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At this year's meeting of the American Society of Clinical Oncology (ASCO 2020), held virtually May 29–31, investigators discussed the latest findings in cancer research. Here, Editor-in-Chief William J. Gradishar, MD, reviews the key presentations on new breast cancer therapies. All meeting abstracts can be viewed in the ASCO meeting library.
One of the new agents introduced for estrogen receptor–positive (ER+) breast cancer was the PI3K inhibitor alpelisib. The prior SOLAR-1 study (NEJM JW Oncol Hematol Jul 2019 and N Engl J Med 2019; 380:1929) showed that progression-free survival (PFS) was improved with alpelisib plus fulvestrant compared with fulvestrant alone in patients with PIK3-mutated tumors. Less clear was whether the effect was similar in patients who had previously received a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, which reflects real-world practice.
To address this issue, Rugo and colleagues reported results of an open-label, noncomparative, phase II trial (BYLieve; abstract 1006), in which 127 patients with PIK3CA-mutated, hormone receptor–positive (HR+), HER2− advanced breast cancer whose last line of therapy was a CDK4/6 inhibitor were assigned to alpelisib plus endocrine therapy (fulvestrant or letrozole).
PFS (the primary endpoint) at 6 months was 50%; median PFS was 7.3 months. These findings were superior to the small group of patients in SOLAR-1 who had received prior CDK4/6 inhibitors and confirm the effectiveness of alpelisib in the post-CDK4/6 inhibitor setting.
The question of whether patients should undergo local surgery in the setting of de novo metastatic breast cancer has been addressed by several trials in recent years, with some discordance in results perhaps explained by issues of trial design and comparability of patients enrolled.
Khan and colleagues reported results of a randomized, phase III trial (E2108; abstract LBA2), in which 256 patients with de novo metastatic disease without progression after 4 to 8 months were assigned to either continue systemic therapy alone (131 patients) or combine it with early local therapy (125). Of the 125 patients who received early local therapy, 109 underwent surgery; of these, 87 had free margins and 74 received locoregional radiation therapy.
At a median follow-up of 59 months, no significant difference in overall survival (OS) or PFS was observed between those who continued systemic therapy and those who underwent surgery. Health-related quality of life was significantly worse in patients who underwent surgery. Based on data from this trial and others, routine use of primary surgery in the de novo metastatic disease setting should be discouraged.
The benefit of immunotherapy in select patients with triple-negative breast cancer (TNBC) was further validated in a randomized, phase III trial by Cortes and colleagues (KEYNOTE-355; abstract 1000), which enrolled 847 patients with previously untreated advanced TNBC who were randomized 2:1 to receive pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine) versus chemotherapy alone.
PFS was nonsignificantly longer with immunotherapy plus chemotherapy than with chemotherapy alone. For those with a PD-L1 clinical and pathological stage (CPS) score ≥10, which accounted for almost 40% of the patients, PFS was significantly longer with immunotherapy plus chemotherapy (9.7 vs. 5.6 months; P=0.0012). For those with a PD-L1 CPS score <10, there was no difference between the two groups. These findings are similar to those in the prior IMPASSION 130 trial, in which PD-L1+ patients had a similar advantage when atezolizumab was added to nab-paclitaxel (NEJM JW Oncol Hematol Dec 2018 and N Engl J Med 2018; 379:2108).
More than 50% of patients with metastatic HER2+ breast cancer ultimately develop brain metastases. Therapies to treat such disease have been a priority and yet an unmet need. Although drugs such as capecitabine, lapatinib, and neratinib have been shown to have some activity in HER2+ brain metastases, the effect has been modest.
The recent FDA approval of the oral tyrosine kinase inhibitor tucatinib was based on the prior HER2CLIMB study (NEJM JW Oncol Hematol Mar 2020 and N Engl J Med 2020; 382:597), which demonstrated not only better PFS and OS by adding tucatinib to capecitabine and trastuzumab for patients with HER2+, but also superior outcomes for those with brain metastases.
Lin and colleagues reported results of an exploratory efficacy analysis of the 291 patients in the HER2CLIMB study with brain metastasis, including those with stable, treated brain metastases as well as those with progressing brain disease (abstract 1005). Patients were randomized 2:1 to receive capecitabine and trastuzumab plus either tucatinib or placebo.
Median PFS in those with brain metastases was longer with tucatinib than with placebo (9.9 vs. 4.2 months; P=0.005); risk for death overall was reduced by 42% in all patients with brain metastases and by 51% in those with active brain metastases.
Findings showing poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to be an option for patients with metastatic breast cancer and BRCA mutations led to the FDA-approval of olaparib and talazoparib. Whether patients with other germline or somatic mutations would benefit from these agents remained unclear.
To address this issue, Tung and colleagues reported results of a phase II study of olaparib monotherapy in patients with metastatic disease who had either somatic or germline mutations in DNA damage response (DDR) pathway genes (abstract 1002). Among 53 patients, 40 had ER+ HER2− breast cancer, 3 had HER2+ breast cancer, and 10 had TNBC; 87% had a mutation in PALB2, BRCA1/2, ATM, or CHEK2. Patients were divided into two cohorts: Patients in cohort 1 had germline mutations in DDR-pathway genes, and patients in cohort 2 had somatic mutations in DDR-pathway genes or BRCA1/2.
The objective response rate (ORR; the primary endpoint) was 29.6% in cohort 1 and 38.5% in cohort 2. Response was gene specific: ORR was 82% among the 11 patients with germline mutations in PALB2 and was 50% among the 16 patients with somatic BRCA1/2 mutations. No responses were observed in patients with ATM or CHEK2 germline or somatic mutations. These data support molecular testing in patients with metastatic disease and may meaningfully expand therapy options for some regardless of subtype.