U.S. FDA Drug Approvals for Breast Cancer - A Decade in Review

Palbociclib^8,9,10,11: In 2015, FDA granted AA to the first CDK4/6i for treatment of patients with HR-positive, HER2-negative advanced or MBC in combination with letrozole as initial endocrine-based therapy in postmenopausal women. The AA was based on a randomized, open-label phase I/II PALOMA-1 trial that compared palbociclib plus letrozole with letrozole alone in postmenopausal women with HR-positive, HER2-negative BC who had not received prior systemic treatment for advanced disease. PALOMA-1 trial demonstrated a substantial improvement in median PFS however given the small trial size and potential uncertainty surrounding the results an AA was granted. This indication was expanded in 2017 to include in combination with any aromatase inhibitor (AI) and converted to regular approval (RA) based on consistent results from a larger randomized PALOMA-2 trial in the same setting.

In 2016, palbociclib received RA in combination with fulvestrant based on the results of randomized, double-blind trial PALOMA-3. In 2019, FDA expanded the approved indications for palbociclib in combination with an AI or fulvestrant, to include men. Given the rarity of BC in males, this expansion of indications was mainly based on the use of trial data from the PALOMA trials and supported by real-world data of men from electronic health records and insurance claims.¹²

Ribociclib^{13,14,15,16,17,18}: In 2017, ribociclib in combination with an AI received RA for the treatment of postmenopausal women based on a randomized, double-blind, placebo-controlled trial MONALEESA-2. The indication was expanded in 2018 in combination with an AI for pre/perimenopausal women based on results from a randomized, double-blind, placebo-controlled trial MONALEESA-7. Ribociclib was also approved in combination with fulvestrant for postmenopausal women with HR-positive, HER2-negative advanced or MBC, as initial endocrine-based therapy or following disease progression on endocrine therapy based on results from a randomized double-blind, placebo-controlled MONALEESA-3 trial demonstrating a significant median PFS. In 2017, ribociclib and letrozole as a co-package was approved.¹⁹

Abemaciclib^{20,21,22,23,24}: In 2017, abemaciclib in combination with fulvestrant received RA for women with HR-positive, HER2-negative advanced or MBC based on MONARCH-2, a placebo-controlled, randomized trial. In addition, abemaciclib was approved as monotherapy for women and men with HR-positive, HER2-negative advanced or MBC with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. The approval as monotherapy was based on MONARCH-1, a single-arm trial which demonstrated a significant objective response rate (ORR) median duration of response (DoR). In 2018, abemaciclib received RA in combination with an AI for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or MBC based on randomized, double-blinded, placebo-controlled MONARCH-3 trial, which demonstrated a significant improvement of median PFS of abemaciclib compared to placebo.

Alpelisib^25,26,27: In 2019, alpelisib, an oral alpha-specific PI3K inhibitor, received RA in combination with fulvestrant for HR-positive, HER2-negative, PIK3CA-mutated, advanced or MBC as detected by an FDA-approved test following progression on or after an endocrine-based regimen. The approval was based on SOLAR-1, a randomized, double-blind, placebo-controlled trial and was the first PI3K inhibitor receiving FDA approval for breast cancer. The median PFS was significant in the PIK3CA tumor-mutated population. No PFS benefit was observed in patients whose tumors did not have a PIK3CA mutation, therefore, the indication was limited to the PIK3CA-mutated population. OS data were immature at the time of the primary PFS analysis. Of note, only 6% of trial participants had received an AI plus CDK inhibitor and no patients had prior fulvestrant plus CDK4/6i prior to receiving alpelisib plus fulvestrant. However, although this subset was small with wide confidence interval intervals, the PFS results favored the use of alpelisib. This was further supported by interim results of the BYLieve trial, in which a cohort treated with prior AI and CDK4/6i benefitted from treatment with alpelisib plus fulvestrant.²⁸

Pertuzumab^29,30,31: In 2012, FDA granted pertuzumab, a monoclonal antibody against HER2, RA in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive MBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on CLEOPATRA, a randomized double-blind, placebo-controlled trial in patients with HER2-positive MBC who received trastuzumab and docetaxel combined with either placebo or pertuzumab. A significant improvement in the primary endpoint of PFS was seen for the addition of pertuzumab. The final OS analysis also showed a statistically significant improvement in favor of the pertuzumab arm. This approval represented the first approval after trastuzumab after a gap of greater than 10 years for an antibody targeting HER2 that showed a survival benefit when combined with trastuzumab.

Lapatinib^32,33: In 2010, this oral tyrosine kinase inhibitor of HER2 (initial approval in 2007) was granted AA for use with letrozole for the treatment of postmenopausal women with HR-positive MBC that overexpresses the HER2 receptor for whom hormonal therapy is indicated. Approval was based on a double-blind, placebo-controlled trial that demonstrated a significant median PFS improvement in the HER2-positive population. No benefit was noted in the HER2-negative population included in the trial. This indication was converted to RA in 2018, based on clinically meaningful and statistically significant improvement in PFS observed in EGF114299/LAP016A2307 trial.

Ado-trastuzumab emtansine (T-DM1)^34,35,36: In 2013, FDA granted RA to T-DM1, an antibody drug conjugate (ADC) targeting HER2 as monotherapy for the treatment of patients with HER2-positive, MBC who previously received trastuzumab and a taxane, separately or in combination. The approval was based on an open-label phase 3 EMILIA trial that randomized patients to receive T-DM1 or lapatinib plus capecitabine. T-DM1 demonstrated a significant improvement in PFS and OS compared to lapatinib plus capecitabine. In addition to the clinically meaningful survival benefit demonstrated, this was also the first ADC granted FDA approval for HER2-positive breast cancer.

Fam-trastuzumab deruxtecan-nxki (T-DXd)^37,38,39: In 2019, T-DXd an ADC targeting HER2, received AA for the treatment of patients with unresectable or metastatic HER2-positive BC who have received two or more prior anti-HER2-based regimens in the metastatic setting. Efficacy was evaluated in DESTINY-Breast01, a single-arm trial with HER2-positive, unresectable or MBC patients, who had received two or more prior anti-HER2 therapies. A clinically meaningful confirmed ORR and median DoR was the basis of approval. At the time of AA, treatment options for HER2-positive patients after two lines of therapy were limited, and the results demonstrated significant improvements over available therapies for a heavily pretreated population.

Neratinib^40,41: In 2020, neratinib, an oral TKI targeting HER2, received RA in combination with capecitabine for patients with HER2-positive advanced or MBC who have received two or more prior anti-HER2 based regimens in the metastatic setting. The approval was based on NALA, an open-label trial in which patients with HER2-positive MBC were randomized to neratinib and capecitabine or lapatinib and capecitabine. A significant improvement in median PFS was demonstrated. Although median PFS data was similar between arms, the 12- and 24-month PFS analyses and Hazard Ratio favored the neratinib arm. Prior to this approval, neratinib was only approved in the early breast cancer setting and now offered another option for heavily pretreated patients in the metastatic setting.

Tucatinib^42,43,44: In 2020, tucatinib, an oral TKI targeting HER2, received RA in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2-positive BC, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. Efficacy was demonstrated in HER2CLIMB, a randomized, double-blind, placebo-controlled trial which enrolled HER2-positive MBC patients who had received prior treatment with trastuzumab, pertuzumab, and T-DM1. Median PFS and OS were significant for tucatinib, trastuzumab, and capecitabine compared to the control arm of trastuzumab and capecitabine. In the subgroup of patients with brain metastases at baseline, the median PFS on the tucatinib arm was significant compared to the control arm. This approval was the first to include the treatment of brain metastases in the indication and was the first new molecular entity to be reviewed under OCE’s Project Orbis.^45,46

Margetuximab-cmkb^47,48: In 2020, margetuximab, a monoclonal antibody targeting HER2 was granted RA in combination with chemotherapy, for the treatment of patients with HER2-positive MBC who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Efficacy and safety were evaluated in SOPHIA, a randomized, open-label trial of patients HER2-positive MBC who had received prior treatment with other anti-HER2 therapies. Patients were randomized to margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Median PFS in the margetuximab arm was significantly improved compared to the control arm. Despite the small magnitude of improvement in median PFS; since trastuzumab plus chemotherapy was an active control in the trial, there was a reasonable assurance that margetuximab plus chemotherapy, at minimum, confers the same amount of benefit, if not more, as trastuzumab plus chemotherapy. Since regular approval does not require demonstration of superiority over available therapies, it was acceptable to grant regular approval to margetuximab-cmkb. Subgroup information for efficacy in various genotypes was not included in the USPI as the FDA considered these exploratory analyses as these were not statistically prespecified.

Atezolizumab^49,50,51,52: Atezolizumab, an anti-PD-1 monoclonal antibody, in combination with paclitaxel protein-bound was granted AA in 2019 for the treatment of patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥ 1% of the tumor area). This approval was based on PFS from IMpassion130, a double-blinded, placebo-controlled, randomized trial. There was a modest improvement in PFS favoring the atezolizumab arm. At the time of final PFS analysis, the first interim analysis for OS was not statistically significant in the ITT population, therefore, OS was not formally tested in the PD-L1 positive population although a difference of approximately 7.5 months was seen in the second interim analysis. Given the modest magnitude of the PFS benefit and the immaturity of OS results at the time of approval, the PFS result for the PD-L1 population appeared reasonably likely to predict clinical benefit at a time when therapies for TNBC were limited and was appropriate for AA as opposed to RA for this indication. A subsequent confirmatory trial comparing atezolizumab in combination with paclitaxel vs. paclitaxel did not verify benefit and indicated a potential detriment in survival thus the label was changed to reflect this information and recommend against use with paclitaxel combination. This approval was discussed at the FDA Oncology Drugs Advisory Committee (ODAC) in April 2021, with committee members voting in favor of maintaining the indication while discussions continued regarding the plans to confirm clinical benefit.⁵³ However, the regular approval of pembrolizumab plus chemotherapy for metastatic TNBC, that occurred after the advisory committee meeting, altered the treatment landscape and changed the risk benefit calculation. Therefore, in consultation with FDA, it was announced by the drug company that the indication for atezolizumab in metastatic TNBC will be voluntarily withdrawn.⁵⁴

Pembrolizumab^55,56: In 2020, pembrolizumab, an anti-PD-1 monoclonal antibody, was granted AA in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10). Approval was based on KEYNOTE-355, a double-blind, placebo-controlled trial that randomized patients to receive pembrolizumab or placebo in combination with different chemotherapy treatments. The main efficacy outcome of PFS was tested in the subgroup of patients with CPS ≥10. Median PFS for this CPS cut-off was significant in the pembrolizumab plus chemotherapy arm compared to the placebo arm. The OS was not statistically significant at the time of approval but on subsequent analyses was announced as significantly improving OS in the CPS ≥ 10 group.⁵⁷ This indication was converted to RA based on results from the KEYNOTE-522, a randomized, double-blind, placebo-controlled trial of pembrolizumab in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with single agent pembrolizumab.⁵⁸

Sacituzumab govitecan-hziy^59,60,61: In 2020, sacituzumab, an ADC directed against Trop-2, was granted AA for patients with metastatic TNBC who received at least two prior therapies for metastatic disease. Efficacy was demonstrated in IMMU-132-01, a single-arm trial enrolling patients with metastatic TNBC who received at least two prior treatments for metastatic disease. The primary efficacy outcomes were ORR and DoR. PFS and OS results from the ASCENT trial verified the clinical benefit of sacituzumab in patients with metastatic TNBC and supported conversion to RA in 2021. Based on results and eligibility of the confirmatory trial, the indication was also modified with the RA to allow earlier use in the metastatic setting.

Olaparib^63,64,65: In 2018, olaparib, was the first PARP inhibitor granted RA for the treatment of patients with deleterious or suspected deleterious gBRCAm, HER2-negative MBC who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. Approval was based on OlympiAD, an open-label trial that randomized patients to olaparib or physician’s choice of chemotherapy. The primary endpoint of median PFS was significant for olaparib compared to chemotherapy.

Talazoparib^66,67: In 2018, talazoparib, a PARP inhibitor, was granted RA for patients with deleterious or suspected deleterious gBRCAm, HER2-negative locally advanced or MBC. Approval was based on EMBRACA, an open-label trial randomizing patients with gBRCAm HER2-negative locally advanced or MBC to receive talazoparib or physician’s choice of chemotherapy. The median PFS was significant in the talazoparib compared to chemotherapy.