Pyrotinib-capecitabine combination improves outcomes in breast cancer subset
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Pyrotinib plus capecitabine extended PFS compared with lapatinib-capecitabine among certain patients with HER2-positive metastatic breast cancer, according to randomized phase 3 study results presented at ASCO20 Virtual Scientific Program.
The results of the PHOEBE trial — which included patients who previously received trastuzumab (Herceptin, Genentech) and chemotherapy — showed the combination of pyrotinib (Hengrui Therapeutics) and capecitabine also had a manageable toxicity profile.
“OS data were not mature, but there was a strong trend toward prolonged survival with pyrotinib plus capecitabine,” Binghe Xu, MD, PhD, of the department of medical oncology at Peking Union Medical College, said during a presentation.
Many targeted therapies are available for HER2-positive metastatic breast cancer. However, availability of certain drugs, such as pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech), varies around the world.
Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets EGFR, HER2 and HER4. Phase 1 and phase 2 studies showed the addition of the agent to capecitabine provided clinically meaningful benefits and acceptable tolerability for patients with HER2-positive metastatic breast cancer, with a higher objective response rate (78.5% vs. 57.1%) and improved PFS by independent review (HR = 0.37; 95% CI, 0.24-0.58) than lapatinib (Tykerb, Novartis) plus capecitabine.
The open-label, multicenter PHOEBE trial included 267 patients with pathologically confirmed HER2-positive metastatic breast cancer who had received trastuzumab and taxanes and/or anthracyclines. Eligible patients received up to two lines of prior chemotherapy for metastatic disease.
Researchers randomly assigned 134 patients to pyrotinib dosed at 400 mg daily, plus capecitabine dosed at 1,000 mg/m2 twice daily on days 1 to 14 of 21-day cycles. The other 133 patients received lapatinib 1,250 mg daily plus capecitabine.
The pyrotinib and lapatinib groups were balanced with regard to median age (50 years vs. 49 years), percentage of patients with ECOG performance status of 0 (35.1% vs. 32.6%) or 1 (64.9% vs. 67.4%), hormone receptor status and number of metastatic sites.
Comparable percentages of patients in the pyrotinib and lapatinib groups received no primary chemotherapy for metastatic disease (42.5% vs. 34.8%), one prior line (41.8% vs. 49.2%) or two prior lines (15.7% vs. 15.9%).
PFS per blinded independent central review served as the primary endpoint. Secondary endpoints included OS, ORR, duration of response, clinical benefit rate, time to progression and safety.
Results of a planned interim analysis showed longer median PFS with pyrotinib than lapatinib in the overall cohort (12.5 months vs. 6.8 months; HR = 0.39; 95% CI, 0.27-0.56). The benefit appeared consistent across all predefined subgroups.
Researchers reported longer median PFS with pyrotinib among trastuzumab-resistant patients (12.5 months vs. 6.9 months; HR = 0.6; 95% CI, 0.29-1.21), as well as among patients who were not resistant to trastuzumab (12.5 months vs. 5.6 months; HR = 0.33; 95% CI, 0.21-0.51).
The pyrotinib-capecitabine combination also appeared associated with a higher ORR (67.2% vs. 51.5%; P = .0091) and higher clinical benefit rate (73.1% vs. 59.1%; P = .0155). In addition, patients assigned pyrotinib-capecitabine achieved longer duration of response (11.1 months vs. 7 months), and a higher percentage of those patients remained in ongoing response at data cutoff (70% vs. 48.5%).
Median OS had not been reached in either treatment group, but 1-year OS favored the pyrotinib-capecitabine combination (91.3% vs. 77.4%; HR = 0.46; 95% CI, 0.22-0.99).
“Follow-up is ongoing to obtain mature OS data,” Xu said.
Nearly all patients experienced any-grade treatment-related adverse events (99.3% with pyrotinib vs. 98.5% with lapatinib).
A higher percentage of those assigned pyrotinib experienced grade 3 or higher adverse events (57.5% vs. 34.1%), the most common of which were diarrhea (30.6% vs. 8.3%) and hand-foot syndrome (16.4% vs. 15.2%).
A higher percentage of patients assigned pyrotinib experienced serious adverse events (10.4% vs. 8.3%), serious treatment-related adverse events (6% vs. 1.5%), adverse events leading to dose modification (47% vs. 33.3%), adverse events leading to treatment interruption (61.9% vs. 48.5%) or adverse events leading to treatment discontinuation (3% vs. 2.3%). One patient in the pyrotinib group and two in the lapatinib group died due to adverse events; one of the deaths in the lapatinib group was treatment related.
Reference:
Xu B, et al. Abstract 1003. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Perspective
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Charles L. Shapiro, MD, FASCO
The HER-positive space keeps expanding with exciting new options recently approved for pretreated women with metastatic HER2-positive breast cancer. This phase 3 trial describes standard lapatinib and capecitabine vs. pyrotinib, a pan-irreversible TKI of the HER (ErbB) family of proteins, and capecitabine. The results show a near-doubling of the primary endpoint, PFS (12.5 months vs. 6.8 months). The clinical benefit rate, ORR and duration of response were superior in the pyrotinib group. However, like neratinib (Nerlynx, Puma Biotechnology), another pan-HER inhibitor, grade 3 or higher diarrhea occurred among 31% patients. With the recent FDA approvals of trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo), an antibody-drug conjugate, and tucatinib (Tukysa, Seattle Genetics), a more specific tyrosine kinase of HER2, it is hard to know where pyrotinib will fit in. Also, it’s time to call into question “first-generation” lapatinib and capecitabine as the control arm for trials of newer HER-targeted therapy, with newly approved agents having demonstrably better activity.
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Xu B, et al. Abstract 1003. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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