the challenges of obtaining information on dose modifications in published clinical trial reports. The examples that they cite are largely restricted to randomized trials of multitargeted vascular endothelial growth factor receptor inhibitors, such as sorafenib, sunitinib, and pazopanib, in metastatic renal cell cancer and hepatocellular carcinoma. They do not specify whether dose reductions with these multitargeted kinase inhibitors were instituted because of on-target or off-target adverse events. This point is relevant given that off-target effects of these less selective inhibitors may have a great influence on dose-modification decisions. It is unknown if reductions from the starting dose are important in enriched subpopulations with highly active therapies, such as tumors with oncogenic addiction to druggable driver mutations. In the phase III randomized BRIM3 (BRAF Inhibitor in Melanoma-3) trial in malignant BRAF V600 mutant melanoma, adverse events led to dose modification or treatment discontinuation in 38% of patients in the oral BRAF inhibitor vemurafenib arm compared with 16% in the intravenous dacarbazine chemotherapy arm. Despite this imbalance, response rate (48% v 5%) and overall survival (hazard ratio 0.37; 95% CI, 0.26 to 0.55) were superior in the vemurafenib arm. The approved starting dose of vemurafenib is 960 mg twice daily. The first (720 mg twice daily) and second (480 mg twice daily) dose level reductions for toxicity in the BRIM3 protocol were at least two-fold greater than the minimum dose (240 mg twice daily) at which responses were observed in the initial dose-escalation phase I trial of vemurafenib, demonstrating that these reduced dose levels were above the threshold of biologic activity for the drug in BRAF V600 mutant melanoma. For most oral anticancer agents, responses are observed infrequently during dose escalation to establish the maximum-tolerated dose (MTD). Relatively small numbers of patients are treated at each dose level. Limited evaluation of target engagement in tumor or surrogate normal tissue is performed during dose escalation. As a result, the MTD that is often selected for further studies may greatly exceed the minimum effective dose (MED) that is required to produce clinical benefit. For example, the MTD of the oral epidermal growth factor receptor (EGFR) inhibitor gefitinib was established at 700 to 800 mg daily in phase I studies. Randomized phase II trials showed comparable efficacy for 250 mg and 500 mg daily in advanced non–smallcell lung cancer (NSCLC), with improved tolerability observed with the 250 mg daily dose. The role of EGFR mutation as a predictive marker of benefit with oral EGFR inhibitor therapy was not known when the randomized phase III INTACT (Iressa NSCLC Trial Assessing Combination Treatment) 1 and INTACT 2 trials, conducted in all patients with chemo-naive NSCLC, failed to showed a benefit for chemotherapy combined with gefinitinib versus chemotherapy alone. The subsequent randomized phase III IPASS (Iressa Pan-Asia Study) trial showed a significant progression-free survival (PFS) benefit for gefinitib 250 mg daily over chemotherapy in patients with treatmentnaive NSCLC who had tumors with sensitizing exon 19 or 21 EGFR mutations, whereas those with wild-type EGFR had a significantly worse PFS with gefitinib 250 mg daily compared with chemotherapy. A similar PFS benefit of geftinib 250 mg daily over chemotherapy was observed in a smaller trial restricted to patients with EGFR mutant tumors. In the gefinitib arm, 46% of patients required dose reduction to 250 mg every other day (250 mg tablets cannot be divided), primarily because of diarrhea, cutaneous toxicity, and elevated liver enzymes. The PFS of the dose-reduced gefinitib group was similar to the standard dose gefinitib group (median, 11.8 v 9.9 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 15 MAY 2