Patients and genetic characteristics
Recruitment for the CLUSTER study (January 2015 – October 2019; China, Guangdong) was halted prematurely because of challenges in identifying patients under the prevailing treatment paradigm for NSCLC in China at the time. Based on the eligibility criteria, the trial enrolled a total of 66 patients harboring MET amplification or MET overexpression (n = 16), ALK or ROS1 rearrangement (n = 26, KRAS/neuroblastoma RAS viral oncogene homolog (NRAS)/BRAF (n = 22) mutations, and PIK3CA mutations and/or amplification (n = 2) who were assigned to receive capmatinib, ceritinib, binimetinib, and alpelisib, respectively. Patients with co-existing mutations were eligible for enrollment but ultimately no such patients were enrolled. The median age of the enrolled patients was 58 years. Most patients (94%) enrolled into the trial had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Overall, 52% of patients were treatment-naïve, and a substantial proportion (23%) was heavily pre-treated with two or more lines of prior treatment. All patients enrolled in the capmatinib, ceritinib, and binimetinib arms had adenocarcinoma, whereas both patients in the alpelisib arm had squamous cell carcinoma. Patient baseline characteristics are summarized in Table 1.
Treatment and outcomes
Of the overall trial population, 24 (36.4%) patients attained confirmed partial response (PR) to their assigned targeted agents. Among the remaining patients, 21 (31.8%) and 13 (19.7%) attained stable disease (SD) and progressive disease (PD), respectively. Responses were unknown for the remaining 8 (12.1%) patients. Forty-five (68.2%) of 66 patients experienced tumor shrinkage (Table 2, Fig. 1a). The median progression-free survival (PFS) calculated for 56 patients (10 patients were censored) was 5.4 months (95% confidence interval [CI], 3.6–6.7), with a 12‑month Kaplan–Meier estimate of 22.4% (95% CI, 13.0–33.4; Fig. 2a). The median overall survival (OS) calculated for 46 patients (20 patients were censored) was 14.0 months (95% CI, 10.4–21.0), with a 12-month Kaplan–Meier estimate of 57.0% (95% CI, 44.1–68.0; Fig. 3a).
Three patients treated with capmatinib, including 1 patient with MET immunohistochemistry (IHC) intensity 3+ in ≥50% of tumor cells and 2 patients with MET gene copy number (GCN) ≥5 by fluorescence in situ histochemistry (FISH) attained confirmed PR, giving an ORR of 18.8% (Table 2, Fig. 1b). No patient attained a complete response (CR). The ORR in capmatinib-treated patients with MET alterations did not fulfill the predefined statistical parameters for preliminary efficacy. Among the 16 patients treated with capmatinib, the median PFS was 1.5 months (95% CI, 0.8–5.4) with a 4-month Kaplan–Meier estimated rate of 31.3% (95% CI, 11.4–53.7) (Fig. 2b). The median OS was 13.3 months (95% CI, 1.2–23.3) (Fig. 3b). Seven out of 16 patients experienced SD or better, giving a disease control rate (DCR) of 43.8%. The median duration of response (DOR) was 3.8 months (95% CI, 3.8–5.6).
Confirmed PR was observed in 19 out of 26 patients treated with ceritinib. No patient achieved a CR, which means an ORR of 73.1% was attained (Table 2, Fig. 1c). The ORR to ceritinib in patients with ALK or ROS1 rearrangement met the predefined statistical threshold for preliminary activity. The estimated ORR posterior median was above the 55% threshold at 68.8%, while the posterior probability of being in the unacceptable efficacy category was below the 5% threshold at 0.02%. The median PFS was 14.4 months (95% CI, 7.3–40.6) in patients treated with ceritinib. The Kaplan–Meier estimate for PFS rate was 84.6% (95% CI, 64.0–94.0) at 4 months, and 53.3% (95% CI, 32.6–70.3) at 12 months (Fig. 2c). The median OS was not reached (Fig. 3c). DCR was 92.3%, with 24 out of 26 patients who attained SD or better. The median DOR was 35.0 months (95% CI, 7.6–not estimated).
Binimetinib treatment resulted in an ORR of 9.1%, with PR confirmed in 2 of the 22 patients treated (Table 2, Fig. 1d). The ORR to binimetinib in patients with KRAS, NRAS, or BRAF mutations did not fulfill the predefined statistical parameters for preliminary efficacy. The median PFS and OS were 3.8 months (95% CI, 1.6–5.4; Fig. 2d) and 9.2 months (95% CI, 3.5–12.0; Fig. 3d), respectively. A DCR of 59.1% was attained because 13 patients achieved SD or better. The median DOR was 5.5 months (95% CI, 3.6–7.4).
In the alpelisib treatment arm, none of the two patients enrolled attained a CR or PR, although one of the patients attained SD. Because only two patients were enrolled in this arm, Kaplan–Meier estimates for PFS and OS were not generated. In the absence of a response, the DOR for alpelisib could not be determined.
Pharmacokinetics (PK) parameters were evaluated for all treatment arms after a single-dose administration on cycle 1, day 1 (alpelisib arm only) and/or multiple-dose administration on cycle 1, day 15. After multiple-dose administration, the geo-mean (coefficient of variation [CV]%) area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) and maximum (peak) plasma drug concentration (Cmax) were 26614 ng´hr/mL (35.2%) and 7224 ng/mL (54.4%) for capmatinib tablet; 27610 ng´hr/mL (19.2%) and 1351 ng/mL (13.9%) for ceritinib, 2463 ng´hr/mL (41.9%) and 561 ng/mL (33.3%) for binimetinib, and 23721 ng´hr/mL and 2630 ng/mL for one of the patients in the alpelisib arm, respectively. The median time to reach maximum (peak) plasma concentration following drug administration (Tmax) was 1 hour for capmatinib tablet and binimetinib, 2 hours for alpelisib, and 6 hours for ceritinib.
This study included a pooled safety evaluation across all study patients, as well as the safety profile of the individual study arms. For the overall study population, the most frequent (³25%) all-grade treatment-related adverse events (AEs) were diarrhea (60.6%), increased aspartate aminotransferase (AST; 54.5%) and alanine aminotransferase (ALT; 50.0%), vomiting (43.9%), rash (40.9%), increased blood creatine phosphokinase (CPK; 33.3%), increased blood alkaline phosphatase (ALP; 31.8%), increased gamma-glutamyl transferase (GGT; 31.8%), nausea (30.3%), decreased appetite (30.3%), and upper abdominal pain (25.8%). Overall, 56.1% of patients experienced grade 3 or 4 treatment-related AEs. The most frequent grade 3 or 4 treatment-related AEs were increased ALT, which occurred in 10 (15.2%) patients, followed by increased GGT in 9 (13.6%) patients, and increased blood CPK in 8 (12.1%) patients (Table 3). PD was the most frequent reason for study drug discontinuation in each treatment arm.
Patients treated with capmatinib had a median duration of exposure (DOE) of 7.2 weeks. Most patients (81.3%) discontinued treatment because of PD. Most AEs were grade 1 or 2 and did not require discontinuation (Table 3). AEs leading to study drug discontinuation were reported in 2 (12.5%) patients (both grade 3/4). The most frequent (³25%) all-grade treatment-related AEs were anemia, nausea, diarrhea, vomiting, decreased appetite, peripheral edema, and ALT elevation (Table 4). Grade 3/4 treatment-related AEs (³5%) included neutropenia, peripheral edema, increased ALT, increased GGT, increased amylase, and interstitial lung disease, which occurred in 1 (6.3%) patient each. Pneumonia (12.5%) was the most frequently reported AE (³10%) that required dose adjustment/interruption.
Patients treated with ceritinib had a median DOE of 63.5 weeks. PD (46.2%) was the most frequent reason for discontinuation of ceritinib. Most AEs were grade 1 or 2 and did not lead to discontinuation (Table 3). AEs leading to ceritinib discontinuation were reported in 8 (30.8%) patients (grade 3/4 events in 5 [19.2%] patients). The most frequent (³25%) all‑grade treatment-related AEs were anemia, nausea, diarrhea, vomiting, decreased appetite, abdominal pain, upper abdominal pain, asthenia, ALT/AST elevation, increased blood ALP and GGT, prolonged electrocardiogram (ECG) QT (per ECGs performed at local institutions), pruritus, and rash (Table 4). Grade 3/4 treatment-related AEs (³5%) included increased ALT in 9 (34.6%) patients; increased GGT in 7 (26.9%) patients; prolonged ECG QT in 4 (15.4%) patients; increased blood ALP and AST in 3 (11.5%) patients each; asthenia and hyperglycemia in 2 (7.7%) patients each. The most frequently reported AEs that required dose adjustment/interruption (³10%) included increased ALT (42.3%), increased AST (23.1%), increased blood ALP (19.2%), prolonged ECG QT (11.5%), increased GGT (19.2%), and decreased appetite (15.4%).
Patients treated with binimetinib had a median DOE of 14.8 weeks. PD (63.6%) was most common reason for discontinuation of binimetinib. Most AEs were grade 1 or 2 and did not require discontinuation (Table 3). AEs leading to study drug discontinuation were reported in 2 (9.1%) patients (both grade 3/4). The most frequent (³25%) all-grade treatment‑related AEs were diarrhea, mouth ulceration, AST elevation, increased blood CPK, and rash (Table 4). Grade 3/4 treatment-related AEs (³5%) included increased blood CPK in 8 (36.4%) patients, prolonged ECG QT interval in 2 (9.1%) patients, and mouth ulceration, increased GGT, and hypertension in 1 (4.5%) patient each. Increased blood CPK was the most frequently reported AE (³10%) that required dose adjustment/interruption (27.3%).
The median DOE to alpelisib was 8.5 weeks. One patient discontinued treatment because of PD. None of the observed treatment-related AEs led to study drug discontinuation (Table 3). The AEs related to alpelisib were of grade 1; malaise and dysgeusia were reported for 1 patient, and hyperglycemia in the other patient.