November 21, 2020 - The addition of sugemalimab to chemotherapy demonstrated a statistically significant and clinically meaningful progression-free survival benefit in the frontline treatment of patients with metastatic non–small cell lung cancer versus placebo plus chemotherapy.
The addition of sugemalimab (formerly CS1001) to chemotherapy demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit in the frontline treatment of patients with metastatic non–small cell lung cancer (NSCLC) versus placebo plus chemotherapy, according to the results of the phase 3 GEMSTONE-302 study (NCT03789604) that were presented during the 2020 ESMO Asia Virtual Congress.
Results showed that the combination elicited an investigator-assessed 6-month PFS rate of 62.9% and a 12-month PFS rate of 28.6% compared with 35.1% and 15.4%, respectively in the chemotherapy/placebo arm. The median PFS achieved in the investigational arm was 7.82 months (95%, 6.90-8.97) versus 4.9 months (95% CI, 4.70-5.03) in the chemotherapy arm (HR, 0.50; 95% CI, 0.39-0.64; P < 0.0001).
Additionally, the 6-month PFS rate per blinded independent central review (BICR) assessment was 65.4% with the sugemalimab regimen versus 39% with chemotherapy/placebo; the 12-month PFS rates were 31.6% and 12.6%, respectively. The median PFS was 8.9 months (95% CI, 7.06-10.9) in the sugemalimab arm versus 4.93 months (95% CI, 4.83-5.59) in the placebo arm (HR, 0.54; 95% CI, 0.41-0.70; P <.0001).
"I do believe that sugemalimab plus chemotherapy provides a new treatment option for patients with metastatic NSCLC [based on these findings],” first author Caicun Zhou, MD, PhD, director of the Department of Oncology at Shanghai Pulmonary Hospital, director of the Cancer Institute of Tongji University Medical School, and chairman of the Oncology Department at Tongji University, said in a virtual presentation during the meeting.
Sugemalimab is a full-length, fully human PD-L1 targeted immunoglobin G4 monoclonal antibody that does not have antibody-dependent cellular mediated cytotoxicity or complement-dependent cytotoxicity. However, the agent was designed to retain its antibody-dependent phagocytosis, which is capable of mediating the direct elimination of tumor cells via microphages. Earlier phase 1b data indicated that the combination of sugemalimab and platinum-based chemotherapy resulted in promising safety and efficacy in patients with squamous and nonsquamous NSCLC.
Patients enrolled on the GEMSTONE-302 trial needed to have chemotherapy-naïve stage IV NSCLC that was measurable by RECIST v1.1 criteria. Moreover, they needed to have an ECOG performance status of 0-1 with no known sensitizing EGFR, ALK, ROS1, or RET genomic alterations. Tumor tissue had to be available to test for PD-L1 expression. Patients were stratified based on histology, PD-L1 expression, and ECOG performance status.
Participants were randomized in a 2:1 fashion. Those on the investigational arm received 1200 mg of intravenous (IV) sugemalimab on day 1, with patients who had squamous histology receiving carboplatin and paclitaxel; those who had nonsquamous histology were given sugemalimab with carboplatin and pemetrexed. Patients in the control arm received IV placebo on day 1 along with the same histology-based chemotherapy regimen as the investigational arm. This induction treatment was given for 4 cycles, every 3 weeks.
In the maintenance phase of treatment, patients with squamous histology in the investigational arm received sugemalimab, while those with nonsquamous histology were given sugemalimab and pemetrexed. Those in the control arm received placebo if they had squamous histology or placebo and pemetrexed if they had nonsquamous histology. This treatment was given for up to 35 cycles.
Notably, patients on the placebo arm were permitted to crossover to receive 1200 mg of sugemalimab for up to 35 cycles. The primary end point of the study was investigator-assessed PFS by RECIST v1.1 criteria, and key secondary end points included overall survival (OS), BICR-assessed PFS, investigator-assessed PFS in patients with PD-L1 expression of 1% or greater, overall response rate (ORR), and duration of response (DOR).
A total of 479 patients were randomized; 320 received the sugemalimab regimen and 159 received chemotherapy/placebo. On the sugemalimab arm, 45.9% of patients (n = 147) are still receiving treatment, while 54.1% (n = 173) have discontinued due to radiographic progressive disease (36.6%; n = 117), adverse effects (AEs; 10.3%; n = 33), patient decision (5.6%; n = 18), clinical progressive disease (0.6%; n = 2), physician decision (0.6%; n = 2), or death (0.3%; n = 1).
On the chemotherapy/placebo arm, 20.1% (n = 32) of patients were still receiving treatment, while 79.9% (n = 127) discontinued treatment. Specifically, 61.6% (n = 98) of patients discontinued due to radiographic disease progression, 6.9% (n = 11) because of toxicities, 7.5% (n = 12) because of patient decision, 1.3% (n = 1) due to clinical progressive disease, 1.3% (n = 2) due to physician decision, 0.6% (n = 1) because of death, and 0.6% (n = 1) for other reasons.
The median age of participants in the investigational arm was 62.0 years versus 64.0 years in the control arm. The majority of patients in both arms had an ECOG performance status of 1, at 81.6% (n = 261) in the sugemalimab arm and 84.3% (n = 134) in the chemotherapy/placebo arm. In the sugemalimab arm, 40.3% (n = 129) of patients had squamous histology, while 59.7% (n = 191) had nonsquamous disease. In the control arm, 39.6% (n = 63) had squamous histology and 60.4% (n = 96) had nonsquamous disease. The majority, or 61.3%, of patients in the investigational arm had a PD-L1 expression of 1% or greater (n = 196), while 38.8% (n = 124) had a PD-L1 expression of less than 1%. In the control arm, 59.7% (n = 95) versus 40.3% (n = 64) had PD-L1 expression of 1% or greater or less than 1%, respectively.
Additional results revealed that patients with a PD-L1 tumor proportion score (TPS) of 1% or greater had an investigator-assessed median PFS of 8.90 months (95% CR, 6.93–not reached [NR]) with the sugemalimab regimen compared with 4.90 months (95% CI, 4.63-5.06) with the control regimen (HR, 0.42; 95% CI, 0.30-0.59). In those with a PD-L1 TPS of 1% or less, a median PFS of 6.97 months (95% CI 5.78-8.77) was reported in those who received the investigational regimen versus 4.93 months (95% CI, 3.98-5.59) in those given the control regimen (HR, 0.66; 95% CI, 0.46-0.94).
Patients with squamous histology who were treated with the sugemalimab regimen had an investigator-assessed median PFS of 7.16 months (95% CI, 6.83-8.90) versus 4.70 months (95% CI, 4.17-4.86) with the chemotherapy regimen (HR, 0.33; 95% CI, 0.22-0.47). In those with nonsquamous histology, the sugemalimab/chemotherapy combination led to a median PFS of 8.57 months (95% CI, 6.87-10.99) versus 5.16 months (95% CI, 4.86-7.06) with chemotherapy alone (HR, 0.66; 95% CI, 0.48-0.92).
“PFS benefit was observed regardless of positive PD-L1 expression. [Improved] PFS benefit was [also] observed in squamous and nonsquamous NSCLC. Almost all patient subgroups, including age, gender, smoking status, and performance status could [achieve] better PFS benefit from sugemalimab plus chemotherapy,” said Zhou. “We also found that different PD-L1 subgroups and [those with] brain metastases and liver metastases also [achieved] better PFS benefit from sugemalimab plus chemotherapy compared with placebo plus chemotherapy.”
Moreover, with regard to responses, patients who were treated with the sugemalimab regimen experienced an ORR of 61.4% (95% CI, 55.8%-66.8%) versus 39.2% (95% CI, 31.6%-47.3%) in the placebo arm (P < .0001). No complete responses were reported, but 61.4% (n = 194) of patients on the sugemalimab arm achieved a partial response compared with 39.2% (n = 62) of those on the chemotherapy/placebo arm. Moreover, 26.9% (n = 85) of those on the investigational arm achieved stable disease compared with 46.2% (n = 73) of those on the control arm. Twenty-two patients who received the sugemalimab combination experienced disease progression versus 15 patients who were given chemotherapy and placebo.
The median DOR in the investigational and control arms was 9.69 months (95% CI, 7.43-NR) and 3.68 months (95% CI, 3.48-5.72), respectively.
“A better tumor response rate was observed across different PD-L1 expression subgroups and different histologies,” Zhou added. In those with a PD-L1 TPS of less than 1% (n = 188), the ORRs in the investigational and control arms were 50.0% versus 39.1%, respectively; in those with a TPS ranging from 1% to 49% (n = 138), these rates were 66.7% versus 35.4%, respectively. In those with a TPS of 50% or greater, the ORR with the sugemalimab regimen was 70.6% versus 43.5% with the chemotherapy/placebo combination.
The preliminary OS analysis revealed that patients in the placebo arm had a median OS of 14.75 months (95% CI, 11.33-NR), while median OS was NR in the sugemalimab arm (HR, 0.66; 95% CI, 0.44-0.97; P = .0338).
With regard to safety, almost all patients on the sugemalimab arm experienced at least 1 treatment-related AE (TRAE; 99.4%; n = 318) versus 98.7% (n = 157) of those on the chemotherapy/placebo arm. Moreover, 61.9% (n = 198) of those on the investigational arm experienced an AE that was grade 3 in severity or higher versus 61.6% (n = 98) of those on the control arm. Moreover, 18.1% (n = 58) versus 2.5% (n = 4) of patients who received the sugemalimab regimen versus chemotherapy/placebo, respectively, experienced TEAEs of special interest; 3.4% (n = 11) versus 0% were grade 3 or greater in severity. Eighteen patients on the investigational arm experienced a treatment-emergent toxicity that resulted in death versus 9 patients on the control arm. Additionally, 10.3% (n = 33) of patients who received sugemalimab/chemotherapy versus 7.5% (n = 12) of those given chemotherapy/placebo experienced TEAEs that ultimately resulted in treatment discontinuation.
The most common all-cause AEs reported in the sugemalimab arm included anemia, neutropenia, and leukopenia. Low-grade AEs of special interest included hypothyroidism, hyperthyroidism, and non-severe skin reaction, with high grade AEs of special interest including hepatitis, pneumonitis, and severe skin reactions.
Zhou C, Wang Z, Sun Y, et al. GEMSTONE-302: randomized double-blind, phase 3 study of sugemalimab or placebo plus platinum-based chemotherapy as first-line treatment for metastatic NSCLC. Presented at: ESMO Asia Virtual Congress 2020; November 20-22, 2020; Virtual. Presentation ID 415 – FPN LBA4.