FDA Approved 7 New Oncology Indications in January-February 2023

In January-February 2023, the US FDA approved seven new indications for cancer management. Gynecologic cancers were well-represented: Two of these approvals were in breast cancer, while a third was in endometrial cancer. Additionally, pembrolizumab received a new indication in NSCLC.

  • Elacestrant for ER-positive, HER2-negative, ESR1-mutated Advanced or Metastatic Breast Cancer. Elacestrant (Orserdu™, Stemline Therapeutics, Inc.) received approval for use in postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. The Guardant360 CDx assay also received approval as a companion diagnostic device. Efficacy data from the randomized, open-label, phase 3 EMERALD trial (NCT03778931) supported this approval Patients, nearly half of whom had ESR1 mutations, were randomized to receive elacestrant 345 mg orally once daily or investigator’s choice of standard endocrine monotherapy, which included fulvestrant or an aromatase inhibitor. Progression-free survival (PFS), the primary endpoint, was extended in all patients (Hazard Ratio [HR] 0.70; 95% Confidence Interval [CI], 0.55 to 0.88; P = 0.002) and patients with ESR1 mutation (HR 0.55; 95% CI, 0.39 to 0.77; P = 0.0005). In patients with ESR1 mutations, the median PFS was 3.8 months (95% CI, 2.2 to 7.3) in the elacestrant arm and 1.9 months (95% CI, 1.9 to 2.1) in the endocrine therapy arm (HR 0.55; 95% CI 0.39 to 0.77; P =0.0005). Treatment-related adverse events (AEs) led to treatment discontinuations in 3.4% of patients the elacestrant arm vs 0.9% in the standard-of-care group. 
  • Sacituzumab Govitecan-hziy for HR-positive, HER2-negative Metastatic Breast Cancer. Sacituzumab govitecan-hziy (Trodelvy™, Gilead Sciences, Inc.) received approval for patients with unresectable locally advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. Data from the open label, randomized, phase 3 TROPiCS-02 trial (NCT03901339) established efficacy. Investigators enrolled 543 patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer, whose disease progressed in any setting after a CDK 4/6 inhibitor, endocrine therapy, and a taxane. Patients received at least two prior chemotherapies in the metastatic setting. Patients were randomized 1:1 to receive sacituzumab govitecan-hziy or single agent physician’s choice chemotherapy. PFS was the primary outcome. In the sacituzumab govitecan-hziy arm, the median PFS was 5.5 months (95% CI, 4.2 to 7.0) vs 4 months (95% CI, 3.1 to 4.4) in the chemotherapy arm (HR 0.661; 95% CI, 0.529 to 0.826; = 0.0003). PFS rates at 6 months were 46% vs 30% and 12-month PFS rates were 21% vs 7%, respectively. Overall, 74% of the sacituzumab govitecan-hziy patients and 60% of the chemotherapy patients had grade ≥3 treatment-emergent AEs, with neutropenia being the most common (51% vs 39%).
  • Dostarlimab-gxly for Mismatch Repair Deficient Endometrial Cancer. The FDA granted approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation. In 2021, the dostarlimab-gxly was granted accelerated approval. The multi-cohort, multicenter open-label phase 1 GARNET trial (NCT02715284) for patients with solid tumors was used to determine efficacy. The efficacy population consisted of a cohort of 141 patients with dMMR recurrent or advanced endometrial cancer who had progressed on or after a platinum-containing regimen. Overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1 were the major efficacy outcome measures. Confirmed ORR was 45.4% (95% CI, 37.0 to 54.0). Of these, 15.6% of patients had a complete response (CR), while 29.8% had a partial response (PR). The median DOR was not reached, but 85.9% of patients had durations of ≥12 months and 54.7%) had durations of ≥24 months. Grade≥3 treatment-related AEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of treatment-related AEs. 
  • Tucatinib with Trastuzumab for Advanced Colorectal Cancer. Tucatinib (Tukysa®, Seagen Inc.) in combination with trastuzumab received accelerated approval for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The approval was based on Efficacy data from the open-label, multicenter phase 2 MOUNTAINEER trial (NCT03043313). Enrolled patients had HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) treatment. The major efficacy measures were ORR and DOR, as assessed by blinded independent central review using RECIST version 1.1 criteria. The confirmed ORR was 38.1% (95% CI, 27.7 to 49.3). The median DOR was 12.4 months (95% CI, 8.5 to 20.5). The most common AE of grade ≥3 was hypertension (7.0%) and 5.8% of patients discontinued tucatinib due to AEs. The recommended tucatinib dose is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity.
  • Pembrolizumab as Adjuvant Treatment for Non-Small Cell Lung Cancer (NSCLC). Pembrolizumab (Keytruda®, Merck) received approval for adjuvant treatment following resection and platinum-based chemotherapy for stage IB (T2a ≥4 cm), II, or IIIA NSCLC, based on efficacy data from the phase 3 KEYNOTE-091 trial (NCT02504372). KEYNOTE-091 is a multicenter, randomized, triple-blind, placebo-controlled trial in which patients have not received neoadjuvant radiotherapy or chemotherapy. Patients were randomized to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 1 year. Of nearly 1200 patients randomized (n = 1177), 86% (n = 1010) received adjuvant platinum-based chemotherapy following complete resection. Investigator-assessed disease-free survival (DFS) in the overall population and in patients with PD-L1 tumor proportion score (TPS) of ≥ 50% were the dual primary endpoints. A statistically significant improvement in DFS in the overall population was demonstrated with a median DFS of 53.6 months (95% CI, 39.2 to not reached) in the pembrolizumab group versus 42.0 months (31.3 to not reached) in the placebo group (HR 0.76; 95% CI, 0.63 to 0.91; P = 0.0014). In an exploratory analysis of a subgroup of patients who did not receive adjuvant chemotherapy (n = 167), the DFS hazard ratio was 1.25 (95% CI: 0.76, 2.05). For patients who received adjuvant chemotherapy, median DFS was 58.7 months with pembrolizumab (95% CI: 39.2, not reached) and 34.9 months with placebo (95% CI: 28.6, not reached) (HR = 0.73; 95% CI: 0.60, 0.89]). Adverse events were generally similar to those seen in patients with NSCLC receiving single-agent pembrolizumab treatment, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.
  • Zanubrutinib for Chronic Lymphocytic Leukemia (CLL). Zanubrutinib (Brukinsa®, BeiGene USA, Inc.) received approval for CLL or small lymphocytic lymphoma (SLL). Efficacy data from the open-label phase 3 SEQUOIA trial (NCT03336333) established its use in the front-line setting. Eligible patients without del(17)(p13.1) were randomized to zanubrutinib (group A) or bendamustine–rituximab (group B). Patients with del(17)(p1.1) were enrolled in group C and received zanubrutinib. The primary endpoint was PFS per independent review in groups A and B. At a median follow-up of 25.0 months, the median PFS was not reached in either group. PFS was significantly improved in group A versus group B (HR 0.42; 95% CI 0.28 to 0.63; < 0.0001). In approving zanubrutinib for use in relapsed CLL or SLL, the FDA considered efficacy data from the phase 3 ALPINE trial (NCT03734016), which had overall response as its primary endpoint. PFS was a key secondary endpoint. With a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib in PFS (HR for disease progression or death 0.65; 95% CI 0.49 to 0.86; P = 0.002). At 24 months, the PFS rates were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer PFS than those in the ibrutinib group (HR for disease progression or death, 0.53; 95% CI, 0.31 to 0.88). The FDA noted that, across trials, neutropenia was the most common AE at 42%, followed by upper respiratory tract infection (39%), and decreased platelet count (34%). Thirteen percent of patients developed second malignancies, and 3.7% of patients reported atrial fibrillation. 
  • Pirtobrutinib for Mantle Cell Lymphoma (MCL). Pirtobrutinib (Jaypirca™, Eli Lilly and Company) received accelerated approval for relapsed or refractory MCL after at least two lines of systemic therapy, including a BTK inhibitor. This approval was based on efficacy data from the phase 1/2 BRUIN (NCT03740529) trial, an open-label, multicenter, single-arm study of pirtobrutinib monotherapy. The trial included 120 patients with MCL previously treated with at least one BTK inhibitor; 83% had discontinued their last BTK inhibitor due to refractory or progressive disease. Themain endpoints were ORR and DOR, as determined by an independent review committee using Lugano criteria. The ORR was 50% (95% CI, 41 to 59) with a complete response rate of 13%. The estimated median DOR was 8.3 months (95% CI, 5.7 to not estimable), and the estimated DOR rate at 6 months was 65.3% (95% CI, 49.8 to 77.1). At least 15% of patients experienced the following AEs: fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. The recommended pirtobrutinib dosage is 200 mg orally once daily until disease progression or unacceptable toxicity. The prescribing information includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies.