Patient demographics and disease characteristics
The median age of the patients who participated in the study was 61.5
years (range: 38-81 years). Patients were equally divided by sex, and
almost all were Caucasian (30 patients [93.8%]). Most patients (24
[75%]) had an ECOG PS of 1. The median body mass index was 23.95
kg/m2.
The most frequent primary site of cancer was colon (10 patients
[31.3%]), followed by lung (eight patients [25%]), esophagus,
oral cavity, pancreas and rectum (two patients [6.3%], each); other
cancers (one patient [3.1%], each; Table 2 ). Predominant
tumor histology was adenocarcinoma (22 patients [68.8%]). A
majority of the patients had metastatic (stage IV) disease at initial
diagnosis (18 patients [56.3%]) and at study entry (27 patients
[84.4%]). Key sites of metastatic disease included lung (21
patients [65.6%]), liver (19 patients [59.4%]), bone, lymph
nodes, and peritoneum (six patients [18.8%], each). All patients
had MET dysregulation at study entry, with some having had more
than one MET alteration. MET mutation was reported in four
patients (9.4%; all had METex14 ), MET overexpression in
24 (75%) and MET amplification in 14 (43.8%) patients.
The median time from initial diagnosis to first study treatment was
25.23 months (range: 8.6 to 124.2) and the median time from most recent
relapse/progression to the first study treatment was 1.99 months (range:
0.7 to 7.1). All patients enrolled in the study received at least one
prior antineoplastic therapy. Overall, 31 patients (96.9%) received
prior antineoplastic chemotherapy. Eleven patients (34.4%) received two
prior lines of chemotherapy, three patients (9.4%) received three prior
lines of chemotherapy and 15 patients (46.9%) received four or more
lines of prior chemotherapy. 68.8% of patients received chemotherapy in
a therapeutic setting as prior antineoplastic therapy. The best response
to last therapy in patients receiving prior antineoplastic therapy
excluding surgery was predominantly PD, which was noted in 21 patients
(65.6%). A total of 84.4% of patients received concomitant
medications. Pharmacokinetics of digoxin
The geometric and arithmetic mean concentration-time profiles of digoxin
are shown in Fig 2 . Digoxin concentration was higher throughout
72-hour sampling with coadministration of capmatinib versus digoxin
alone. The pharmacokinetic parameters are summarized in Table
3 . Coadministration of capmatinib increased digoxin
AUCinf, AUClast and Cmaxby 47%, 63% and 74%, respectively, compared to digoxin alone. The
geometric mean ratios (90% CI) were 1.47 (1.28, 1.68) for
AUCinf, 1.63 (1.42, 1.89) for AUClastand 1.74 (1.43, 2.13) for Cmax (Table 4 ).
Consistently, the apparent clearance (CL/F) was lower with
coadministration of capmatinib (7.33 L/h) compared to digoxin alone
(9.89 L/h). Slightly longer half-life (T1/2/) was observed with
coadministration of capmatinib (61.4 h) compared to digoxin alone (47 h)
as the elimination slope was parallel in general. Tmaxwas not affected by capmatinib.
Pharmacokinetics of
rosuvastatin
The geometric and arithmetic mean concentration-time profiles of
rosuvastatin are shown in Fig 2 . The concentration of
rosuvastatin was higher throughout the 72 hours timeframe following
capmatinib coadministration with the more significant difference
observed in the absorption phase (first 12 hours). The elimination slope
was very similar with or without coadministration of capmatinib. The
pharmacokinetic parameters for rosuvastatin are summarized inTable 3 . Coadministration of capmatinib increased the geometric
means of AUCinf, AUClast and
Cmax by 108%, 103%, and 204%, respectively, compared
to rosuvastatin alone. The geometric mean ratios (90% CI) were 2.08
(1.56, 2.76) for AUCinf, 2.03 (1.61, 2.56) for
AUClast and 3.04 (2.36, 3.92) for Cmax(Table 4 ). Consistently, the apparent clearance (CL/F) was
significantly lower (62.8 L/hr) with coadministration of capmatinib
compared to rosuvastatin alone (128 L/hr). However, the elimination
half-life was not affected by capmatinib.
Pharmacokinetics of capmatinib
The geometric mean pre-dose concentration of capmatinib on Day 22 (DDI
phase) was 407 ng/mL. On Cycle 2 Day 1 (post-DDI phase), the geometric
mean pre-dose and 2 hour post-dose concentrations of capmatinib were 529
and 3960 ng/mL, confirming that steady state has been obtained.
Efficacy assessments
No patient achieved a complete response (CR) or partial response (PR).
Eight (25%) patients had stable disease (SD) as best overall response
(BOR), while 17 (53.1%) had PD. Response was unknown for seven patients
(21.9%). The disease control rate (CR+PR+SD) was 25% (Table
5 ).
Safety assessments
The median (range) percentage of the relative dose intensity was 100%
(76.8-100.0), and the mean (±SD) percentage was 98.28% (±4.82). The
median actual dose intensity was 800 mg/day (range: 614.3, 800). The
median duration of exposure for capmatinib was 7.14 weeks (range: 1.4 to
42.0) for all patients. 43.8% patients received capmatinib for a
duration of 6 to 12 weeks.
All 32 enrolled patients experienced at least one AE, regardless of
study drug relationship; of these, 18 patients (56.3%) had Grade 3/4
AEs (Table 6 ). The most frequent AEs regardless of study drug
relationship (≥20% for all grades) were nausea (56.3%), asthenia
(43.8%), constipation and vomiting (40.6%, each), peripheral edema
(28.1%), pyrexia (25%), anemia, decreased appetite, and dyspepsia
(21.9%, each). The most frequent Grade 3/4 AEs (≥5%) regardless of
study drug relationship were anemia and pulmonary embolism (9.4%,
each), asthenia, dyspnea, nausea and vomiting (6.3%, each). No
clinically relevant alterations were observed in the electrocardiograph.
Treatment-related AEs were reported in 25 patients (78.1%); of these,
eight (25.0%) had Grade 3/4 AEs. Most common treatment-related AEs
(≥10%, all grades) were nausea and vomiting (34.4%, each), asthenia
(18.8%), dyspepsia (15.6%), and peripheral edema (12.5%). Most
frequent treatment-related Grade 3/4 AE (≥5%) was vomiting (6.3%). AEs
leading to study drug discontinuation were reported in three patients
(9.4%); all of the events were grade 3/4 in severity. Treatment-related
AEs leading to study drug discontinuation were Grade 3 abdominal pain
and Grade 3 vomiting. AEs requiring dose adjustment or study drug
interruption were reported in 13 patients (40.6%). The most frequent AE
that led to dose adjustment or dose interruption was nausea (6.3%; both
Grade ≤2 in severity).
Seventeen patients (53.1%) experienced SAEs of any grade, regardless of
study drug relationship; of these, 13 patients (40.6%) had Grade 3/4
SAEs. Treatment-related SAEs were reported in four patients (12.5%).
Most frequently reported treatment-related SAE was vomiting occurring in
three patients (9.4%). Other treatment-related SAEs were anemia,
abdominal pain and malaise, reported in one patient each. In total,
eight patients (25.0%) died during the study; of these, six (18.8%)
were on-treatment deaths. Of the on-treatment deaths, two deaths (6.3%)
were due to disease progression, three (9.4%) due to AEs with disease
progression as contributing reason and one (3.1%) died due to AE
(respiratory tract infection).