High Risk for Interactions With New Oral Anticancer Agents

Megan Brooks

October 27, 2016

Oncologists need to be more aware of drug-drug interactions (DDIs) with newer oral antineoplastic agents, say the authors of an article published online October 13 in JAMA Oncology.

This new era of personalized cancer therapy has brought a "welcome surge" in the number of approved oral antineoplastic agents. "However, this paradigmatic change requires prescribers to be much more knowledgeable about drug absorption, metabolism, and transport as the potential for DDIs is high," write Mark Ratain, MD, of the Department of Medicine and the Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Illinois, and coauthor Sandeep Parsad, PharmD, also of the University of Chicago.

PPIs Interact With Capecitabine

A case in point: a companion article in JAMA Oncology reports that proton pump inhibitors (PPIs) that suppress gastric acid may impair the activity of the oral chemotherapeutic agent capecitabine (Xeloda, Roche).

In a secondary analysis of the phase 3 TRIO-013/LOGIC trial, the researchers found an association between poorer outcomes from capecitabine therapy with concomitant PPI use, suggesting that a potentially harmful drug-drug interaction may exist.

"I think these results are very concerning for concurrently prescribing PPIs and capecitabine," study author Michael Sawyer, MD, medical oncologist/clinical pharmacologist, Cross Cancer Institute, Edmonton, Alberta, Canada, told Medscape Medical News. "Medical oncologists should avoid prescribing PPIs with capecitabine," he said.

Medical oncologists should avoid prescribing PPIs with capecitabine. Dr Michael Sawyer

The interaction was found in a secondary analysis of the TRIO-013/LOGiC trial, which compared capecitabine and oxaliplatin (Eloxatin, Sanofi) with or without lapatinib (Tykerb, Novartis) in 545 patients with ERBB2/HER2-positive metastatic gastroesophageal cancer. In this secondary analysis, patients were divided on the basis of PPI use, and outcomes were assessed. Of the 545 patients, 229 received PPIs (42%), including 110 (40%) in the lapatinib arm and 119 (43%) in the control arm.

In the control arm, PPI use had a significant negative effect on PFS, overall survival, and disease control rate.

Outcome PPI No PPI Hazard Ratio (95% CI)
PFS 4.2 months 5.7 months 1.55 (1.29 - 1.81) P < .001
OS 9.2 months 11.3 months 1.34 (1.06 - 1.62) P = .04
Disease control 72% 83% P = .02

CI, confidence interval; PFS, progression-free survival; OS, overall survival


In the lapatinib arm, in contrast, there was no significant difference with or without PPI therapy in PFS (5.7 vs 6.8 months; HR 1.08; 95% CI, 0.82 - 1.34; P = .54) or median OS (9.6 vs 13.6 months; HR, 1.26; 95% CI, 0.97 - 1.55; P = .10).

However, multivariate analysis in the lapatinib arm did show a significant negative effect of PPI use on OS (HR, 1.38; 95% CI, 1.06 - 1.66; P = .03) but not PFS (HR, 1.14; P = .33).

Dr Sawyer and colleagues emphasize that a direct link between the use of PPIs and a potential reduction in the absorption of capecitabine cannot be made on the basis of this analysis because it did not examine pharmacokinetics and circulating drug levels.

Nonetheless, Dr Sawyer told Medscape Medical News, "When we saw these results, we went back and did a chart review of early-stage adjuvant colorectal cancer patients treated at our center with single-agent capecitabine and whether or not they were taking PPIs. We found similarly concerning results.

"In univariate analysis," he explained, "patients who took PPIs concurrently had a decreased recurrence-free survival compared to patients who did not (74% vs 83%; P = .03). In multivariate analysis, there was a strong trend for decreased recurrence-free survival in patients who took PPIs compared to patients who did not (HR, 1.65; P = .09)." These results were published in September in Clinical Colorectal Cancer.

"At our center, we have not prescribed PPIs with capecitabine when treating colon, rectal, esophageal, gastric, or breast cancer for the last year and a half since we have completed these studies," Dr Sawyer told Medscape Medical News.

However, Dr Ratain cautions that, on the basis of this secondary analysis of TRIO-013/LOGiC, no firm conclusions can be drawn at this time and says more study is needed before any changes in current clinical practice are recommended.

"I think there are very significant flaws in the methods, as well as some inconsistencies in the data. I would strenuously object to a label change, but do agree that a simple pharmacokinetic study is warranted, which I do not think will show a clinically relevant interaction," Dr Ratain told Medscape Medical News.

It has also recently been shown that coadministration of a PPI or a histamine receptor antagonist can lead to poorer efficacy of erlotinib (Tarceva, Genentech) in advanced and/or metastatic non–small cell lung cancer (Clin Lung Cancer. 2014;16:33-39) and sunitinib (Sutent, Pfizer Inc) in renal cell cancer (J Oncol Pharm Pract. 2014;21:194-200).

Onus on Oncologist

Most oral antineoplastic drugs approved since 2010 are associated with multiple, clinically significant DDIs, Dr Ratain and Dr Parsad note in their article. Concurrent medications prescribed in the primary care setting for preexisting chronic diseases common in the aging oncology population increase the risk.

"Chronic medications may be prescribed by the patient's primary care physician who may be unaffiliated with the oncologist. It is the responsibility of the oncologist to communicate with these additional clinicians to understand the patient's full medication list. Furthermore, the oncologist (and/or other delegate) should discuss the threat of DDIs with the patient, with particular attention to potential perpetrators, including OTC agents, cannabinoids, and nutraceuticals. Patients should be informed that no new medications should be started for nonemergent indications without discussion with the oncologist," Dr Ratain and Dr Parsad advise.

The onus remains on the oncologist to be aware of potential DDIs, they say.

Healthcare systems can help by applying the same level of detailed institutional policies currently applied to weight-based anticancer drug calculations to the amelioration and prevention of DDIs that may result in "dramatic effects on drug exposure. Ideally, this would include automated checking of potential DDIs (via the electronic medical record) and/or careful medication review by an experienced pharmacist," Dr Ratain and Dr Parsad suggest.

Dr Ratain is a cofounder of and has equity in PrescriptIQ and has received personal fees from multiple drug companies.

JAMA Oncol. Published online October 13, 2016. Article 1 abstract, Article 2 abstract

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