Pyrotinib Yields Promising Efficacy and Tolerability Among HER2-Altered Solid Tumors

The investigational TKI pyrotinib demonstrated encouraging antitumor activity and a manageable toxicity profile in patients with heavily pretreated HER2-mutant non–small cell lung cancer (NSCLC), as well as other advanced solid tumors harboring activating HER2 alterations, according to findings from a phase 1 basket trial (NCT02500199) that were recently published in the Journal of Clinical Oncology.¹

The results, which were presented in a poster during the 2020 ASCO Virtual Scientific Program, revealed that pyrotinib led to a median progression-free survival (PFS) of 5.3 months in patients with NSCLC (n = 31; 95% CI, 3.6-7.3) and 4.4 months in patients with other HER2-altered solid tumors (n = 31; 95% CI, 3.5-9).

There were 4 confirmed responses in each cohort of patients, and the confirmed overall response rate was 13% (95% CI, 4%-30%) in both groups.

“Pyrotinib has shown a manageable safety profile and encouraging anticancer activity in patients with heavily pretreated HER2-mutant lung cancers,” said Bob T. Li, MD, MPH, lead study author and medical oncologist at Memorial Sloan Kettering Cancer Center.

The study enrolled patients with HER2-mutant NSCLC and those with advanced solid tumors harboring a HER2 mutation or amplification.

All patients had confirmed HER2 alterations determined by next-generation sequencing or fluorescence in situ hybridization.

The tumor types that were included in the basket cohorts included carcinoma of unknown origin/adenocarcinoma (n = 2), breast cancer (n = 3), biliary tract cancer (n = 3), colorectal cancer (n = 3), endometrial cancer (n = 2), gastroesophageal cancer (n = 2), lung cancer (n = 4), ovarian cancer (n = 3), pancreatic cancer (n = 3), peritoneal cancer (n = 1), salivary duct cancer (n = 1), urothelial carcinoma (n = 1), and uterine cancer (n = 3).

Patients enrolled in the open-label, multicenter, dose-expansion study received 400 mg of oral pyrotinib daily in 28-day cycles.

The majority of patients in the NSCLC cohort and the basket cohort were male (61.3%). The median age in the NSCLC group was 70 years (range, 40-86) compared with 65 years (range, 43-78) in the basket group.

In both groups, patients were exposed to a median of 3 prior lines of therapy (range, 1-8). Nearly 75% of patients in the NSCLC cohort had less than 3 prior lines of therapy versus 61.3% in the basket cohort.

The median time to response with pyrotinib was 7.7 weeks (95% CI, 7.3-7.9) in the NSCLC group versus 7.5 weeks (95% CI, 6.9-7.9) in the basket group.

Regarding treatment-emergent adverse effects (AEs), any-grade diarrhea was reported in 82.3% of patients, 24.2% of which was grade 3 or greater. Any-grade anemia was reported in 11.3% of patients, with 3.2% being grade 3 or greater.

Of note, 85% of patients received prophylactic loperamide at a minimum of 2 mg daily to manage diarrhea. The remaining 15% of patients did not receive prophylactic antidiarrheal medication.

Three patients discontinued treatment due to AEs, including 1 case of grade 3 vomiting/nausea, 1 case of grade 4 Steven-Johnson’s syndrome, and 1 case of grade 4 diarrhea. Additionally, vomiting/nausea and diarrhea were found to be a definite direct result of treatment with pyrotinib, whereas the emergence of Steven-Johnson’s syndrome had possible causality from treatment. Patients who discontinued treatment due to vomiting/nausea and Steven-Johnson’s syndrome did so in cycle 2 of therapy. The patients who stopped treated due to diarrhea stopped pyrotinib in cycle 1.

No treatment-related deaths were reported in the study.

“Pyrotinib is the first TKI to produce durable responses in patients with HER2-amplified biliary tract, ovarian, endometrial and salivary gland tumors,” said Li. “As a clinical investigator, I would like to see pyrotinib further developed to address unmet medical needs of these patients.”

Findings from the phase 3 PHOEBE trial, also presented at the 2020 ASCO Virtual Scientific Program, demonstrated improved PFS with pyrotinib plus capecitabine compared with lapatinib (Tykerb) plus capecitabine in patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab (Herceptin) and chemotherapy.²

These positive findings support further studies with pyrotinib in HER2-altered NSCLC and other solid tumors, concluded Li.

References

1. Li BT, Li T, Johnson ML, et al. Safety and efficacy of pyrotinib in patients with NSCLC and other advanced solid tumors with activating HER2 alterations: A phase I basket trial. J Clin Oncol. 2020;38(15 suppl):3510. doi:10.1200/JCO.2020.38.15_suppl.3510
2. Xu B, Yan M, Ma F, et al. Pyrotinib or lapatinib plus capecitabine for HER2+ metastatic breast cancer (PHOEBE): A randomized phase III trial. J Clin Oncol. 2020;38(15 suppl):1003. doi:10.1200/JCO.2020.38.15_suppl.1003