Regulatory Watch: US FDA Hematology-Oncology Approvals
Regulatory Watch: US FDA Hematology-Oncology Approvals
A brief overview of FDA approvals from January 1 to March 27, 2023
02.09.2023: Dostarlimab-gxly for dMMR endometrial cancer
The FDA granted regular approval to dostarlimab-gxly (Jemperli) for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer who have progressed on or following a prior platinum-containing regimen and are not candidates for curative surgery or radiation. The drug received accelerated approval in April 2021 for a tissue-agnostic indication (all solid tumors with aMMR) but in the multi-refractory setting. The regular approval was based on a multicenter, multicohort (nonrandomized), open-label trial that demonstrated an overall response rate of 45.4% and a duration of response that was not reached in patients with dMMR recurrent or advanced endometrial cancer. The most common adverse reactions were fatigue/asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting. The recommended dose and schedule is 500 mg every 3 weeks for the first 4 doses, followed by 1,000 mg every 6 weeks until disease progression or unacceptable toxicity.
Dostarlimab-gxly is a humanized IgG4 monoclonal antibody that binds to programmed death-1 (PD-1) receptor, a protein found on the surface of certain immune cells, and blocks its interaction with its ligands, PD-L1 and PD-L2. This increased/restores the ability of effector T cells to recognize and attack cancer cells.
02.03.2023: Sacituzumab govitecan-hziy for HR-positive breast cancer
The FDA approved sacituzumab govitecan-hziy (Trodelvy) for patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. The approval was based on the results of the TROPiCS-02 study, which showed that sacituzumab govitecan-hziy improved progression-free survival (primary endpoint) and overall survival (key secondary endpoint) compared to single agent chemotherapy. The most common adverse events included decreased leukocyte count, decreased neutrophil count, and diarrhea. The recommended dose is 10 mg/kg administered once weekly on Days 1 and 8 of 21-day treatment cycles until disease progression or unacceptable toxicity. This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence in collaboration with international partners.
This approval is the first antibody-drug conjugates (ADCs) approved for the treatment of breast cancer. The antibody in govitecan-hziy is specific for the Trop-2 receptor, which is overexpressed in many types of cancer, including breast cancer. The cytotoxic component is SN-38, the active metabolite of the chemotherapy drug irinotecan.
01.27.2023: Elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer
The FDA approved elacestrant for the treatment of 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 drug was evaluated in a randomized study where patients received elacestrant or endocrine therapy, with the major efficacy outcome measure being progression-free survival (PFS). In the ESR1-mutated population, the median PFS was 3.8 months for elacestrant and 1.9 months for endocrine therapy. The most common adverse events were musculoskeletal pain, nausea, increased cholesterol, and fatigue. The recommended dose is 345 mg taken orally with food once daily until disease progression or unacceptable toxicity. The FDA also approved the Guardant360 CDx assay as a companion diagnostic device concurrently.
ESR1 (estrogen receptor 1), also known as ERα (estrogen receptor alpha), is a protein that binds to estrogen and plays an important role in regulating the growth and development of breast tissue. “Resistance” mutations in the ESR1 gene are found in up to 40% of patients with advanced or metastatic breast cancer who have received endocrine therapy. There are several types of ESR1 mutations, but the most common are missense mutations in the ligand binding domain of the ESR1 protein, making it constitutively active.
01.27.2023: Pirtobrutinib for relapsed or refractory mantle cell lymphoma
The FDA granted accelerated approval to pirtobrutinib (Jaypirca) for the treatment of relapsed or refractory mantle cell lymphoma in patients who have received at least two lines of systemic therapy, including a BTK inhibitor. The approval was based on the results of an open-label, multicenter, single-arm trial of pirtobrutinib monotherapy that showed an overall response rate of 50% and a complete response rate of 13%. The most common adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. The recommended 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.
Mantle cell lymphoma is a rare and very aggressive type of non-Hodgkin lymphoma that often becomes rapidly resistant to standard treatments (ironically, the first lymphoma patient I treated as a fellow at NCI was a mantle cell patient). Pirtobrutinib is a small molecule “second generation” Bruton's tyrosine kinase (BTK) inhibitor. In recent years, the introduction of targeted therapies like BTK inhibitors (e.g., ibrutinib, acalabrutinib, and zanubrutinib) has improved outcomes for some patients with mantle cell lymphoma, particularly those who are refractory to other treatments. BTK inhibitors’ approved indications include chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL).
01.26.2023: Pembrolizumab as adjuvant treatment for non-small cell lung cancer
The FDA approved pembrolizumab (Keytruda) for adjuvant treatment following resection and platinum-based chemotherapy for stage IB (T2a ≥4 cm), II, or IIIA non-small cell lung cancer (NSCLC). The approval was based on the results of the KEYNOTE-091 trial, which demonstrated a statistically significant improvement in disease-free survival in patients who received pembrolizumab compared to placebo. The adverse reactions observed were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism, hyperthyroidism, and pneumonitis. The recommended dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease recurrence, unacceptable toxicity, or up to 12 months. This review was another application under Project Orbis.
This study didn’t include patients receiving neoadjuvant treatment but did include those who had received standard adjuvant chemotherapy. In an exploratory subgroup analysis of patients who did not receive adjuvant chemotherapy, 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 in the pembrolizumab arm (95% CI: 39.2, not reached) and 34.9 months in the placebo arm (95% CI: 28.6, not reached) (hazard ratio=0.73; 95% CI: 0.60, 0.89]).
01.19.2023: Zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma
The FDA granted approval to the BTK inhibitor zanubrutinib (Brukinsa, BeiGene) for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) based on the following studies:
The SEQUOIA trial evaluated the efficacy of zanubrutinib in treatment-naive CLL/SLL patients in a randomized cohort of 479 patients without 17p deletion, comparing it to bendamustine plus rituximab (BR) for 6 cycles. Zanubrutinib demonstrated a significant improvement in progression-free survival (PFS) compared to BR. The median PFS was not reached (95% CI: NE, NE) in the zanubrutinib arm and was 33.7 months (95% CI: 28.1, NE) in the BR arm (HR= 0.42, 95% CI: 0.28, 0.63; p=<0.0001). In a separate non-randomized cohort of 110 patients with previously untreated CLL/SLL with 17p deletion, zanubrutinib showed an overall response rate (ORR) of 88% and a median duration of response (DOR) that was not reached after a median follow-up of 25.1 months.
The ALPINE trial evaluated zanubrutinib's efficacy in relapsed or refractory CLL/SLL patients in a randomized cohort of 652 patients, comparing it to ibrutinib. Zanubrutinib demonstrated an ORR of 80%, which was higher than the 73% ORR observed with ibrutinib. The response rate ratio was 1.10 and the median DOR was not reached in either arm after a median follow-up of 14.1 months.
The most common adverse reactions across all studies to zanubrutinib were neutrophil count decreased, upper respiratory tract infection, platelet count decreased, hemorrhage, and musculoskeletal pain. The recommended dosage of zanubrutinib is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity. Zanubrutinib was granted orphan drug designation and the FDA.
It’s important to note that 17p deletion is found in a subset of patients with CLL and SLL and caused by the deletion of a portion of chromosome 17, which contains the TP53 gene encoding for a tumor suppressor protein that regulates cell division. In patients with 17p deletion, the loss of the TP53 gene is typically associated with resistance to standard treatments and a poor prognosis. Patients with 17p deletion are often considered to have high-risk disease and may require more aggressive treatment options. Zanubrutinib in this setting has shown efficacy in previously untreated patients with CLL/SLL with 17p deletion, providing a new treatment option for this patient high risk population.
01.19.2023: Tucatinib with trastuzumab for colorectal cancer
The FDA has granted accelerated approval to tucatinib (Tukysa, a small molecule inhibitor of human epidermal growth factor receptor 2 [HER2]) in combination with trastuzumab for the treatment of RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed after chemotherapy. The efficacy of combination treatment was evaluated in an open-label, multicenter trial involving 84 patients. The major efficacy measures were overall response rate (ORR) and duration of response (DOR), which were 38% and 12.4 months, respectively. The most common adverse events were diarrhea, fatigue, rash, and nausea. The recommended tucatinib dose is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity. This review was also conducted under Project Orbis.
HER2 is a growth factor receptor that is normally present in low levels on the surface of some cells, but when it is overexpressed, it can promote the growth and spread of cancer cells. HER2-positive colorectal cancer is relatively rare, accounting for only about 5% of all cases of colorectal cancer, but it tends to be more aggressive and resistant to standard treatments than other types of colorectal cancer.
A small percentage of patients with metastatic colorectal cancer (3-5%) have HER2 alterations, including somatic mutations and amplifications. While HER2 was initially assessed as a biomarker of resistance to anti-EGFR therapy in this setting, its potential role as an actionable therapeutic target has been getting increasing attention in recent years.