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BRAFTOVI®Clinical Studies (encorafenib)

14 CLINICAL STUDIES

14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

BRAFTOVI in combination with binimetinib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no).

Patients were randomized (1:1:1) to receive BRAFTOVI 450 mg once daily in combination with binimetinib 45 mg twice daily (BRAFTOVI in combination with binimetinib), BRAFTOVI 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (BRAFTOVI 450 mg in combination with binimetinib 45 mg) are described below.

The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare BRAFTOVI in combination with binimetinib with vemurafenib. Additional efficacy outcome measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review.

A total of 577 patients were randomized, 192 to the BRAFTOVI in combination with binimetinib arm, 194 to the BRAFTOVI arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the BRAFTOVI in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥ 3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients' tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%).

BRAFTOVI in combination with binimetinib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 9 and Figure 1.

Table 9: Efficacy Results for COLUMBUS
BRAFTOVI with binimetinib
N=192
Vemurafenib
N=191
CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NE = Not estimable; ORR = Overall response rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response.
*
Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1).
Log-rank test adjusted by the same stratification factors.
Based on a cutoff date of 17.6 months after the date of the PFS analysis.
Progression-Free Survival
  Number of events (%)98 (51)106 (55)
    Progressive disease88 (46)104 (54)
    Death10 (5)2 (1)
  Median PFS, months (95% CI)14.9 (11, 18.5)7.3 (5.6, 8.2)
  HR (95% CI)*0.54 (0.41, 0.71)
  P-value<0.0001
Overall Survival
  Number of events (%)105 (55)127 (67)
  Median OS, months (95% CI)33.6 (24.4, 39.2)16.9 (14.0, 24.5)
  HR (95% CI)*0.61 (0.47, 0.79)
Overall Response Rate
  ORR (95% CI)63% (56%, 70%)40% (33%, 48%)
    CR8%6%
    PR55%35%
Duration of Response
  Median DoR, months (95% CI)16.6 (12.2, 20.4)12.3 (6.9, 16.9)

Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS

Figure 1

14.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)

BRAFTOVI in combination with cetuximab was evaluated in a randomized, active-controlled, open-label, multicenter trial (BEACON CRC; NCT02928224). Eligible patients were required to have BRAF V600E mutation-positive metastatic colorectal cancer (CRC), as detected using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction (PCR) Kit, with disease progression after 1 or 2 prior regimens. Other key eligibility criteria included absence of prior treatment with a RAF, MEK, or EGFR inhibitor, eligibility to receive cetuximab per local labeling with respect to tumor RAS status, and ECOG performance status (PS) 0–1. Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab product used (US-licensed versus EU-approved).

Patients were randomized 1:1:1 to one of the following treatment arms:

  • BRAFTOVI 300 mg orally once daily in combination with cetuximab (BRAFTOVI/cetuximab arm)
  • BRAFTOVI 300 mg orally once daily in combination with binimetinib and cetuximab
  • Irinotecan with cetuximab or FOLFIRI with cetuximab (control arm)

The dosage of cetuximab in all patients was 400 mg/m2 intravenously for the first dose followed by 250 mg/m2 weekly.

Patients in the control arm received cetuximab with either irinotecan 180 mg/m2 intravenously on Days 1 and 15 of each 28-day cycle or FOLFIRI intravenously (irinotecan 180 mg/m2 on Days 1 and 15; folinic acid 400 mg/m2 on Days 1 and 15; then fluorouracil 400 mg/m2 bolus on Days 1 and 15 followed by fluorouracil 2400 mg/m2/day by continuous infusion over 2 days).

Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved regimen (BRAFTOVI in combination with cetuximab) are described below.

The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures included progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR) as assessed by blinded independent central review (BICR). OS and PFS were assessed in all randomized patients. ORR and DoR were assessed in the subset of the first 220 patients included in the randomized portion of the BRAFTOVI/cetuximab and control arm of the study.

A total of 220 patients were randomized to the BRAFTOVI/cetuximab arm and 221 to the control arm. Of these 441 patients, the median age was 61 years; 53% were female; 80% were White and 15% were Asian. Fifty percent (50%) had baseline ECOG performance status of 0; 66% received 1 prior therapy and 34% received 2; 93% received prior oxaliplatin and 52% received prior irinotecan.

BRAFTOVI in combination with cetuximab demonstrated a statistically significant improvement in OS, ORR, and PFS compared to the active comparator. Efficacy results are summarized in Table 10 and Figure 2.

Table 10: Efficacy Results from BEACON CRC
BRAFTOVI with cetuximab
N = 220
Irinotecan with cetuximab or FOLFIRI with cetuximab
N = 221
CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NR = Not reached; ORR = Overall response rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response.
*
Stratified by ECOG PS, source of cetuximab (US-licensed versus EU-approved) and prior irinotecan use at randomization.
Stratified Cox proportional hazard model.
Stratified log-rank test, tested at alpha level of 0.0084.
§
BRAFTOVI/cetuximab arm (n=113) and control arm (n=107).
Cochran-Mantel-Haenszel test; tested at alpha level of 0.05.
#
Stratified log-rank test, tested at alpha level of 0.0234.
Overall Survival
  Number of Events (%)93 (42)114 (52)
  Median OS, months (95% CI)8.4 (7.5, 11.0)5.4 (4.8, 6.6)
  HR (95% CI)*,0.60 (0.45, 0.79)
  P-value*,0.0003
Overall Response Rate (per BICR)
  ORR (95% CI)§20% (13%, 29%)2% (0%, 7%)
    CR5%0%
    PR15%2%
  P-value*,<0.0001
  Median DoR, months (95% CI)6.1 (4.1, 8.3)NR (2.6, NR)
Progression Free Survival (per BICR)
  Number of events (%)133 (60)128 (58)
    Progressive disease110 (50)101 (46)
    Death23 (10)27 (12)
  Median PFS, months (95% CI)4.2 (3.7, 5.4)1.5 (1.4, 1.7)
  HR (95% CI)*,0.40 (0.31, 0.52)
  P-value*,#< 0.0001

Figure 2: Kaplan-Meier Curves for Overall Survival in BEACON CRC

Figure 2

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