Drug-drug interactions with oncolytics (in particular PPIs and TKIs)

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1 Drug-drug interactions with oncolytics (in particular PPIs and TKIs) Prof. Ron Mathijssen, MD PhD Medical Oncologist/ Clinical Pharmacologist Erasmus MC Cancer Institute Rotterdam ICPAD Workshop November 9, 2018

2 Disclosures Unrestricted Grants Astellas Bayer Boehringer Ingelheim Cristal Therapeutics GSK Novartis Pfizer ProStrakan (Kyowa Kirin) Roche Sanofi Servier

3 Factors influencing drug exposure Nat Rev Clin Oncol 2014

4 Drug-drug interactions 20-55% of cancer patients in North America and Europe routinely use gastric acid-suppressive (GAS) drugs Br J Cancer 2013 Mol Pharm 2013

5 Gastric Acid Suppressive (GAS) drugs Hypothesis: ph (2 5) with acid reducing drugs. Consequence: absorption/solubility pka: acid dissociation constant Nat Rev Clin Oncol 2014 Lancet Oncol 2014

6 A ph-dependent DDI is not expected for every TKI Ther Adv Med Oncol in press

7 Exposure-response relationship for TKIs Axitinib mrcc AUC OS/PFS Erlotinib NSCLC C trough OR/OS/PFS Gefitinib NSCLC C trough OS/PFS Imatinib GIST C trough TTP Pazopanib mrcc C trough PFS/RR/PR Sorafenib HCC C max OS Sunitinib mrcc AUC TTP/OS Sunitinib GIST AUC TTP/OS Drug Discov Today 2015

8 Effect of GAS drugs on survival Soft tissue sarcoma treated with pazopanib CTOS 2016/ paper submitted

9 Effects of GAS drugs on survival mrcc treated with pazopanib: Retrospective cohort study PFS 9.0 vs 11.0 months for PPI/H2RA users vs non-users OS 28.0 vs 30.1 months for PPI/H2RA users vs non-users Conclusion: Concomitant PPI or H2RA usage was not shown to be associated with a significant reduction in PFS or OS Oncologist 2018

10 Pooled analysis mrcc treated with sunitinib, axitinib, and sorafenib Clin Genitourin Cancer 2017

11 Impact of PPIs on sunitinib PK and activity in GIST patients Abstract #11538: 32% used PPIs during sunitinib treatment. Sunitinib clearance increased by a factor 1.55 during PPI use. Co-variate modeling showed that PPI intake decreased the fraction of dose absorbed by 40%. Median PFS was 3.0 months in PPI users, versus 7.7 months in non- PPI users. ASCO 2018

12 Proof of principle: Effects of an acidic beverage (i.e. cola) cola

13 Erlotinib with water or cola? % OR J Clin Oncol 2016

14 Erlotinib with water or cola? + + 9% OR J Clin Oncol 2016

15 Wide inter-patient variability in AUC and C max. Gastric emptying rates, volume of cola, and potential PPI induced inhibition of drug transporters may affect erlotinib absorption. Caffeine (in cola) may potentially interact with erlotinib PK (caffeine is a CYP1A2 substrate). Effects on other TKIs (e.g. gefitinib) could be expected. Effects of other acidic beverages (e.g. orange juice) could be expected.

16 Clinical application?

17 Other solutions? Stop GAS therapy? Or choose the most optimal timepoint to take the TKI and the PPI: Clin Pharmacokinet 2017

18 REGORA study (#P16 Femke de Man) Regorafenib PPI DDI study in GIST and CRC patients. ESMO 2018/ ICPAD 2018

19 Results A similar study for afatinib is ongoing: the BIO-GIO study (NTR6652) ESMO 2018/ ICPAD 2018

20 Other oral anticancer agents Capecitabine (oral 5-FU prodrug): will PPIs also affect outcome? Is there also ph-dependent absorption?

21 Effect of PPIs on survival Gastroesophageal cancer treated with capecitabine/oxaliplatin PFS OS Patients not treated with PPIs were found to have an improved median PFS (5.7 vs 4.2 months; HR, 1.55; 95% CI, ; P <.001 and median OS (11.3 vs 9.2 months; 95% CI, ; HR, 1.34; P =.04) compared with PPI-treated patients. JAMA Oncol 2017

22 Pittfalls study Retrospective analysis: Time of PPI intake was unknown PPI dose was unknown Type of PPI was unknown Use of other co-medication was unknown JAMA Oncol 2018

23 Effects of PPIs on RFS in early stage CRC treated with capecitabine Clin Colorectal Cancer 2016

24 Impact of PPIs on capecitabine/oxaliplatin as adjuvant treatment for stage II/III CRC Abstract #3614: Canadian study: 23.4% used a PPI concurrently. CapOx-treated PPI patients were twice as likely to experience cancer recurrence or death as non PPI patients (HR 2.03; p = 0.03). Conclusion: PPI negatively impact RFS in early stage CapOx-treated CRC patients. ASCO 2018

25 End of study CoCa study (ongoing; trial registry #NTR7027) Most important question: is the negative effect of PPI use in capecitabine users caused by a ph effect? Capecitabine ee Esomeprazole Capecitabine Esomeprazole Capecitabine and cola Randomisation Phase A Phase B Phase And Afatinib C (cycle 1/ day 1-14) (cycle 2/ day 1-14) (cycle 3/ day 1-14) 17 patients - Phase A-B-C BN 17 patients -Phase C-B-A PK= pharmacokinetic sampling day Phase A: Capecitabine alone Phase B: Capecitabine with esomeprazole 40 mg q.d. for 5 days Phase C: Capecitabine with esomeprazole 40 mg q.d. for 5 days and Cola 250 ml All patients receive : Capecitabine from day 1-14 during the whole treatment period C

26 Conclusions For several TKIs interactions with GAS are clinically relevant: PFS/OS This interaction is --most likely-- caused by reduced ph dependent absorption. An acidic beverage may be a simple option to (partly) solve this ph-related problem. Another solution might be to make use of the time window during which the PPI has not (yet) an effect on gastric ph. Also for capecitabine an interaction with PPIs seems to be clinically relevant. Reason is currently unknown.

27 Thank you! Workgroup Personalized Medicine