DISCUSSION

In vitro data suggested that capmatinib can inhibit transporters P-gp (Ki of 12.0 µM) and BCRP (Ki of 8.20 µM) (data on file). At the therapeutic dose of 400 mg twice daily, the estimated maximum luminal concentration in the gut was approximately 3880 µM (dose/250 mL), which was >300-fold of the Ki for P-gp and BCRP. Therefore, a clinical DDI study was considered necessary to confirm whether capmatinib is likely to inhibit intestinal P-gp and BCRP and potentially result in an increase in the absorption of P-gp and BCRP substrates. This study was thus conducted in patients with MET -dysregulated advanced solid tumors, and capmatinib was given as multiple doses until attaining steady state which allows for an assessment of the maximum inhibition effect of capmatinib on P-gp and BCRP in the relevant patient population.
The two selected probe drugs (digoxin and rosuvastatin) were administered simultaneously as a two-drug cocktail, as the cocktail approach offers advantages such as reduced study duration and increased efficiency [23] compared to the administration of individual probes in separate studies. Digoxin and rosuvastatin are established as sensitive probes to evaluate the potential impact of other drugs on P-gp and BCRP, and no interaction between these two probe drugs are expected [24].
Digoxin is rapidly absorbed following oral administration, with a peak serum concentrations occuring at 1 to 3 hours. Digoxin is mostly eliminated via urinary excretion as parent drug. The T1/2 in healthy subjects with normal renal function is 1.5-2 days [25, 26]. As [Imax,u]/Ki for renal P-gp is 0.04 compared to the ratio of >300 for intestinal P-gp, capmatinib was not expected to inhibit renal clearance of digoxin. Thus, this study would reflect the inhibition of intestinal P-gp by capmatinib. Rosuvastatin is eliminated mainly through an efflux-mediated process in the gut and in bile with minimum metabolism. The T1/2 is approximately 19 hours [27, 28]. Based on the half-lives, a total of 21-day washout period was implemented between the first and second dose of probe drugs to allow a complete elimination of probe drugs. A long pharmacokinetic sampling schedule up to 240 hours has ensured the capture of complete pharmacokinetic profiles for both probe drugs.
The study population consisted of 32 patients with MET-dysregulated advanced solid tumors, who had been treated with at least one prior line of treatment. The pharmacokinetics of digoxin and rosuvastatin, considered independently, were comparable to those reported in literature reports [25-30]. Co-administration of capmatinib and digoxin increased Cmax, AUClast and AUCinf by 74%, 63%, and 47%, respectively and co-administration of capmatinib and rosuvastatin increased the Cmax, AUClast and AUCinfby 204%, 103%, and 108%, respectively.
In vitro, capmatinib showed inhibition of hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 with Ki values of 5.1 and 5.2 µM, respectively (data on file). The DDI assessment resulted in R-values of 1.12 and 1.13, respectively, using calculated hepatic inlet concentration, which indicated a low risk of inhibition (R=1+ [(fu,p × Iin,max)/Ki]) [31]. In this study, the probe substrate rosuvastatin is a substrate for BCRP and OATP, so the result obtained reflected the worst-case scenario of the impact on rosuvastatin pharmacokinetics by capmatinib. However, based on R-value assessment for BCRP and OATP, the increase of rosuvastatin exposure should be mainly due to the inhibition on BCRP with little or no contribution from the inhibition of OATP. Consistent with this, the rosuvastatin clinical pharmacokinetics data indicated that the increase occurred mainly in the absorption phase, with no/little change on the T1/2 of rosuvastatin.
In this population with MET -dysregulated advanced solid tumors, no patient achieved CR or PR. BOR of SD was observed in 25% of the patients. While the predictive role of specific MET alterations, primarily METex14 skipping mutations, has recently become more established in some indications like NSCLC, the predictive role of others, like MET amplification and overexpression, remain exploratory particularly in indications other than NSCLC. Taken altogether with the limited sample size of this study, which was not primarily designed or powered to evaluate antitumor activity of capmatinib, no conclusions can be made on efficacy of capmatinib in patients withMET -dysregulated advanced solid tumors.
The overall safety results of capmatinib in this study were mostly in line with those seen with other capmatinib studies conducted in patients with advanced solid malignancies with no new or unexpected safety concerns observed [13-15, 17]. The most common treatment-related AEs were nausea and vomiting, asthenia, dyspepsia, and peripheral edema, while treatment-related SAEs were vomiting, anemia, abdominal pain and malaise. All these AEs were manageable by routine oncology patient monitoring and supportive care.
In summary, the clinical data from this study confirms that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant DDI potential. In addition, capmatinib was well-tolerated by the study population with no major or new safety concerns.