Novel Checkpoint Inhibitor and TKI Flex Muscle Against SCLC

Neil Osterweil

May 05, 2020

Although approximately 60% to 65% of patients with extensive-stage small cell lung cancer (ES-SCLC) ― the type of lung cancer most closely linked to smoking ― respond to first-line platinum-based chemotherapy with etoposide, nearly all patients experience relapse after treatment, and there are very few options for second- or third-line therapy.

"Standard second-line therapy for extensive-disease small cell lung cancer patients remains topotecan, with objective response rates [ORR] of 9% to 23%, and the response duration is short," said Jie Wang, MD, from the National Cancer Center/Cancer Hospital in Beijing, China.

So the ORR of 34% that Wang reported with a new drug combination has sparked some interest among lung cancer experts.

The result comes from the phase 2 PASSION trial, which tested second-line treatment for ES-SCLC with the investigational immune checkpoint inhibitor camrelizumab (Incyte Biosciences and Jiangsu Hengrui Medicine Co) and the tyrosine kinase inhibitor (TKI) apatinib (Jiangsu), which is approved only in China.

The results were presented during the American Association for Cancer Research (AACR) 2020 virtual annual meeting.

The new data "certainly provide preliminary evidence of antitumor activity for the combination," commented invited discussant Ferdinand Skoulidis, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

"However, precise estimates of efficacy are confounded by the high proportion of never-smokers, who exhibit significantly better outcomes," he said.

In the trial, 22% of patients were never-smokers, compared to approximately 10% in previous studies in East Asian populations and 5% to 7% in studies in Western populations, Skoulidis noted.

Immunotherapy has been shown to offer some benefit to patients with ES-SCLC. Currently, the immune checkpoint inhibitors nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) are approved for third-line but not second-line treatment of ES-SCLC.

Skoulidis noted that with the new combination, the median duration of response was shorter than might be expected with other programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) inhibitors, which "raises the possibility that responses observed in this study may be mostly attributed to apatinib, especially in the fraction of patients who were never-smokers," he said.

"The data nonetheless support development of the combination," he added.

Therapeutic Rationale

Camrelizumab, a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody, was recently shown in a phase 3 randomized trial to have strong activity against advanced/metastatic non–small cell lung cancer in the first line in combination with platinum-based doublet chemotherapy, with superior survival compared with chemotherapy alone (World Conference on Lung Cancer 2019, Abstract OA04,03).

Apatanib is an oral selective TKI directed at vascular endothelial growth factor receptor–2 that has demonstrated single-agent activity against ES-SCLC after disease progression following two or more prior lines of systemic therapy. It is approved in China for gastric cancer.

"The scientific rationale for a combination of camrelizumab and apatinib is solid and is based on favorable modulation of the tumor immune microenvironment by low-dose apatinib," Skoulidis said, pointing to preclinical data that show antitumor efficacy in a non–small cell lung cancer model.

Study Details

The phase 2 PASSION trial tested camrelizumab 200 mg every 2 weeks plus apatinib 375 mg daily (the schedule was selected on the basis of tolerability for the first 28 days of the study) in 47 patients (QD cohort). In addition, 12 patients from two other six-patient cohorts from phase 1 were included in the final analysis; these patients received the same dose of camrelizumab plus apatanib 375 mg either 5 days on/2 days off or 7 days on/7 days off.

For the 47 patients in the QD cohort, the median age was 62 years; 40 were men. Ten of the patients in this group were never-smokers, one was a current smoker, and 36 were former smokers.

The overall response rate was 34% for patients in the QD cohort and 33.3% for those in each of the other two cohorts (33.9% among all 59 patients).

The responses in the QD cohort consisted entirely of partial responses in 16 patients; 16 additional patients had stable disease, for a disease control rate of 68.1%. The remaining 15 patients experienced disease progression.

In the apatinib 5 days on/2 days off cohort, two of the six patients had a partial response, and four had stable disease.

In the 7 days on/7 days off cohort, two of six patients had partial responses, one had stable disease, and three experienced disease progression.

Among patients in the QD cohort, the ORR for those with chemotherapy-sensitive disease was 37.5%. For those with chemotherapy-resistant disease, the ORR was 32.3%.

Median overall survival of patients in the QD cohort was 8.4 months. The 6- and 12-month survival rates were 63.3% and 36.3%, respectively.

Median overall survival was 9.6 months for patient with chemotherapy-sensitive disease, vs 8 months for those with chemotherapy-resistant disease.

Median progression-free survival was 3.6 months among all patients in this cohort, with respective PFS of 3.6 months and 2.7 months for patients with chemotherapy-sensitive and chemotherapy-resistant disease.

Among all 59 patients treated in the three cohorts, the most common treatment-related adverse event was hypertension, followed by elevated aspartate aminotransferase levels and decreased white blood cell and platelet counts. The most common events of grade 3 or greater were hypertension, decreased platelet count, and hand-foot syndrome.

The study was supported by the Jiangsu Hengrui Medicine Co. Wang and colleagues have disclosed no relevant financial relationships. Skoulidis has received sponsored travel from Tango Therapeutics and honoraria from Bristol-Myers Squibb.

American Association for Cancer Research (AACR) 2020. Abstract CT083. Presented April 27, 2020.

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