In a single-arm phase 2 clinical trial, pyrotinib had promising antitumor activity as treatment of patients with HER2-positive non–small cell lung cancer.
Pyrotinib had promising antitumor activity as treatment of patients with HER2-positive non–small cell lung cancer (NSCLC) and demonstrated an acceptable safety profile, according to the results of a single-arm phase 2 clinical trial.
“Patients with HER2-mutant NSCLC account for 1% - 4% of patients with lung adenocarcinoma. However, until now, no treatment has been approved for this patient population,” study authors led by Caicun Zhou, MD, PhD, wrote. “This multicenter, open-label, single-arm, phase 2 study explored the efficacy and safety of pyrotinib in patients with HER2-mutant advanced NSCLC. This study contained 60 patients, and to our knowledge, this is the largest study in HER2-mutant NSCLC.”
The primary end point of the trial was objective response rate (ORR) per RECIST 1.1 by Independent Reviewing Committee (IRC) assessment, while secondary end points included ORR by investigator assessment, duration of response, progression-free survival (PFS), and time to progression.
The median follow-up was 11.7 months (range, 6.5-16.3), and 49 patients had discontinued treatment as of June 20, 2019. According to IRC assessment, the ORR was 30.0% (95% CI, 18.8%-43.2%), all of which were partial responses (PRs). Stable disease (SD) was observed in 55.0% of patients, 21.7 of whom showed SD for a minimum of 24 weeks. Six patients (10.0%) had progressive disease (PD), and 3 (5.0%) were not evaluable. Responses were ongoing in 33.3% of the study population. The median duration of response was 6.9 months (range, 4.9-11.1). Six patients (33.3%) had ongoing responses.
By investigator assessment, the ORR was 31.7% (95% CI, 20.3%-45.0%), and the median duration of response was 7.0 months (range, 5.5-11.0). Three patients had ongoing responses (15.8%). The best response observed in these patients was a PR, which occurred in 19 patients (31.7%). Thirty-five patients (58.3%) had SD, 13 (21.7%) had SD ongoing for at least 24 weeks, and 4 patients (6.7%) had PD. Two patients (3.3%) were not evaluable.
According to IRC assessment, 39 patients (65.0%) had PFS events, and the median PFS was 6.9 months (95% CI, 5.5-8.3). The 12-month PFS rate was 22.5% (95% CI, 10.8%-36.8%).
According to investigator assessment, 46 patients had died or experienced disease progression for a median PFS of 6.9 months (95% CI, 5.5-8.2), and the median time to progression was 6.9 months (95% CI, 5.5-8.3). Thirty patients (50.0%) died. The median OS was 14.4 months (95% CI, 12.3-21.3), and the 12-month OS rate was 69.1% (95% CI, 55.0%-79.6%).
Among the subgroups of patients with mutations, the IRC-assessed ORR was 27.3% (95% CI, 15.0%-42.8%) among those with a 12-bp exon 20 insertion, 16.7% (95% CI, 0.4%-64.1%) among patients with G776mutations, 60.0% (95% CI, 14.7%- 94.7%) in those with 9-bp exon 20 insertion, 25.0% (95% CI, 0.6%-80.6%) among those with an L755P mutation, and 100% (95% CI, 2.5%-100.0%) in the 1 patient with V777L mutations.
One patient who had a 12-bp exon 20 insertion was identified to have a single nucleotide polymorphism rs1050171 mutation in EGFR, and this patient had a PR per IRC, which was maintained for a treatment duration of 12.9 months.
The IRC-assessed ORR was 25.0% (95% CI, 5.5%-57.2%) among 12 patients with brain metastases versus 31.3% (95% CI, 18.7%046.3%) among those without brain metastases (n = 48), and the median PFS was 5.5 months (95% CI, 2.7-6.9) versus 6.9 months (95% CI, 5.5-9.6), respectively.
Among patients with at least 2 prior lines of chemotherapy, the IRC-assessed ORR was 44.0% (95% CI, 24.4%-65.1%), which was numerically greater than the ORR among patients with 1 prior line of chemotherapy (20.0%; 95% CI, 8.4%-36.9%).
The main reason for treatment discontinuation in the study was disease progression, however, there were 2 withdrawals of consent, and 1 patients discontinued treatment due to adverse events (AEs).
Treatment-related AEs (TRAEs) of any grade occurred in 59 patients (98.3%), but most TRAEs were grade 1/2. The most common TRAEs included diarrhea (91.7%), elevated blood creatinine (30.0%), vomiting (28.3%), elevated alanine aminotransferase (15.0%), and elevated aspartate aminotransferase (15.0%).
Grade 3 TRAEs were observed in 16 patients (26.7%), and a grade 4 TRAE was reported in 1 patient (1.7%), which was elevated gamma-glutamyltransferase. Diarrhea was the grade 3 or greater TRAE with the highest incidence and occurred in 20% of patients.
A total of 3 patients died as a result of AEs, but none were treatment-related. One patient (1.7%) discontinued treatment due to TRAEs, and 13 patients (21.7%) had dose interruptions due to TRAEs. Two patients (3.3%) had serious TRAEs, which included increased amylase in 1 patient and abnormal hepatic function in 1 patient.
In terms of AEs of special interest, diarrhea occurred in 56 patients (93.3%), and grade 3 diarrhea occurred in 12 patients (20.0%), while no grade 4 or 5 diarrhea was observed. Fifty patients (83.3%) had experienced diarrhea during the first treatment cycle, and 11.7% had grade 3 diarrhea during the first cycle. The median time to onset was 4.5 days, and the median cumulative duration of grade 3 diarrhea was 6.0 days. Five percent of patients required dose adjustments, but no dose discontinuations occurred as a result of diarrhea. The incidence of diarrhea gradually declined after the first cycle.
The incidence of grade 3 diarrhea was significantly higher among patients aged ≥ 65 years old, occurring in 6 patients (50.0%) compared with 6 (12.5%) among patients < 65 years.
Other AEs of special interest included abnormal hepatic function, occurring in 14 patients (23.3%). Thirteen patients (21.7%) experienced this AE in grades 1 or 2, and 1 patient (1.7%) experienced grade 4. Hand-foot syndrome, another AE of special interest, occurred in 3 patients (5.0%), only in grade 1, and rash occurred in 7 patients (11.7%), all of which were grade 1.
To be eligible for the trial, patients had to have a histologically or cytologically confirmed diagnosis of HER2-positive NSCLC with unresectable stage IIIB to IV disease. They had to have received at least 1 prior line of platinum-based chemotherapy and have had their disease relapse or progress during, after, or within 6 months of neoadjuvant or adjuvant therapy. Patients also had to have at least 1 measurable disease, an ECOG performance status of 0 or 1, a predicted life expectancy of ≥ 3 months, and adequate organ function. Patients could not be included in the trial if they had received any prior HER2-targeted therapy, radiotherapy, chemotherapy, surgery or other targeted treatments within 4 weeks before the first dose of the study drug.
Eighty-six patients were screened for the study between October 2016 and December 2018, and 60 patients were enrolled to the study. The median age was 57 years, and 58 patients (96.7%) had stage IV disease. All patients on the study had received prior conventional chemotherapy, and 25 (41.7%) had at least 2 prior lines of therapy, while no patients had received prior immunotherapy. Forty-four patients had 12-bp exon 20 insertion, 6 patients had G776 mutations, 5 had 9-bp exon 20 insertion, 4 had L755P mutation, and 1 patient had V777L mutation.
Two important limitations from this study were that there was no control arm, and the sample size of patients with missense point mutations in HER2 was small. Due to this, investigators were unable to adequately assess the clinical benefit of different HER2 subtypes.
“A global, multicenter, randomized phase 3 trial is being planned and will be started soon,” wrote the study authors. “In conclusion, pyrotinib as a single agent showed promising antitumor activity and an acceptable safety profile in chemotherapy-treated patients with HER2-mutant NSCLC.”
Zhou C, Li X, Wang Q, et al. Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study [Published Online July 2, 2020]. Journal of Clinical Oncology. doi: 10.1200/JCO.20.00297