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The addition of the PD-L1 inhibitor sugemalimab to chemotherapy significantly improved overall survival compared with chemotherapy alone in the frontline treatment of patients with stage IV non–small cell lung cancer.
The addition of the PD-L1 inhibitor sugemalimab to chemotherapy significantly improved overall survival (OS) compared with chemotherapy alone in the frontline treatment of patients with stage IV non–small cell lung cancer (NSCLC), according to data from a planned interim analysis for OS in the phase 3 GEMSTONE-02 trial (NCT03789604).1
Notably, clinical benefit was reported with the sugemalimab combination across the patient subsets analyzed, including those with squamous and nonsquamous histologies and irrespective of PD-L1 expression levels.
Detailed findings from the analysis will be shared at an upcoming medical meeting, according to EQRx, Inc. and CStone Pharmaceuticals.
“We are highly encouraged to see that sugemalimab in combination with chemotherapy demonstrates significant clinical benefit, including improvement in both PFS and OS, when compared to placebo plus chemotherapy across a broad spectrum of patients with stage IV NSCLC in this phase 3 study,” Vince Miller, MD, physician-in-chief at EQRx, stated in a press release.
The randomized, double-blind GEMSTONE-302 trial enrolled patients with histologically or cytologically confirmed stage IV squamous or nonsquamous NSCLC without a known EGFR sensitizing mutation or ALK, ROS1, or RET fusions.2
To be eligible for enrollment, patients needed to be at least 18 years of age, have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and acceptable organ function. Patients could not have received prior systemic treatment for metastatic disease, and they needed to be able to provide a tumor sample to determine PD-L1 expression status.
If patients had pathologically confirmed small cell lung cancer or tumors with a small cell component, symptomatic central nervous system metastases, autoimmune disease, or they previously received immune checkpoint therapies, they were excluded.
Study participants were randomized 2:1 to receive sugemalimab plus platinum-based chemotherapy (n = 320) or placebo plus platinum-based chemotherapy (n = 159). Those with nonsquamous disease were given intravenous sugemalimab at 1200 mg or placebo, plus carboplatin at area under the curve (AUC) 5 mg/mL per min, and IV pemetrexed at 500 mg/m2 on day 1 of every 3-week treatment cycle, for up to 4 cycles, followed by maintenance treatment with pemetrexed with sugemalimab or placebo.
Those with squamous disease were given 1200 mg of sugemalimab or placebo, plus carboplatin at AUC 5 mg/mL per min and paclitaxel at 175 mg/m2 on day 1 of every 3-week cycle for up to 4 cycles, followed by maintenance sugemalimab or placebo.
Treatment with either sugemalimab or placebo was continued for up to 35 cycles, or until progressive disease or intolerable toxicity. Dose adjustments for sugemalimab or placebo were not permitted; however, treatment could be withheld for up to 12 weeks or discontinued per prespecified criteria. Dose modifications for chemotherapy were allowed.
The primary end point of the trial was investigator-assessed progression-free survival (PFS) in the intention-to-treat population, and secondary end points were overall survival, investigator-assessed PFS in patients with PD-L1 expression of at least 1%, PFS per blinded independent central review (BICR) committee, investigator-assessed objective response rate (ORR), duration of response (DOR), safety, pharmacokinetics, and immunogenicity.
Baseline demographic and clinical characteristics were noted to be well balanced between the arms. Most patients were male and younger than 65 years of age, had an ECOG performance status of 1, and were current or former smokers. In both arms, 40% had squamous histology and 60% had nonsquamous histology.
Regarding PD-L1 expression, in the investigative arm, 39% had expression of less than 1% and 61% had expression of 1% or higher; these rates were 40% and 60%, respectively, in the control arm. Moreover, 12% of those who received sugemalimab had liver metastases at baseline and 16% had brain metastases; these rates were 11% and 11%, respectively, in the control arm.
Data recently published in The Lancet Oncology showed that at a median follow-up of 8.6 months (range, 6.1-11.4), and a data cutoff of June 8, 2020, the trial met its primary end point, with sugemalimab plus chemotherapy resulting in a significant improvement in investigator-assessed PFS vs chemotherapy alone. The median PFS was 7.8 months (95% CI, 6.9-9.0) with sugemalimab vs 4.9 months (95% CI, 4.7-5.0) with chemotherapy alone (stratified HR, 0.50; 95% CI, 0.39-0.64; P < .0001).
At the final analysis for PFS, with a data cutoff of March 15, 2021, the improvement in PFS that was observed with sugemalimab plus chemotherapy was maintained. The median PFS in the investigative arm was 9.0 months (95% CI, 7.4-10.8) vs 4.9 months (95% CI, 4.8-5.1) in the control arm (stratified HR, 0.48; 95% CI, 0.39-0.60; P < .0001). Moreover, the estimated 12-month PFS rates in the sugemalimab and placebo arms were 36.4% (95% CI, 31.0%-41.8%) and 14.8% (95% CI, 9.7%-21.1%), respectively.
Notably, similar improvements in PFS were observed per BICR assessment in both the interim and final analyses. Data from a prespecified subgroup analysis of investigator-assessed PFS also demonstrated comparable improvements with sugemalimab over placebo, and findings from a post-hoc analysis indicated that the PFS improvement was irrespective of PD-L1 expression for both squamous and nonsquamous subsets.
Additional data from the post-hoc analysis revealed that sugemalimab plus chemotherapy improved intracranial investigator-assessed PFS vs chemotherapy alone in those with brain metastases at baseline. The addition of the immunotherapy also resulted in a lower rate of new brain lesions in those with or without brain metastases at baseline.
Sugemalimab plus chemotherapy elicited an ORR of 63.4% (95% CI, 57.9%-68.7%) vs 40.3% (95% CI, 32.6%-48.3%) with chemotherapy alone, translating to a 23.2% difference in ORRs (95% CI, 13.9%-32.5%). The median DOR in the investigative arm was 9.8 months (95% CI, 8.6-13.2) vs 4.4 months (95% CI, 3.5-5.8) in the control arm.
Regarding safety, treatment-emergent adverse effects (TEAEs) were experienced by most patients on the trial, and the incidence of grade 3 or 4 TEAEs and fatal TEAEs were comparable between the arms. Any-grade treatment-related AEs were reported in 99% of those on the investigative arm and 96% of those on the control arm; these effects were grade 3 or 4 in 54% vs 56% of patients, respectively.
The most common grade 3 or 4 effects in the investigative and control arms were decreased neutrophil count (33% vs 33%, respectively), decreased white blood cell count (14% vs 17%), anemia (13% vs 11%), decreased platelet count (10% vs 9%), and neutropenia (4% vs 4%).
Treatment-related serious AEs were experienced by 23% of those who received sugemalimab vs 20% of those who received chemotherapy alone. The most frequent serious AEs associated with treatment in the investigative and control arms included anemia (3% vs 3%, respectively), pneumonia (3% vs 4%), and decreased platelet count (3% vs 3%).
AEs resulted in treatment discontinuation in 14% of those on the investigative arm and 9% of those on the control arm. The most common treatment-related toxicities that resulted in discontinuation included anemia (2% vs 2%), pneumonia (2% vs 2%), and abnormal hepatic function (1% vs 1%).
“Price remains a barrier to accessing innovative therapies for many people with lung cancer around the world, despite the availability of multiple anti–PD(L)1 therapies,” Miller added in the release. “We look forward to engaging with global regulatory authorities with the aim of delivering a lower-cost treatment option to patients upon approval.”