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FDA NEWS: January 10, 2022, and January 25, 2022

TOP - March 2022 Vol 15, No 2 - FDA Updates

This section provides a brief overview of new cancer drugs and new fast-track designations approved by the FDA between January 10, 2022, and January 25, 2022.


Kimmtrak, a Bispecific CD3 T-Cell Engager, First FDA-Approved Drug for Unresectable or Metastatic Uveal Melanoma

On January 25, 2022, the FDA accelerated the approval of tebentafusp-tebn (Kimmtrak; Immunocore), a bispecific gp100 peptide-HLA–directed CD3 T-cell engager, for the treatment of adults with HLA-A*02:01 unresectable or metastatic uveal (intraocular) melanoma. The FDA granted tebentafusp breakthrough therapy and orphan drug designations for this indication.

The efficacy was evaluated in the IMCgp100-202 clinical trial, a randomized, open-label, multicenter study of 378 patients with metastatic uveal melanoma. All patients had to have the HLA-A*02:01 genotype, as detected by a central assay. Patients who had previously received systemic therapy or localized liver-directed therapy were excluded, but patients who had undergone surgical resection of oligometastatic disease were allowed to participate. Patients with cardiac disease or symptomatic, untreated brain metastases were also excluded from the study.

The patients were randomized (2:1) to tebentafusp (N = 252) or to the investigator’s choice (N = 126) of either pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. Tebentafusp was administered weekly by intravenous infusion at 20 mcg on day 1; 30 mcg on day 8; 68 mcg on day 15; and every subsequent week, until disease progression or unacceptable adverse events.

The main end point was overall survival. An additional efficacy outcome was investigator-assessed progression-free survival per RECIST version 1.1.

The median overall survival was 21.7 months (95% confidence interval [CI], 18.6-28.6) in patients who received tebentafusp versus 16 months (95% CI, 9.7-18.4) in the investigator’s choice arm (hazard ratio, 0.51; 95% CI, 0.37-0.71; P <.0001). The progression-free survival was 3.3 months (95% CI, 3-5) with tebentafusp and 2.9 months (95% CI, 2.8-3) with the investigator’s choice (hazard ratio, 0.73; 95% CI, 0.58-0.94; P = .0139).

The most common (≥30%) adverse reactions were cytokine-release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate levels.

The recommended intravenous dose of tebentafusp is 20 mcg on day 1; 30 mcg on day 8; 68 mcg on day 15; and 68 mcg once weekly, thereafter.

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FDA Grants Gedatolisib, a Dual PI3K and mTOR inhibitor, Fast-Track Review for ER-Positive, HER2-Negative Breast Cancer

On January 18, 2022, the FDA granted a fast-track designation to the investigational drug gedatolisib (from Celcuity Inc), a PI3K and mTOR inhibitor, as a potential therapeutic option in patients with hormone receptor–positive, HER2-negative metastatic breast cancer whose disease progressed during CDK4/6 therapy, based on data from the phase 2 dose-escalation portion of a dose-expansion clinical trial. Gedatolisib is a potent, reversible, dual inhibitor that selectively targets all class I isoforms of PI3K and mTOR.

Preclinical data have indicated that the combination of gedatolisib, palbociclib (Ibrance), and fulvestrant (Faslodex) had superior activity to any single agent or to dual combinations in a mouse xenograft model of an estrogen receptor (ER)-positive, HER2-negative breast cancer and PIK3CA mutation.

In a phase 1b multicenter, open-label clinical trial, investigators sought to identify the maximum tolerated dose of the triplet of gedatolisib, palbociclib, and letrozole (L cohort) or of gedatolisib, palbociclib, and fulvestrant (F cohort).

The phase 2 dose-escalation portion of the dose-expansion study enrolled women with a diagnosis of ER-positive, HER2-negative metastatic breast cancer aged ≥18 years. For the dose-escalation portion, patients had to have progressing metastatic disease. For the dose-expansion portion of the study, patients must have not received previous endocrine-based systemic treatment in the metastatic setting, had metastatic disease during or after 1 endocrine-based therapy in the metastatic setting and no CDK4/6 inhibitor, or they had to have metastatic disease during or after 1 or 2 endocrine-based treatments in the metastatic setting after previous CDK inhibition.

The primary end point of the dose-escalation portion was first-cycle dose-limiting toxicities, and the primary end point for the expansion portion of the study was investigator-assessed objective response rate (ORR). Key secondary end points included safety, tumor response in the dose-escalation portion, duration of response and progression-free survival in the expansion portion only, corrected QT interval, and pharmacokinetics.

Data from the dose-expansion portion of the study, in which patients had received gedatolisib 180 mg, were presented at the 2021 San Antonio Breast Cancer Symposium. That study portion included 103 patients, who were divided into 4 treatment arms. The patients in arm A received gedatolisib, palbociclib, and letrozole as first-line treatment (N = 31); patients in arm B were CDK inhibitor–naïve and received gedatolisib plus palbociclib or fulvestrant as second-line treatment

(N = 13); those in arm C had previously received a CDK inhibitor and now received gedatolisib plus palbociclib or fulvestrant in the second- or third-line setting on a weekly basis (N = 32); finally, patients in arm D had previously received CDK inhibitors and now received gedatolisib plus palbociclib or fulvestrant as second- or third-line treatment on a 3-weeks-on, 1-week-off basis (N = 27).

The ORRs in arms A, B, C, and D were 85%, 77%, 32%, and 63%, respectively, and the clinical benefit rates were 96%, 100%, 79%, and 96%, respectively. In addition, the median progression-free survival was 31.1 months in arm A, 12.9 months in arm D, 11.9 months in arm B, and 5.1 months in arm C.

An exploratory analysis of ORR and the duration of therapy showed a significantly higher ORR and longer duration of therapy in arm D versus arm C in those whose disease progressed within 6 months and 12 months. Moreover, the ORR was superior in arm D relative to arm C, regardless of previous therapies received.

The most common (>1%) grade 3 or 4 adverse effects reported across the 4 arms included stomatitis, decreased neutrophils, fatigue, vomiting, anemia, diarrhea, leukopenia, constipation, pruritus, rash, maculopapular rash, hyperglycemia, and decreased lymphocyte count. The treatment discontinuing rates were 64.5% in arm A, 76.9% in arm B, 100% in arm C, and 88.9% in arm D. Conversely, 32.3%, 23.1%, 0%, and 11.1% of patients, respectively, were still using the treatment at the time of the data cutoff, on May 10, 2021.

A phase 3 clinical trial is planned based on these data.

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Enobosarm Granted Fast-Track FDA Review for AR- and ER-Positive, HER2-Negative Metastatic Breast Cancer

On January 10, 2022, the FDA granted a fast-track designation to enobosarm (Ostarine; Veru), a selective androgen receptor (AR)-targeting agonist, for the treatment of patients with AR-positive, estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, based on data from the phase 3 ARTEST clinical trial.

The ARTEST study included approximately 210 patients who received oral enobosarm, 9 mg daily. Patients had to have metastatic disease that had progressed after treatment with a nonsteroidal aromatase inhibitor, fulvestrant, and a CDK4/6 inhibitor with an AR nucleus staining of ≥40%. A companion diagnostic test is being developed and validated to identify appropriate patients for this therapy.

Enobosarm was recently assessed as part of the open-label phase 2 G200802 clinical trial in patients with AR-positive, ER-positive metastatic breast cancer. Patients were randomized to 9 mg (N = 72) or 18 mg (N = 64) of oral enobosarm daily. The primary end point of the study was the clinical benefit rate at 6 months, per RECIST version 1.1. The key secondary end points were objective response rate, best overall response, radiographic progression-free survival, and duration of clinical benefit.

The clinically meaningful benefit rate was 32% in the 9-mg group compared with 29% in the 18-mg group. By the study end, the median duration of clinical benefit was not reached in the 9-mg group versus 14.1 months in the 18-mg group.

A post-hoc analysis showed that the presence of AR and the amount of expression could predict which patients were most likely to have an antitumor response to enobosarm. The analysis combined patients from the 9-mg and 18-mg groups with a known AR status and measurable disease (N = 84). The 40% AR expression cutoff rate was determined to indicate which patients were most likely to benefit from enobosarm treatment.

At 24 weeks, the clinical benefit rate was 52% at 40% AR staining compared with 14% for <40% staining (P <.0004). Patients had a combined partial and complete response of 34% at 40% AR staining versus 2.7% for those with <40% staining (P <.0003). The median radiographic progression-free survival was 5.47 months for 40% AR staining versus 2.7 months for <40% staining (P <.001).

When using the 40% cutoff, 57% of women with AR-positive, ER-positive, and HER2-negative metastatic breast cancer would qualify for treatment with enobosarm. Women who received 9 mg or 18 mg of enobosarm reported to have an improvement in quality of life, including improved mobility, reduced anxiety or depression, and less pain. A total of 6 patients had drug-related grade 3 or 4 adverse events in the 9-mg group, and 10 patients in the 18-mg group.

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Last modified: March 21, 2022