ENHERTU® Approved in the U.S. as First HER2 Directed Therapy for Patients with HER2 Low or HER2 Ultralow Metastatic Breast Cancer Following Disease Progression After One or More Endocrine Therapies

• This approval, which is based on results from the DESTINY-Breast06 phase 3 trial presented at ASCO24 & published in New England, follows Priority Review and Breakthrough Therapy Designation by the FDA for ENHERTU in this indication

• In the DESTINY-Breast06 trial, ENHERTU demonstrated a 36% reduction in the risk of disease progression or death versus chemotherapy in the overall trial population of patients with chemotherapy-naïve HR positive, HER2 low or HER2 ultralow metastatic breast cancer (n=866) (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.54-0.76; p<0.0001). A median progression-free survival (PFS) of 13.2 months (95% CI: 12.0-15.2) was seen in patients treated with ENHERTU compared to 8.1 months (95% CI: 7.0-9.0) in patients treated with chemotherapy

FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer

• Efficacy was evaluated in CodeBreaK 300 (NCT05198934). total of 160 patients were randomized (1:1:1) to receive either sotorasib 960 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks, sotorasib 240 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks, or investigator’s choice of SOC trifluridine/tipiracil or regorafenib

• Median PFS was 5.6 months in the sotorasib 960 mg/panitumumab arm and 2 months in the SOC arm (HR 0.48 , 2-sided p-value 0.005)

• The study was not statistically powered for OS. The final analysis of OS was not statistically significant. ORR was 26% in the sotorasib 960 mg/panitumumab arm and 0 in the SOC arm. Median DOR was 4.4 months (range: 1.9+, 6+) in the sotorasib 960 mg/panitumumab arm

• The final analysis of PFS for patients randomized to the sotorasib 240 mg/panitumumab arm compared to the SOC arm was not statistically significant

FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer

• Efficacy was evaluated in TROPION-Breast01 (NCT05104866). Randomization was stratified by previous lines of chemotherapy, prior CDK4/6 inhibitor treatment, and geographical region. A total of 732 patients were randomized (1:1) to datopotamab deruxtecan-dlnk (n=365) or investigator’s choice of chemotherapy (n=367); eribulin (60%), capecitabine (21%), vinorelbine (10%), or gemcitabine (9%). The major efficacy outcome measures were PFS and OS

• Median PFS was 6.9 months (95% CI: 5.7, 7.4) in the datopotamab deruxtecan-dlnk arm and 4.9 months (95% CI: 4.2, 5.5) in the chemotherapy arm (Hazard ratio 0.63 [95% CI: 0.52, 0.76] two-sided p-value <0.0001)

• Median OS was 18.6 months (95% CI: 17.3, 20.1) in the datopotamab deruxtecan-dlnk arm and 18.3 months (95% CI: 17.3, 20.5) in the chemotherapy arm (Hazard ratio 1.01 [95% CI: 0.83, 1.22]; two-sided p-value was not statistically significant)

FDA approves acalabrutinib with bendamustine and rituximab for previously untreated MCL

• FDA grants traditional approval to acalabrutinib (Calquence, AstraZeneca) with bendamustine and rituximab for adults with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT).

• FDA also granted traditional approval to acalabrutinib as a single agent for adults with previously treated MCL. Acalabrutinib received accelerated approval for this indication in 2017.

• Efficacy was evaluated in ECHO (NCT02972840), with a median follow-up of 49.8 months, PFS was statistically significantly longer in the acalabrutinib arm (HR 0.73 [95% CI: 0.57, 0.94], p-value 0.016). The median PFS was 66.4 months (95% CI: 55.1, not estimable) in the acalabrutinib plus BR arm and 49.6 months (95% CI: 36.0, 64.1) in placebo plus BR.

BMS Receives EU Approval for nivo+ipi plus for the First-Line Treatment of Adult Patients with Microsatellite Instability–High or Mismatch Repair Deficient Metastatic Colorectal Cancer

• Approval based on results of the Phase 3 CheckMate -8HW trial.

• Opdivo plus Yervoy reduced the risk of disease progression or death by 79%. Median PFS was not yet reached in the Opdivo plus Yervoy arm (95% CI: 38.4-NE) vs. 5.9 months in the chemotherapy arm (95% CI: 4.4-7.8). Consistent PFS benefit was observed across all pre-specified subgroups, including patients with KRAS or NRAS mutations, and those with baseline liver, lung, or peritoneal metastases.

• Safety profile for the combination of Opdivo plus Yervoy remained consistent with previously reported data and was manageable with established protocols, with no new safety signals identified

• Further data disclosure is planned at The American Society of Clinical Oncology Gastrointestinal Cancers Symposium taking place January 23, 2025, through January 25, 2025.

Approved across approved adult, solid tumor nivolumab indications as monotherapy, monotherapy maintenance following completion of Opdivo plus Yervoy (ipilimumab) combination therapy, or in combination with chemotherapy or cabozantinib.

The approval includes indications for renal cell carcinoma, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal carcinoma, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. Opdivo Qvantig is not indicated in combination with intravenous ipilimumab.

• The subcutaneous injection was evaluated in CHECKMATE-67T (NCT04810078), a multicenter, randomized, open-label trial in patients with advanced or metastatic clear cell renal cell carcinoma who received no more than 2 prior systemic treatment regimens.

• A total of 495 patients were randomized to receive either subcutaneous nivolumab and hyaluronidase-nvhy or intravenous nivolumab.

• The trial met the predefined acceptance margin for pharmacokinetic endpoints, with the lower boundary of 90% confidence interval of geometric mean ratios of not less than 0.8 for both serum nivolumab Cavg over 28 days and Cmin at steady state.

In general, CHECKMATE-67T showed a similar safety profile between OPDIVO QVANTIG and intravenous nivolumab. The most common adverse reactions (≥10%) were fatigue, musculoskeletal pain, pruritus, rash, and cough.

TEVIMBRA Approved in U.S. for First-line Treatment of Gastric and Gastroesophageal Junction Cancers in Combination with Chemotherapy

• New indication based on results from BeiGene’s RATIONALE-305 (NCT03777657), a randomized, double-blind, placebo-controlled, global Phase 3 trial to evaluate the efficacy and safety of TEVIMBRA in combination with chemotherapy as a first-line treatment for adult patients with advanced unresectable or metastatic G/GEJ cancer.

• The study demonstrated a statistically significant OS benefit of 15.0 months for patients treated with TEVIMBRA in combination with the investigator’s choice of chemotherapy vs. 12.9 months for patients treated with placebo plus chemotherapy (n=997; HR: 0.80 [95% CI: 0.70, 0.92]; P=0.0011), resulting in a 20% reduction in the risk of death.

• The most common Grade 3 or 4 adverse reactions for TEVIMBRA given in combination with chemotherapy were neutropenia, thrombocytopenia, anemia, fatigue, hypokalemia, hyponatremia, pneumonia, decreased appetite, rash, lymphopenia, alanine aminotransferase increased, aspartate aminotransferase increased, diarrhea, pneumonitis, and hepatitis.

FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation

• ORR was 61% (95% CI: 52%, 70%) in the encorafenib+ cetuximab, + mFOLFOX6 arm and 40% (95% CI: 31%, 49%) in the control arm. Median DoR was 13.9 months (95% CI: 8.5, not estimable) and 11.1 months (95% CI: 6.7, 12.7) in the respective arms

  Evaluation of PFS and OS in the ongoing BREAKWATER trial will serve as post-marketing confirmatory evidence for this accelerated approval

• This application is an example of the Oncology Center of Excellence’s Project FrontRunner aimed at moving important therapies to earlier disease settings; Project Orbis also saw Health Canada join FDA for this review - currently ongoing in Canada

• Additionally, this priority review was reviewed under FDA Real-time oncology review