Neoadjuvant SHR-1701 Increases Response, Resectability in Stage III Unresectable NSCLC

Neoadjuvant treatment with SHR-1701 with or without chemotherapy followed by surgery or radiotherapy induced responses in more than half of patients with stage III unresectable non–small cell lung cancer (NSCLC) and increased resectability in those assigned to definitive surgery, according to findings from a phase 2 study (NCT04580489) presented at the 2022 ESMO Immuno-Oncology Annual Congress.

The post-induction objective response rate (ORR) was 56.1% (95% CI, 46.2%-65.7%). After treatment completion, the response rate increased 25% to 70.1% (95% CI, 60.5%-78.6%). The disease control rate (DCR) following induction and end of treatment was 92.5% (95% CI, 85.8%-96.7%) and was comprised mostly of partial responses and stable disease.

“Neoadjuvant SHR-1701 with or without chemotherapy followed by surgery or radiation therapy showed promising antitumor activity despite a relatively high proportion of patients with poor baseline disease characteristics,” lead author Yi-Long Wu, MD, tenured professor of oncology at Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences and Guangdong Lung Cancer Institute in Guangzhou, China, said in a presentation of the data.

Standard therapy for patients with stage III unresectable NSCLC consists of consolidation immunotherapy after concurrent chemoradiation. However, neoadjuvant immunotherapy with or without chemotherapy has previously shown evidence of tumor and nodal downstaging in resectable NSCLC. The addition of immunotherapy-based induction therapy to consolidation therapy may improve outcomes in stage III unresectable disease by increasing resectability.

SHR-1701 is a novel, bifunctional fusion protein targeting PD-L1 and TGF-β. In a phase 1 trial, SHR-1701 was effective and tolerable in patients with advanced cancers.

To be eligible for enrollment in the phase 2 trial, patients had to have unresectable, stage III NSCLC; an ECOG performance status of 0 or 1; no prior systemic therapy or radiotherapy to the thorax; and no sensitizing EGFR or ALK alterations.

Following screening, patients were stratified into 2 groups depending on PD-L1 expression level. Patients with a PD-L1 tumor proportion score (TPS) below 50% received 30 mg/kg of SHR-1701 plus 175 mg/m2 of paclitaxel and carboplatin at an area under the curve of 5 every 3 weeks for 3 cycles (arm A; n = 88). Patients with a PD-L1 TPS of 50% or greater were randomly assigned to SHR-1701 plus the same chemotherapy regimen every 3 weeks for 3 cycles (arm B; n = 9) or the same schedule of SHR-1701 alone (arm C; n = 10).

After multidisciplinary assessment, patients proceeded to definitive surgery followed by SHR-1701 every 3 weeks or definitive radiation therapy administered as 60 Gy/30 fractions plus 30 mg/m2 of concurrent cisplatin followed by the same schedule of SHR-1701 alone. Treatment with SHR-1701 was continued for 16 cycles or until progressive disease or unacceptable toxicity.

The primary end points were post-induction response and event-free survival (EFS). Secondary end points included overall survival, time to distant metastasis, and safety. Major pathological response (MPR) and surgical rate were evaluated as exploratory end points.

Among all patients, the median age was 59 years (range, 31-70), and most patients were male (n = 101; 94.4%). Most patients had an ECOG performance status of 1 (n = 71; 66.4%), squamous histology (n = 79; 73.8%), stage IIIB (n = 47; 43.9%) and IIIC (n = 32; 29.9%) disease, and a PD-L1 TPS below 1% (n = 48; 44.9%) and between 1% and 49% (n = 40; 37.4%). Additionally, 89.7% (n = 96) of patients were current or former smokers.

Additional findings showed that the combination of SHR-1701 and chemotherapy led to higher response rates compared with SHR-1701 alone. In arms A and B, the ORRs post-induction and after treatment completion were 57.7% (95% CI, 47.3%-67.7%) and 71.1% (95% CI, 61.0%-79.9%), respectively. The DCR was 92.8% (95% CI, 85.7%-97.0%). This compared favorably with the post-induction and end of treatment response rates of 40.0% (95% CI, 12.2%-73.8%) and 60.0% (95% CI, 26.2%-87.8%) in arm C, respectively. The DCR in this subset was 90.0% (95% CI, 55.5%-99.7%).

At a median follow-up of 11.8 months, the overall median EFS was 18.2 months (95% CI, 11.8-not reached [NR]). In arms A and B, the median EFS was 14.9 months (95% CI, 11.5-NR); the median EFS in arm C was NR (95% CI, 2.0-NR).

Notably, patients who underwent surgery did not reach the median EFS (95% CI, 11.8-NR). Those who received definitive radiation therapy achieved a median EFS of 14.9 months (95% CI, 11.4-NR). The 12-month EFS rates with surgery and radiation therapy were 74.4% and 55.9%, respectively.

“Benefits with induction treatment were partly conferred by allowing surgery conversion, with a conversion rate of 25.2% [n = 27/107],” Wu said, adding that conversions occurred in patients with stage IIIA (n = 10), IIIB (n = 12), and IIIC (n = 5) disease at baseline.

Additionally, among resected patients, the N2 and N3 downstaging rates were 57.1% [n = 8/14] and 66.7% [n = 6/9], respectively. Moreover, the MPR rate was 44.4% (n = 12) and the pathologic complete response rate was 25.9% (n = 7).

“Favorable efficacy was observed in resected patients, and [the overall] safety profile was tolerable, with no new safety signals identified,” Wu said.

Treatment-related adverse effects (TRAEs) that occurred in at least 15% of patients included white blood cell count decrease (68.2%), anemia (66.4%), neutrophil count decrease (64.5%), platelet count decrease (50.5%), decreased appetite (47.7%), alopecia (41.1%), nausea (38.3%), lymphocyte count decrease (37.4%), hypoesthesia (30.8%), asthenia (29.9%), rash (29.9%), alanine aminotransferase increase (29.0%), hypoalbuminemia (27.1%), vomiting (25.2%), aspartate aminotransferase (24.3%), hyponatremia (23.4%), pyrexia (17.8%), infusion-related reaction (16.8%), pruritus (16.8%), and pain in the extremity (15.0%).

Grade 3 or greater AEs (n = 84; 78.5%) and TRAEs (n = 77; 72.0%) occurred in most patients. SHR-1701 was the primary agent leading to treatment discontinuation in 15.9% (n = 17) of patients, followed by paclitaxel (n = 1; 0.9%), carboplatin (n = 1; 0.9%), and cisplatin (n = 4; 2.8%).

Immune-related AEs occurred in 57.0% (n = 61) of patients, and 3 deaths occurred.

“Our data support phase 3 investigation of neoadjuvant SHR-1701 as combination therapy for untreated stage III unresectable NSCLC,” Wu concluded.

Reference

Wu YL, et al. A phase 2 study of neoadjuvant SHR-1701 with or without chemotherapy (chemo) followed by surgery or radiotherapy (RT) in stage III unresectable NSCLC (uNSCLC). Presented at: 2022 ESMO Immuno-Oncology Annual Congress; December 7-9, 2022; Geneva, Switzerland. Presentation LBA5