Recent FDA Actions: Spring 2023

Evidence-Based OncologyApril 2023
Volume 29
Issue 4
Pages: SP315-SP316

In breast cancer, approval for elacestrant and a new indication for sacituzumab govitecan; approval for pirtobrutinib for mantle cell lymphoma.

FDA Approves Sacituzumab Govitecan for Pretreated HR+/HER2– Metastatic Breast Cancer

The FDA approved sacituzumab govitecan (Trodelvy) on February 3 to treat patients with unresectable locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer following endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.1 The approval is based on results from the phase 3 TROPiCS-02 trial (NCT03901339), which demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit with sacituzumab govitecan compared with physician’s choice of single-agent chemotherapy.2
A total of 543 patients were enrolled in the global, multicenter, open-label TROPiCS-02 study and were randomly assigned to receive either sacituzumab govitecan or physician’s choice of single-agent chemotherapy with eribulin, capecitabine, gemcitabine, or vinorelbine. All patients had hormone receptor–positive, HER2-negative metastatic breast cancer and had undergone treatment with endocrine therapy, a CDK4/6 inhibitor, and 2 to 4 lines of chemotherapy for metastatic disease.

Patients treated with sacituzumab govitecan showed a median OS of 14.4 months (95% CI, 13.0-15.7), whereas patients treated with single-agent chemotherapy had a median OS of 11.2 months (95% CI, 10.1-12.7), which is a 21% decrease in the risk of death among the sacituzumab govitecan cohort (HR, 0.79; 95% CI, 0.65-0.96; P = .02).
The median progression-free survival (PFS) was 5.5 months in the sacituzumab govitecan arm (95% CI, 4.2-7.0), whereas PFS in the chemotherapy arm was 4 months (95% CI, 3.1-4.4). The difference amounts to a 34% reduction in the risk of disease progression or death in the sacituzumab govitecan cohort (HR, 0.66; 95% CI, 0.53-0.83; P = .0003).



“Despite decades of advances, [patients] living with pretreated hormone receptor–positive, HER2-negative metastatic breast cancer need new treatment options. Nearly all [patients] with this type of breast cancer will eventually develop resistance to endocrine-based therapies and progress on available chemotherapies,” Hope S. Rugo, MD, FASCO, professor of medicine and director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center, said in a statement. “This approval is significant for the breast cancer community. We have had limited options to offer patients after endocrine-based therapy and chemotherapy, and to see a clinically meaningful survival benefit of more than 3 months with a quality-of-life benefit for these women is exceptional.”

The primary end point in the study was PFS, and secondary end points included OS, overall response rate (ORR), clinical benefit rate, duration of response, assessment of tolerability and safety, and quality-of-life measures.

The sacituzumab govitecan arm significantly improved ORR and time to deterioration of global health status, among other secondary end points. No new safety signals were identified in the study.

Sacituzumab govitecan was first FDA approved in April 2021 for the treatment of patients with unresectable, locally advanced or metastatic triple-negative breast cancer following 2 or more systemic therapies, with at least 1 of them being for metastatic disease.3

“We are pleased that Trodelvy [can] now provide new hope for [patients] living with pretreated hormone receptor–positive, HER2-negative metastatic breast cancer, building on the transformative role that Trodelvy is already playing for [those] with metastatic triple-negative breast cancer,” Daniel O’Day, chairman and CEO of Gilead Sciences, Inc, said. “We thank the physicians, patients, and their families who put their trust in the TROPiCS-02 study and helped make this milestone possible.” 

1. US FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead Sciences, Inc. February 3, 2023. Accessed February 3, 2023.
2. Rugo HS, Bardia A, Marmé F, et al. Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). Ann Oncol. 2022;33(suppl 7):S1386. doi:10.1016/j.annonc.2022.08.012
FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. News release. FDA. Updated April 8, 2021. Accessed February 3, 2023.

FDA Approves Elacestrant for ER+/HER2–, ESR1-Mutated Advanced or Metastatic Breast Cancer

The FDA approved elacestrant (Orserdu) on January 27 for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.1 The FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients who are eligible to receive elacestrant.

The regulatory decision was based on data from the randomized, open-label, active-controlled, multicenter phase 3 EMERALD trial (NCT03778931), in which the oral selective estrogen degrader (n = 115) reduced the risk of disease progression or death by 45% compared with fulvestrant (Faslodex) or an aromatase inhibitor (n = 113) in this population. The median progression-free survival (PFS) with elacestrant was 3.8 months (95% CI, 2.2-7.3) vs 1.9 months (95% CI, 1.9-2.1) with the control arm (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).2

EMERALD enrolled patients with ER-positive/HER2-negative breast cancer who had progressed on 1 to 2 lines of endocrine therapy, including 1 line that contained a CDK4/6 inhibitor. Patients were able to have received up to 1 previous line of chemotherapy in either the advanced or metastatic setting.

Enrolled patients were randomly assigned 1:1 to receive 345 mg of oral elacestrant per day (n = 239) or investigator’s choice of endocrine therapy, which could have been fulvestrant (Faslodex; n = 166) or an aromatase inhibitor such as anastrozole, letrozole, or exemestane (n = 73). Patients received treatment until progressive disease or intolerable toxicity.

Patients were stratified based on ESR1 mutational status (yes vs no), previous fulvestrant exposure (yes vs no), and the presence of visceral metastases (yes vs no). ESR1 status was determined by blood circulating tumor DNA using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand-binding domain.

PFS by blinded imaging review committee assessment served as the major efficacy outcome of the trial. Overall survival was an additional efficacy outcome. An exploratory analysis of PFS for patients without ESR1 mutations (n = 250) showed an HR of 0.86 (95% CI, 0.63-1.19), which is indicative that the improvement observed in the intention-to-treat population was primarily attributed to the data observed in the ESR1-mutated population.

Among the patients with ESR1 mutations, the median age was 63 years (range, 28-89) and all were women. Most (72%) of the patients were White, 5.7% were Asian, 3.5% were Black, and 0.4% were identified as another race; this information was not known or reported in 18.4% of patients. Fifty-seven percent of patients had an Eastern Cooperative Oncology Group performance status of 0 at baseline and 43% had a status of 1. Most patients (71%) had visceral disease (71%).

Additionally, 62% of patients had received 1 line of endocrine therapy and 39% had received 2 lines in the advanced or metastatic setting. All patients had previous treatment with a CDK4/6 inhibitor, 24% had prior fulvestrant, and 25% had prior chemotherapy.

Regarding safety, the most common adverse effects observed in at least 10% of patients treated with elacestrant, including laboratory abnormalities, were musculoskeletal pain, nausea, increased cholesterol, increased aspartate aminotransferase, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased alanine transaminase, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia. 

A version of this article first appeared on OncLive®.

1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed February 25, 2023.
2. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the phase 3 EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

FDA Approves Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma

On January 27, the FDA approved pirtobrutinib (Jaypirca) for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) following at least 2 lines of systemic therapy, including a previous Bruton tyrosine kinase (BTK) inhibitor.1 The approval was granted to Eli Lilly and Company under the regulatory agency’s accelerated approval pathway, with the decision supported by findings from a subset of patients enrolled to the open-label, single-arm phase 1/2 BRUIN trial (NCT03740529).2

Pirtobrutinib elicited an overall response rate of 50% (95% CI, 41%-59%) in those who received the agent at a daily dose of 200 mg (n = 120); this included a complete response rate of 13% and a partial response rate of 38%. The median time to response was 1.8 months (range, 0.8-4.2) and the median duration of response (DOR) was 8.3 months (95% CI, 5.7–not evaluable). The Kaplan-Meier estimate for the 6-month DOR rate was 65.3% (95% CI, 49.8%-77.1%).

Pirtobrutinib is a highly potent and selective noncovalent BTK inhibitor that has nanomolar potency against wild-type and C481-mutant BTK in cell and enzyme assays. Additionally, favorable pharmacologic properties allow sustained BTK inhibition throughout dosing intervals.

BRUIN consisted of a phase 1 dose-escalation and -expansion portion, which evaluated between 25 mg and 300 mg of pirtobrutinib daily, as well as a phase 2 portion, which evaluated 200 mg of pirtobrutinib daily, both as part of 28-day cycles.2 Eligible patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status between 0 and 2, and had active disease requiring treatment. Patients were excluded if they had active central nervous system lymphoma or received allogeneic hematopoietic stem cell transplantation or chimeric antigen receptor (CAR) T-cell therapy within 60 days.

The efficacy assessment was based on the 120 patients with MCL. The median age of these patients was 71 years (range, 46-88). Most patients were men (79%) and White (78%). Moreover, 78% of patients had the classic/leukemic variant of the disease, 12% had pleomorphic MCL, and 11% had blastoid MCL. The simplified Mantle Cell Lymphoma International Prognostic Index score was low, intermediate, and high in 15%, 59%, and 26% of patients, respectively.

Additionally, patients had received a median of 3 previous lines of therapy, with a range of 1 to 9 lines of treatment. Notably, 93% of patients had received at least 2 prior lines of treatment. All participants received 1 or more prior lines of therapy that contained a BTK inhibitor. Other previous therapies included chemoimmunotherapy (88%), hematopoietic stem cell transplant (20%), lenalidomide (Revlimid; 18%), and CAR T-cell therapy (9%).

The most common prior BTK inhibitors that patients received included ibrutinib (67%), followed by acalabrutinib (30%), and zanubrutinib (8%). Eighty-three percent of patients discontinued their last BTK inhibitor because of refractory or progressive disease, 10% did so due to toxicity, and 5% discontinued for other unspecified reasons.

Data from the pooled safety analysis of the full study population (n = 583) indicated that the most common toxicities experienced with pirtobrutinib were decreased neutrophil count, decreased hemoglobin, decreased platelet count, fatigue, musculoskeletal pain, decreased lymphocyte count, bruising, and diarrhea.

Of the 128 patients with MCL, 36% received the agent for at least 6 months and 10% received it for 1 year or longer. The most common adverse events (AEs) to occur in 10% or more of patients with MCL who received pirtobrutinib included fatigue (all-grade, 29; grade 3/4, 1.6%), edema (18%; 0.8%), fever (13%; 0%), musculoskeletal pain (27%; 3.9%), arthritis or arthralgia (12%; 0.8%), diarrhea (19%; 0%), constipation (13%; 0%), abdominal pain (11%; 0.8%), nausea (11%; 0%), dyspnea (17%; 2.3%), cough (14%; 0%), bruising (16%; 0%), pneumonia (16%; 14%), upper respiratory tract infections (10%; 0.8%), peripheral neuropathy (14%; 0.8%), dizziness (10%; 0%), rash (14%; 0%), and hemorrhage (11%; 3.1%).

Dose reductions and treatment interruptions due to AEs were required in 4.7% and 32% of patients, respectively. Moreover, 9% of patients experienced AEs that led to permanent discontinuation of pirtobrutinib.
Thirty-eight percent of patients experienced serious AEs. Serious toxicities that occurred in 2% or more of patients included pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%).

Continued approval for the indication may be contingent upon verification of clinical benefit in a confirmatory trial. To this end, the phase 3 BRUIN-MCL-321 trial (NCT04662255) is currently enrolling participants. 

A version of this article first appeared on OncLive®.

1. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. News release. FDA. January 27, 2023. Accessed February 25, 2023.
2. Cohen JB, Shah NN, Alencar AJ, et al. MCL-133 pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in previously treated mantle cell lymphoma: updated results from the phase 1/2 BRUIN study. Clin Lymphoma Myeloma Leuk. 2022;22(suppl 2):S394-S395. doi:10.1016/S2152-2650(22)01569-5

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