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New Oncology Drugs/Indications Approved by the FDA: December 16 2020 - February 3, 2021

JHOP - February 2021 Vol 11, No 1 - FDA Updates
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This section provides a brief overview of new cancer drugs and new indications approved by the FDA between December 16, 2020, and February 3, 2021.


NEW DRUGS

FDA Approves Tepmetko for Metastatic NSCLC and MET Exon 14 Skipping Alterations

On February 3, 2021, the FDA accelerated the approval of oral tepotinib (Tepmetko; EMD Serono) for adults with metastatic non–small-cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping alterations. This approval is for treatment-naïve patients as well as for patients who have received previous therapy. Tepotinib is the first MET inhibitor approved by the FDA and should be selected for treatment based on the presence of METex14. The FDA has granted tepotinib breakthrough therapy and orphan drug designations.

METex14 skipping occurs in approximately 3% to 4% of NSCLC cases, and patients with this aggressive lung cancer are often elderly and face a poor clinical prognosis,” said Paul K. Paik, MD, VISION lead investigator and Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY. “There is a pressing need for targeted treatments that have the potential to generate durable anti-tumor activity and improve the lives of patients with this challenging disease.”

“The availability of a new precision medicine for NSCLC with METex14 skipping alterations advances patient access to targeted treatment and underscores the importance of routine comprehensive biomarker testing for patients with this challenging cancer,” said Andrea Ferris, LUNGevity President and CEO.

The FDA approved tepotinib based on data from the phase 2 clinical trial VISION, a multicenter, nonrandomized, open-label, multicohort study that enrolled 152 patients with advanced or metastatic NSCLC and METex14 skipping alterations.

The study included 69 treatment-naïve patients and 83 patients who have received previous therapy. All patients received monotherapy with tepotinib 450 mg orally once daily until disease progression or until unacceptable adverse events. The main efficacy outcome measures were overall response rate (ORR) and duration of response (DOR).

Among the 69 treatment-naïve patients, the ORR was 43% (95% confidence interval [CI], 32%-56%), with a median DOR of 10.8 months (95% CI, 6.9-not estimable). Among the 83 patients who received previous treatment, the ORR was 43% (95% CI, 33%-55%), with a median DOR of 11.1 months (95% CI, 9.5-18.5).

The most common (≥20% of patients) adverse reactions were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. Tepotinib can also cause interstitial lung disease, hepatotoxicity, and embryo-fetal toxicity.

The recommended dose of tepotinib tablets is 450 mg orally once daily.

This approval was based on ORR and DOR data. Continued approval may be contingent on the verification of clinical benefit in confirmatory clinical trials.

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Orgovyx First FDA-Approved Oral Hormone Therapy for Advanced Prostate Cancer

On December 18, 2020, the FDA approved relugolix (Orgovyx; Myovant Sciences), a new oral gonadotropin-releasing hormone (GnRH) receptor antagonist, for the treatment of adults with advanced prostate cancer. Relugolix is the first oral androgen-deprivation therapy (ADT) and the first oral GnRH receptor antagonist approved for the treatment of patients with advanced prostate cancer. The FDA granted relugolix priority review for this indication.

“Today’s approval marks the first oral drug in this class, and it may eliminate some patients’ need to visit the clinic for treatments that require administration by a health care provider,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “This potential to reduce clinic visits can be especially beneficial in helping patients with cancer stay home and avoid exposure during the coronavirus pandemic.”

The American Cancer Society estimated that >190,000 cases of prostate cancer would be diagnosed in the United States in 2020.

The FDA approved relugolix based on data from HERO, a randomized, open-label clinical trial of 622 patients with prostate cancer requiring at least 1 year of ADT because of prostate cancer recurrence after radiation or surgery or patients with newly diagnosed castration-sensitive advanced prostate cancer.

The patients were randomized in a 2:1 ratio to receive 48 weeks of either relugolix 360 mg oral loading dose on the first day, followed by daily oral doses of 120 mg, or to another GnRH receptor antagonist, leuprolide acetate 22.5-mg injection subcutaneously, administered every 3 months.

The study’s main efficacy measure was medical castration rate, which was defined as maintaining serum testosterone suppression to castrate levels (ie, <50 ng/dL) by day 29 through 48 weeks of treatment. In the relugolix arm, the medical castration rate was 96.7% (95% confidence interval, 94.9%-97.9%), an almost complete efficacy rate.

The most common (≥10%) adverse reactions reported with relugolix were hot flushes, musculoskeletal pain, fatigue, diarrhea, and constipation. The most common (≥15%) laboratory abnormalities were increased glucose, triglyceride, alanine aminotransferase, and aspartate aminotransferase levels. Decreased hemoglobin level was also observed.

The recommended relugolix dose is an oral loading dose of 360 mg on the first day, then a daily oral dose of 120 mg.

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FDA Approves Margenza for the Treatment of Metastatic HER2-Positive Breast Cancer

On December 16, 2020, the FDA approved margetuximab-cmkb (Margenza; MacroGenics) in combination with chemotherapy for the treatment of adults with metastatic HER2-positive breast cancer who have received ≥2 previous anti-HER2 regimens, of which at least 1 was for metastatic disease. The application for this approval received a fast-track designation.

“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head phase 3 clinical trial, Margenza with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Hope S. Rugo, MD, Director of Breast Oncology and Clinical Trials Education, University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

The FDA approved margetuximab based on SOPHIA, a randomized, multicenter, phase 3 clinical trial that included 536 patients with IHC (immunohistochemistry)3-positive or ISH (in situ hybridization)-amplified HER2-positive metastatic breast cancer who had received previous treatment with other anti-HER2 therapies.

Patients were randomized in a 1:1 ratio to margetuximab plus chemotherapy or to trastuzumab plus chemotherapy. Patients were stratified to treatment groups by the choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of lines of therapy received in the metastatic setting

(≤2 or >2), and the number of metastatic sites (≤2 or >2). The primary end points were progression-free survival (PFS) and overall survival. The secondary end points were objective response rate (ORR) and duration of response (DOR).

The median PFS in the margetuximab arm was 5.8 months (95% confidence interval [CI], 5.5-7) compared with 4.9 months (95% CI, 4.2-5.6) in the control arm (hazard ratio, 0.76; 95% CI, 0.59-0.98; P = .033). The confirmed ORR was 22% (95% CI, 17-27), with a median DOR of 6.1 months (95% CI, 4.1-9.1) in the margetuximab arm versus an ORR of 16% (95% CI, 12-20) in the control arm and a median DOR of 6 months (95% CI, 4.0-6.9).

The most common (>10%) adverse reactions with margetuximab plus chemotherapy were fatigue or asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia or myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain. Treatment with margetuximab is associated with the risks for left-ventricular dysfunction and embryo-fetal toxicity.

The recommended dose of margetuximab is 15 mg/kg by intravenous infusion over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks.

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NEW INDICATIONS

Xalkori Approved for Anaplastic Large-Cell Lymphoma and ALK Mutation in Young Patients

On January 14, 2021, the FDA approved crizotinib (Xalkori; Pfizer) for the treatment of young patients aged 1 to 21 years with relapsed or refractory systemic anaplastic large-cell lymphoma (ALCL) and ALK mutation. The safety and efficacy of crizotinib have not been established in older adults with this diagnosis. The FDA granted this application priority review and breakthrough therapy and orphan drug designations.

Crizotinib was previously approved for patients with metastatic non–small-lung cancer and ALK or ROS1 mutation.

This new indication for crizotinib was based on data from the ADVL0912 study, a multicenter, single-arm, open-label clinical trial in patients aged 1 to 21 years. A total of 26 patients with relapsed or refractory ALCL and ALK mutation were enrolled in the study. All patients had previously received at least 1 systemic treatment.

In the ADVL0912 study, 20 patients received oral crizotinib 280 mg/m2 and the other 6 patients received 165 mg/m2 twice daily until disease progression or until unacceptable adverse events. The patients were permitted to discontinue crizotinib therapy so they could undergo hematopoietic stem-cell transplant.

The study efficacy was based on the objective response rate (ORR) and the duration of response (DOR), as assessed by an independent review committee. The ORR in the 26 patients was 88% (95% confidence interval, 71-96), with an 81% rate of complete remission. Of the 23 patients who achieved a response, 39% of patients had a DOR of ≥6 months, and 22% had a DOR of ≥12 months.

Grade 1 or 2 ocular adverse events were reported in 65% of patients with ALCL; gastrointestinal adverse events were reported in 92% of the patients, and serious adverse reactions occurred in 35% of the patients, most often from neutropenia and infection. Grade 3 or 4 laboratory abnormalities (≥15%) included neutropenia, lymphopenia, and thrombocytopenia.

The most common (≥35%) adverse reactions, excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus.

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Tagrisso Receives New Indication as Adjuvant Therapy for NSCLC with EGFR Mutations

On December 18, 2020, the FDA approved osimertinib (Tagrisso; AstraZeneca) for adjuvant therapy after tumor resection in patients with non–small-cell lung cancer (NSCLC) and EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. The FDA approved this application 2 months ahead of the FDA goal date and granted it a breakthrough therapy designation.

Osimertinib was previously approved for the first-line treatment of metastatic NSCLC and EGFR exon 19 deletions or exon 21 L858R mutations, and for the treatment of metastatic NSCLC and EGFR T790M mutation after EGFR tyrosine kinase inhibitor therapy.

The FDA approved the new indication based on a randomized, double-blind, placebo-controlled clinical trial in 682 patients with NSCLC and EGFR exon 19 deletions or exon 21 L858R mutation who had complete tumor resection, with or without previous adjuvant chemotherapy. Eligible patients with resectable (stage II-IIIA) tumors had to have predominantly nonsquamous histology and EGFR exon 19 deletions or exon 21 L858R mutations.

The patients were randomized in a 1:1 ratio to oral osimertinib 80 mg once daily or to placebo after recovery from surgery and standard adjuvant chemotherapy, if used.

The major efficacy outcome measure was disease-free survival (DFS) in patients with stage II to stage IIIA NSCLC. The median DFS was not reached in the osimertinib arm compared with 19.6 months in the placebo arm (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.12-0.23; P <.0001). The secondary efficacy end point was DFS in the overall study population; the median was not reached in the osimertinib arm versus 27.5 months in the placebo arm (HR, 0.20; 95% CI, 0.15-0.27; P <.0001).

The most common (>20%) adverse reactions reported with osimertinib, including laboratory abnormalities, were lymphopenia, leukopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough.

The recommended dose of osimertinib as adjuvant treatment of early-stage NSCLC is 80 mg once daily until disease recurrence or until unacceptable adverse events, or for up to 3 years.

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Xpovio Approved for Patients with Relapsed or Refractory Multiple Myeloma

On December 18, 2020, the FDA approved selinexor (Xpovio; Karyopharm Therapeutics) in combination with bortezomib and dexamethasone for the treatment of adults with multiple myeloma after ≥1 previous therapies. The FDA granted this indication an orphan drug designation.

Selinexor was previously approved in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who have received ≥4 previous therapies, and for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after ≥2 lines of systemic therapy.

The FDA approved the new indication based on data from the BOSTON clinical trial, a randomized open-label, multicenter, active comparator–controlled study in patients with relapsed or refractory multiple myeloma who had received between 1 and 3 previous therapies. Patients were randomized in a 1:1 ratio to once-weekly selinexor orally, in combination with once-weekly bortezomib subcutaneously and low-dose dexamethasone twice-weekly (SVd) or to the standard twice-weekly bortezomib plus low-dose dexamethasone (Vd) regimen.

The main end point was progression-free survival (PFS). The estimated median PFS was 13.9 months (95% confidence interval [CI], 11.7-not estimable) in the SVd arm versus 9.5 months (95% CI, 7.6-10.8) in the Vd arm (estimated hazard ratio, 0.70; 95% CI, 0.53-0.93).

The most common (≥20%) adverse reactions reported in the SVd arm were nausea, fatigue, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting. Grade 3 or 4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia.

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Last modified: April 9, 2021