Sugemalimab Shows Efficacy as Consolidation Therapy in Unresectable Stage III NSCLC

Sugemalimab significantly prolonged progression-free survival (PFS) vs placebo in Chinese patients with locally advanced, unresectable, stage III non–small cell lung cancer (NSCLC) who did not progress after concurrent or sequential chemoradiotherapy, according to data from the interim analysis of the phase 3 GEMSTONE-301 trial (NCT03728556) published in The Lancet.¹

At a median follow-up of 14.3 months (interquartile range [IQR], 6.4-19.4) for the sugemalimab arm (n = 255) and 13.7 months (IQR, 7.1-18.4) for the placebo arm (n = 126), results showed that patients who received sugemalimab experienced a median PFS of 9.0 months (95% CI, 8.1-14.1) per blinded independent central review (BICR) vs 5.8 months (95% CI, 4.2-6.6) with placebo (HR, 0.64; 95% CI, 0.48-0.85; P = .0026). The 12-month PFS rate was 45.4% (95% CI, 38.2%-52.4%) in the sugemalimab arm vs 25.6% (95% CI, 16.2%-36.1%) in the placebo arm.

“Median PFS was longer with sugemalimab than with placebo, regardless of patient age, smoking history, ECOG performance status, radiotherapy dose, squamous or nonsquamous histology, and disease stage,” lead study author Qing Zhou, MD, of Guangdong Lung Cancer Institute, Guangzhou, China, and colleagues, wrote in the paper. “Efficacy results were inconclusive for female patients because of low enrolment numbers, similar to another phase 3 study [NCT01015443] of stage III NSCLC in an East-Asian population.”

Previously, durvalumab received regulatory approval for use in patients with unresectable, stage III NSCLC who did not progress after concurrent chemoradiotherapy, based on results from the phase 3 PACIFIC trial (NCT02125461). Following this decision, the regimen became the new standard.2 However, PACIFIC included only patients who received concurrent chemoradiotherapy, and many patients were unable to tolerate that concurrent treatment, restricting its use to those with a good ECOG performance status and limited comorbidities.³

It is unknown whether an anti–PD-1/PD-L1 drug could prolong survival in patients with unresectable stage III NSCLC who have not progress after sequential chemoradiotherapy. In the phase 3 GEMSTONE-302 trial (NCT03789604), the addition of the PD-L1–targeted monoclonal antibody sugemalimab to chemotherapy significantly improved PFS compared with the addition of placebo in patients with chemotherapy-naïve stage IV NSCLC.⁴

The double-blind GEMSTONE-301 trial enrolled patients who were at least 18 years of age with histologically or cytologically confirmed locally advanced, unresectable, stage III NSCLC. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and acceptable organ function, among other criteria.

Moreover, patients needed to have received at least 2 cycles of platinum-based chemotherapy, either concurrently or sequentially, with definitive radiotherapy. Chemotherapy regimens were required to have 1 or more of etoposide, vinorelbine, vinblastine, pemetrexed, taxanes, or gemcitabine, plus cisplatin, carboplatin, or nedaplatin.

Radiotherapy was required to have reached a total dose of 54 Gy to 66 Gy, with either the mean dose to the lung not exceeding 20 Gy, or the volume of lung parenchyma that received 20 Gy or more not exceeding 35%. For sequential chemoradiotherapy regimens, the interval between the end of a chemotherapy cycle and the initiation of radiotherapy must not have exceeded 35 days. Patients could not have progressed after concurrent or sequential chemoradiotherapy.

If patients had prior exposure to antibodies or other drugs that targeted T-cell co-regulatory proteins, known sensitizing EGFR, ALK, or ROS1 mutations, received another investigational drug within 28 days before first dose, or had active or prior autoimmune disease, they were excluded. Moreover, patients could not have evidence of uncontrolled concomitant diseases or active infection, unresolved pneumonitis that was grade 2 or higher and caused by prior chemoradiotherapy, nor could they have symptomatic interstitial lung disease.

Those enrolled to the investigative arm (n = 255) received sugemalimab at a dose of 1200 mg intravenously once every 3 weeks as consolidation therapy for up to 24 months; those in the control arm (n = 126) received matching placebo. Participants were randomized 2:1.

Notably, dose adjustments were not permitted in either group. Treatment continued until confirmed disease progression, unacceptable toxicity, or withdrawn consent. Patients could continue treatment after initial disease progression if there was no clinical deterioration or rapid disease progression, and if the patient remained tolerant to treatment with a stable ECOG performance status, per investigator discretion.

The primary end point of the rial was PFS per RECIST v1.1 criteria and as assessed by blinded independent central review. Secondary end points included investigator-assessed PFS, overall survival (OS), objective response rate, duration of response (DOR), and time to death or distant metastasis.

Of the patients randomized to the investigative and control arms, the median age was 61 years (range, 56-65) and 60 years (range, 55-65), respectively. Most patients were male (93% vs 91%, respectively), were former or current smokers (84% vs 87%), had an ECOG performance status of 1 (69% vs 70%), received concurrent chemoradiotherapy (66% vs 67%), received a radiotherapy dose of at least 60 Gy (83% vs 84%), had stage IIIB disease (57% vs 52%), and had squamous cell carcinoma (69% vs 68%).

Additionally, in the sugemalimab arm, 51%, 32%, and 22% of patients, respectively, received cisplatin, carboplatin, or nedaplatin as their previous platinum chemotherapy, compared with 48%, 37%, and 16%, respectively, in the placebo group.

Furthermore, 67% and 61% of patients in the sugemalimab and placebo arms, respectively, achieved partial responses to chemoradiotherapy, and 2% in each arm experienced complete responses. Additionally, 31% of the patients in the sugemalimab arm and 37% of those in the placebo arm had stable disease after chemoradiotherapy.

The median DOR in the sugemalimab arm was not reached (NR; 95% CI, 8.5-NR), vs 6.0 months 95% CI, 2.2-NR) in the placebo arm. OS data remained immature at data cutoff, a;though 13% of patients in the sugemalimab arm and 25% of patients in the placebo arm had died.

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 76% of patients in the sugemalimab arm and 58% of those in the placebo arm. Additionally, grade 3 or 4 TEAEs related to the study drug occurred in 9% of patients in the investigative arm and 6% of those in the control arm. The most common grade 3 or 4 TEAEs were pneumonitis or immune-mediated pneumonitis (3% in the sugemalimab arm vs 1% in the placebo arm).

Serious treatment-related AEs (TRAEs) were reported in 15% of patients in the sugemalimab arm and 10% of those in the placebo arm. The most frequent serious TRAEs were pneumonitis or immune-mediated pneumonitis (9% in the sugemalimab arm vs 7% in the placebo arm), pneumonia (2% vs <1%), and interstitial lung disease (2% vs 2%).

TEAEs that led to discontinuation of study drug occurred in 9% of patients in the sugemalimab arm vs 3% of those in the placebo arm. The most frequent TEAEs that resulted in discontinuation were pneumonitis or immune-mediated pneumonitis (2% in sugemalimab vs 2% in placebo), pneumonia (1% vs <1%), and interstitial lung disease (<1% vs 0%). Furthermore, 12 total deaths occurred; this included 4 treatment-related deaths in the sugemalimab arm.

Notably, PD-L1 status was not evaluated at baseline for more than half of patients on the study. Investigating expression of PD-L1 in this patient population and how it relates to the efficacy of sugemalimab remains an area ripe for further investigation.

“A limitation of our study is that data for PD-L1 expression are not included at present because this was not a preplanned stratification factor and was instead an exploratory end point,” the study authors wrote. “We will assess the association between PD-L1 expression and efficacy outcomes after longer follow-up of the patients.”

References

1. Zhou Q, Chen M, Jiang O, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non­-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet. 2022;23(2):209-219. doi:10.1016/S1470-2045(21)00630-6
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
3. Conibear J. Rationale for concurrent chemoradiotherapy for patients with stage III non-small-cell lung cancer. Br J Cancer. 2020;123(suppl 1):10-17. doi:10.1038/s41416-020-01070-6
4. Zhou C, Wang Z, Sun Y, et al. LBA4 GEMSTONE-302: a phase III study of platinum-based chemotherapy (chemo) with placebo or CS1001, an anti-PDL1 antibody, for first-line (1L) advanced non-small cell lung cancer (NSCLC). Ann Oncol. 2020;31(suppl 6):S1386. doi:10.1016/j.annonc.2020.10.368