Margetuximab for Metastatic HER2-Positive Breast Cancer
The FDA approved margetuximab-cmkb in combination with chemotherapy for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.
Efficacy was evaluated in SOPHIA (NCT02492711), a randomized, multicenter, open-label trial of 536 patients with IHC 3+ or ISH-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Patients were randomized (1:1) to margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Randomization was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), number of lines of therapy in the metastatic setting (<= 2, >2), and number of metastatic sites (<= 2, >2).
The main efficacy outcome measures were progression-free survival (PFS) by blinded independent central review and overall survival. Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) assessed by BICR.
Median PFS in the margetuximab arm was 5.8 months (95% CI: 5.5, 7.0) compared with 4.9 months (95% CI: 4.2, 5.6) in the control arm (HR 0.76; 95% CI: 0.59, 0.98; p=0.033). Confirmed ORR was 22 percent (95% CI: 17, 27) with a median DOR of 6.1 months (95% CI: 4.1, 9.1) in the margetuximab arm compared to an ORR of 16 percent (95% CI: 12, 20) and median DOR of 6.0 months (95%CI: 4.0, 6.9) in the control arm.
The most common adverse drug reactions (>10%) with margetuximab in combination with chemotherapy are fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain. The prescribing information includes a boxed warning to advise health professionals of the risks of left ventricular dysfunction and embryo-fetal toxicity.
The recommended margetuximab dose is 15 mg/kg by intravenous infusion over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses. On days when both margetuximab and chemotherapy are to be administered, margetuximab may be administered immediately after chemotherapy completion. Refer to the respective prescribing information for each therapeutic agent administered in combination with margetuximab for the recommended dosage information, as appropriate.
Selinexor for Refractory or Relapsed Multiple Myeloma
Selinexor in combination with bortezomib and dexamethasone has been approved for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
FDA granted selinexor accelerated approval in 2019 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
Efficacy of selinexor in combination with bortezomib and dexamethasone was evaluated in the BOSTON Trial (KCP-330-023, NCT03110562), a randomized (1:1) open-label, multicenter, active comparator-controlled trial in patients with RRMM who had previously received at least one and at most three prior therapies. Patients received once-weekly selinexor orally in combination with once-weekly bortezomib subcutaneous and low-dose dexamethasone twice weekly orally (SVd) compared to the standard twice-weekly bortezomib plus low-dose dexamethasone (Vd).
The main efficacy outcome measure was progression-free survival (PFS) assessed by an independent review committee using International Myeloma Working Group response criteria. The estimated median PFS was 13.9 months (95% CI: 11.7, Not Estimable) for the SVd arm and 9.5 months (95% CI: 7.6, 10.8) for the Vd arm (estimated hazard ratio 0.70; 95% CI: 0.53, 0.93).
Common adverse reactions reported in at least 20 percent of patients include nausea, fatigue, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataracts, and vomiting. Grade 3-4 laboratory abnormalities (>=10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia hyponatremia, and neutropenia.
The prescribing information provides warnings and precautions for thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, serious infection, neurological toxicity, embryo-fetal toxicity, and cataracts.
The recommended selinexor dose is 100 mg orally once weekly on day 1 of each week of a 35-day cycle until disease progression or unacceptable toxicity in combination with:
* Bortezomib 1.3 mg/m2 administered subcutaneously once weekly on day 1 of each week for 4 weeks followed by 1 week off.
* Dexamethasone 20 mg taken orally twice weekly on days 1 and 2 of each week.
Instruct patients to swallow tablets whole and not to crush or chew tablets.
Relugolix for Advanced Prostate Cancer
The FDA approved the first oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, for adult patients with advanced prostate cancer.
Efficacy was evaluated in HERO (NCT03085095), a randomized, open-label trial in men requiring at least 1 year of androgen deprivation therapy with either prostate cancer recurrence following radiation or surgery or newly diagnosed castration-sensitive advanced prostate cancer. Patients (N=934) were randomized (2:1) to receive relugolix 360 mg oral loading dose on the first day, followed by daily oral doses of 120 mg, or leuprolide acetate 22.5 mg injection subcutaneously every 3 months for 48 weeks.
The main efficacy outcome measure was medical castration rate defined as achieving and maintaining serum testosterone suppression to castrate levels (< 50 ng/dL) by day 29 through 48 weeks of treatment. The medical castration rate was 96.7 percent (95% CI: 94.9%, 97.9%) in the relugolix arm.
The most common adverse reactions (>=10%) in patients receiving relugolix in HERO were hot flush, musculoskeletal pain, fatigue, diarrhea, and constipation. The most common laboratory abnormalities (>=15%) were increased glucose, triglycerides, alanine aminotransferase, and aspartate aminotransferase. Decreased hemoglobin was also observed.
The recommended relugolix dose is a loading dose of 360 mg on the first day followed by a daily oral dose of 120 mg at approximately the same time with or without food.
Osimertinib as Adjuvant Therapy for NSCLC With EGFR Mutations
The FDA approved osimertinib for adjuvant therapy after tumor resection in patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
Efficacy was demonstrated in a randomized, double-blind, placebo-controlled trial (ADAURA, NCT02511106) in patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. Eligible patients with resectable tumors (stage IB-IIIA) were required to have predominantly non-squamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas EGFR Mutation Test. A total of 682 patients were randomized (1:1) to receive osimertinib 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant chemotherapy, if given.
The major efficacy outcome measure was disease-free survival (DFS) in patients with stage II-IIIA NSCLC determined by investigator assessment. Median DFS was not reached (38.8, NE) in patients on the osimertinib arm compared with 19.6 months (16.6, 24.5) on the placebo arm (HR 0.17 95% CI: 0.12, 0.23; <0.0001). DFS in the overall study population was a secondary efficacy outcome measure; the median was not reached (NE, NE) in patients on the osimertinib arm compared with 27.5 months (22, 36) on the placebo arm (HR 0.20 95% CI: 0.15, 0.27; <0.0001).
The recommended osimertinib dose for adjuvant treatment of early-stage NSCLC is 80 mg orally once daily, with or without food, until disease recurrence, or unacceptable toxicity, or for up to 3 years. Most common (>20%) adverse reactions in patients taking osimertinib, including laboratory abnormalities, were lymphopenia, leukopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough.
Rintatolimod Awarded Orphan Drug Designation for Pancreatic Cancer
The FDA granted rintatolimod Orphan Drug Designation status for the treatment of pancreatic cancer. The approval is based on a statistically significant positive pancreatic cancer survival results from a multi-year Early Access Program conducted at Erasmus University Medical Center in the Netherlands. The median overall survival was approximately two-fold higher-that is 200 percent-in the rintatolimod arm, as compared to a historical control cohort matched for age, gender, stage of disease, and number of cycles of FOLFIRINOX therapy.
Breakthrough Therapy Designation of Sotorasib for NSCLC With KRAS G12C
Breakthrough Therapy designation was granted for the investigational KRAS G12C inhibitor, sotorasib, for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS G12C mutation, as determined by an FDA-approved test, following at least one prior systemic therapy.
"For more than 40 years, scientists have been trying to target KRAS. Today's news is a welcome update for the many non-small cell lung cancer patients with the KRAS G12C mutation, who currently have no targeted therapies," said Bonnie J. Addario, cofounder and Board Chair of the GO2 Foundation for Lung Cancer.
KRAS G12C is the most common KRAS mutation in NSCLC. In the U.S., about 13 percent of patients with NSCLC adenocarcinoma harbor the KRAS G12C mutation, and each year approximately 25,000 new patients in the U.S. are diagnosed with KRAS G12C-mutated NSCLC. Unmet need remains high and options are limited for NSCLC patients with the KRAS G12C mutation that have failed first-line treatment. The outcomes with current therapies are suboptimal with response rates of approximately 9-18 percent and a median progression-free survival of approximately 4 months for second-line NSCLC.
Sotorasib was the first KRAS G12C inhibitor to enter the clinic and is being studied in the broadest clinical program exploring 10 combinations with global sites spanning across four continents. In just over 2 years, the sotorasib clinical program has also established the deepest clinical dataset with more than 600 patients studied across 13 tumor types.
A Breakthrough Therapy designation is designed to expedite the development and regulatory review of medicines that may demonstrate substantial improvement on a clinically significant endpoint over available medicines. The Real-Time Oncology Review (RTOR) pilot program aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible.
The designation and RTOR are supported by positive Phase II results in patients with advanced NSCLC from the CodeBreaK 100 clinical study, whose cancer had progressed despite prior treatment with chemotherapy and/or immunotherapy. In the study, treatment with sotorasib provided durable anticancer activity with a positive benefit-risk profile.