Gastric Acid Suppression & Oral Cancer Therapy Should Not Mix

Alexander M. Castellino, PhD

February 19, 2019

As many as 50% of patients receiving cancer therapy take gastric acid suppressants (GAS), such as proton pump inhibitors, for medical problems such as gastric ulcers and acid reflux, but a new analysis suggests that these drugs may interact with orally administered cancer drugs and compromise their efficacy.

The report showed that clinical outcomes with the oral cancer agent pazopanib (Votrient, Novartis) in the treatment of advanced soft tissue sarcoma were significantly worse for patients who were concomitantly taking GAS.

The finding comes from a retrospective analysis of data from the phase 2 EORTC 62043 study and the phase 3 EORTC 62072 (PALETTE) study. Pazopanib was approved by the US Food and Drug Administration (FDA) in 2012 for use in the treatment of soft tissue sarcoma on the basis of the combined results of the EORTC 62072 (PALETTE).

The new analysis shows that participants in the two ​studies who were taking GAS as well as pazopanib had a 81% increased risk for death and a 49% increased risk for disease progression compared with patients who were taking pazopanib alone.

The findings were published online February 14 in Clinical Cancer Research.

"The intake of GAS decreased the outcomes of pazopanib for patients in these studies in a clinically meaningful manner and may have biased the results of the original study," lead author Olivier Mir, MD, of the Gustave Roussy Cancer Campus in Paris, France, told Medscape Medical News.

"Oncologists and pharmacists should pay close attention to patients' concurrent medications, as they may have a significant impact on cancer treatment outcomes," Mir said in a statement.

"I think that our results are practice-changing, and I would discourage oncologists against prescribing gastric acid suppressants when patients are treated with pazopanib, unless it is the only option for the patient," he added.

Approached for comment, sarcoma expert George D. Demetri, MD, Quick Family Chair in Medical Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, was not convinced.

This was an unplanned retrospective analysis of collected data from a large clinical trial, and these data are not likely to change clinical practice, Demetri told Medscape Medical News. The impact and statistics are based on a subset of the overall study population, he pointed out.

"Nonetheless, the data are interesting and intriguing and make mechanistic sense, since pazopanib is best absorbed in a relatively acidic environment from the stomach and upper GI [gastrointestinal] tract," he said.

Demetri added: "The impact of pazopanib in sarcoma management is rather small in most cases, but given the paucity of available effective options, it was nonetheless judged sufficiently effective to gain FDA and EMA [the European Medicines Agency] regulatory approval for chemotherapy-resistant soft tissue sarcomas other than GIST [gastrointestinal stromal tumor] or liposarcomas," Demetri said.

Demetri noted that he was a clinical investigator in the PALETTE study but was not involved with this retrospective analysis.

Study Details

This analysis was prompted by published data that suggested that low plasma concentrations of pazopanib (<20.5 μg/mL) were associated with inferior outcomes for patients with renal cell carcinoma or soft tissue sarcoma.

For this analysis, Mir and colleagues included 118 patients from EORTC 62043 and 215 from PALETTE, as well as 110 patients who were in the placebo arm of the PALETTE study.

Approximately 35% of patients were receiving GAS therapy while undergoing treatment with pazopanib. GAS therapy included proton pump inhibitors and/or H2 blockers.

"The percentage of pazopanib administration period during which there was an overlapping administration of GAS therapy was used to classify patients between users and nonusers of GAS agents," write the researchers. The threshold for this was set at ≥80%.

For the combined cohort, 64.9% of patients received no concomitant therapy while taking pazopanib, vs 68.2% for patients taking placebo; 17.7% received concomitant therapy, vs 21.8% for placebo.

Median progression-free survival was almost double for patients who did not use GAS — 4.6 months vs 2.8 months for patients who used GAS while taking pazopanib (P = .0008).

Median overall survival was also significantly longer for patients who did not use GAS — 12.6 months vs 8.0 months for patients who received concomitant therapy (P < .0001).

Lessons for Clinical Practice

Mir explained to Medscape Medical News that interaction with drugs used to suppress gastric acid is an underestimated problem, and most physicians typically do not take the interaction into account.

"Patients often utilize GAS therapy for abdominal pain, which is not always related to stomach acidity," Mir told Medscape Medical News. "The majority of patients taking GAS drugs could utilize a different therapy to aid in their abdominal discomfort," he added.

He also pointed out that because GAS therapy is available over the counter (OTC), patients may often take these without a physician's recommendation, or even without their knowledge. "It is important for patients to inform their oncologists of all the medications that they are taking during cancer treatment (including those available OTC) so that potential drug-drug interactions can be identified and avoided," Mir said.

"If a patient does not need the anti-acid therapy, it is a compelling reason to avoid it," Demetri agreed. Pharmacology is very important and is often overlooked when considering the impact of any therapy for cancer, particularly oral agents, Demetri explained. "This is especially true for orally available tyrosine kinase inhibitors [TKIs], where interindividual drug levels can vary even by an order of magnitude, due to differences in drug bioavailability, absorption, metabolism, and other factors," he said.

Mir provided a perspective that went well beyond sarcoma. "While this analysis was in patients with soft tissue sarcoma, pazopanib is also indicated for renal cell carcinoma," he said.

In addition, the pH-dependent solubility of oral TKIs used in the treatment of several types of cancers is decreased (van Leeuwen et al. Clin Pharmacokinetic. 2017;56:683).

These TKIs include cabozantinib (Cabometyx, Exelixis), dabrafenib (Tafinlar, Novartis), dasatinib (Sprycel, Bristol-Myers Squibb), erlotinib (Tarceva, Genentech), gefitinib (Iressa, AstraZeneca), ibrutinib (Imbruvica, Pharmacyclics), and lapatinib (Tykerb, Novartis).

The product information available for these agents indicates that drug-drug interactions with GAS are currently listed only for dasatinib, erlotinib, and lapatinib, and there was limited guidance on coadministration of these drugs.

Mir offered some practical options for patients who require taking both a TKI and a GAS. One would be to increase the dose of the TKI when taken with GAS. However, the FDA does not allow doses to be increased beyond the indicated dose, he pointed out.

One way around this may be to time meals carefully, he suggested. "When these drugs are required to be taken in a fasting state, taking it in the fed state is an option, since there is an increase in drug concentration by about 30%," Mir said. He suggested that the drugs be given with a meal and that plasma levels be checked. If the drug concentration is suboptimal, the dose should be split in two, and the two doses should be administered 12 hours apart. Absorption is higher when the dose is split, Mir explained.

However, Demetri pointed out that it is a matter of what is in the best overall medical interests of the individual patient. As with any drug and drug combinations, one must be aware of pharmacology and drug-drug interactions, and the risks must be balanced against potential benefits, Demetri explained. "The differences in outcomes are a matter of weeks or at most 2 months, so this is not a major change," he said.

"Medical care is complex, and this is one example of individualized decision making based on a rational use of pharmacology and drug therapy," Demetri said.

Mir suggested that it would be useful to have global recommendations for taking oral cancer drugs with GAS. In addition, he advocated discussing the issue with media and with scientific societies, as well as at meetings, to disseminate the information regarding possible drug-drug interactions that could diminish the efficacy of oral cancer drugs.

"Keeping patients and patient advocacy groups informed will also ensure that patients are better informed," Mir said.

Mir has ownership interests, including patents, with Amplitude Surgical and Transgene, has received speakers bureau honoraria from Eli Lilly, Roche, Pfizer, and Servier, and is a consultant/advisory board member for Amgen, Bayer, Bristol-Myers Squibb, Eli Lilly, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, and Vifor Pharma. Demetri has received research support from and/or consults with Bayer, Novartis, Pfizer, EMD-Serono, Sanofi Oncology, Janssen Oncology, Roche, Loxo Oncology, AbbVie, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, WIRB Copernicus Group, ZioPharm, Polaris Pharmaceuticals, M J Hennessey/OncLive, Medscape CME, Adaptimmune, GlaxoSmithKline, Blueprint Medicines, Merrimack Pharmaceuticals, GI Therapeutics, Caris Life Sciences, Champion Oncology, and Bessor Pharmaceutics. He is also on the board of directors of some of the companies.

Clin Cancer Res. Published online February 14, 2019. Full text

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