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.