Background

TIGIT is a novel immune checkpoint present on activated T cells and NK cells; inhibition of TIGIT may further amplify the inhibition of the PD-L1/PD-1 pathway. CITYSCAPE (NCT03563716) is the first randomised Phase II study of an anti-TIGIT antibody; the combination of TA showed clinically meaningful improvement in ORR and PFS compared with PA in patients (pts) with metastatic PD-L1+ NSCLC. Here we present updated PFS, OS, and PROs.

Methods

Eligible pts with chemotherapy-naïve PD-L1+ (TPS ≥1% by local or central 22C3 IHC pharmDX assay) locally advanced, unresectable or metastatic NSCLC were randomised 1:1 to receive TA (T 600 mg IV + A 1200 mg IV) or PA (A 1200 mg IV) every 3 weeks until disease progression or loss of clinical benefit. The EORTC QLQ-C30 was administered at baseline and throughout study treatment. Co-primary endpoints: investigator-assessed ORR and PFS. Additional endpoints: DOR, OS, safety, association of tumour PD-L1 expression levels with clinical outcomes and PROs from the ITT population.

Results

At this updated analysis (16 Aug 2021), median follow-up was 16.3 mo (range 0.2–35.5) in ITT population. TA improved ORR, PFS and OS compared to PA. For PA vs TA, treatment-related AEs (TRAEs) were 70.6% vs 82.1%; Grade 3–4 TRAEs were 25.0% vs 22.4%; AEs leading to discontinuation were 13.2% vs 14.9%. Changes from baseline scores of global health status and functioning scales were maintained and comparable between arms but showed clinically meaningful improvement in dyspnea (-10.6) and pain (-12.1) for pts who remained on TA at Cycle 16. Table: 1+

Conclusion

TA continues to provide a clinically meaningful benefit in pts with metastatic NSCLC, driven by the PD-L1+ TPS ≥50% subgroup. TA has a manageable safety profile consistent with PD-L1/PD-1 inhibitors. Patients on TA maintained global health status and functioning and showed improvements in dyspnea and pain. Durable response and encouraging OS continue to support evaluating TA in metastatic PD-L1-high NSCLC.

Clinical trial identification

NCT03563716.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Abigail Robertson, PhD, of Ashfield MedComms, an Ashfield Health company, and funded by F. Hoffmann-La Roche Ltd.

Disclosure

B.C. Cho: Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc., Brigebio therapeutics, Cyrus therapeutics, Guardant Health, Joseah BIO; Financial Interests, Personal, Member of the Board of Directors: Gencurix Inc., Interpark Bio Convergence Corp.; Financial Interests, Personal, Full or part-time Employment: Yonsei University College of Medicine; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc., Gencurix Inc., Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp.; Financial Interests, Personal, Royalties: Champions Oncology; Financial Interests, Institutional, Research Grant: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp.; Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, Medpacto, Blueprint medicines; Other, Personal, Other, Founder: DAAN Biotherapeutics. D. Rodriguez-Abreu: Financial Interests, Personal, Other, honoraria: Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Eli Lilly, Pfizer, and Novartis; Financial Interests, Institutional, Invited Speaker, travel support: Roche, Bristol-Myers Squibb, MSD and Novartis. M. Hussein: Financial Interests, Personal, Advisory Role: IntegraConnect, Coherus Biosciences, Athenex, Karyopharm Therapeutics, BMS, AstraZeneca, Mirati Therapeutics, Exelixis. N. Secen: Non-Financial Interests, Personal and Institutional, Principal Investigator: Institute for Pulmonary Diseases of Vojvodina, Serbia. D. Kim: Financial Interests, Institutional, Research Grant: Alpha Biopharma, Amgen, Astrazeneca/Medimmune, Boehringer-Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang,Bridge Bi; Financial Interests, Personal, Other, Travel support for advisory board meeting attendance: Amgen, Daiichi-Sankyo. E. Huang: Financial Interests, Personal, Full or part-time Employment: Roche Products Ltd. N. Patil: Financial Interests, Personal, Full or part-time Employment: Genentech. M. Huang: Financial Interests, Personal, Full or part-time Employment: Roche. X. Wen: Financial Interests, Personal, Full or part-time Employment: Roche Genentech. D. Mendus: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. T. Hoang: Financial Interests, Personal, Full or part-time Employment: Roche Genentech; Financial Interests, Personal, Stocks/Shares: Roche Genentech. R.D. Meng: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi; Financial Interests, Personal, Advisory Role: Achilles Therapeutics, Bristol-Myers Squibb, Editas Medicine, Eisai, G1 Therapeutics, Ideaya Biosciences, Lilly Association of Community Cancer Centers. All other authors have declared no conflicts of interest.

Background

Pembro plus lenva showed antitumor activity and acceptable safety in patients (pts) with metastatic NSCLC (mNSCLC) in Study 111/KEYNOTE-146. We report outcomes of pembro with/without lenva in pts with mNSCLC from the phase 3 LEAP-007 study (NCT03829332).

Methods

Eligible pts were ≥18 y with previously untreated, stage IV NSCLC with PD-L1 TPS ≥1%, ECOG PS 0/1, and without targetable EGFR, ROS1, or ALK aberrations. Pts were randomized 1:1 to pembro 200 mg IV Q3W for up to 35 cycles plus oral lenva 20 mg/d or placebo (pbo) until PD/toxicity. Primary endpoints were PFS (per RECIST v1.1 by BICR) and OS. An independent data monitoring committee (DMC) regularly reviewed safety data; for the fourth review, a prespecified nonbinding futility analysis to first evaluate OS (1-sided P < 0.4960), then PFS (HR < 1), then OS (HR ≥ 0.9) was performed.

Results

623 pts were randomized (median age, 66 y; ECOG PS 1, 65.0%). The study met the prespecified futility criterion for OS; median OS was not improved with pembro + lenva vs pembro + pbo (HR 1.10; 95% CI 0.87–1.39; P = 0.79744). Median PFS was longer and ORR was higher with pembro + lenva vs pembro + pbo (Table). Grade 3-5 treatment-related AEs occurred in 57.9% of pts with pembro + lenva and 24.4% with pembro + pbo. Grade 5 treatment-related AEs occurred in 5.2% and 1.9% of pts, respectively. Table: 120O

Conclusions

Based on the prespecified futility criteria for OS provided to the DMC, the benefit/risk for pembro + lenva was not considered positive vs pembro + pbo in mNSCLC with PD-L1 TPS ≥1%. Treatment with lenva/pbo was discontinued, but pts could continue on open-label pembro monotherapy for up to 35 cycles. Safety was consistent with prior studies evaluating pembro + lenva, without new safety signals. Other phase 3 studies evaluating pembro + lenva therapy in NSCLC are ongoing. Pembro monotherapy remains a standard of care in 1L mNSCLC with PD-L1 TPS ≥1% and without EGFR/ALK alterations in many regions globally.

Clinical trial identification

NCT03829332.

Editorial acknowledgement

Medical writing assistance was provided by Shilpa Kamboj, PhD, of ICON plc (North Wales, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Eisai Inc., Woodcliff Lake, NJ, USA.

Legal entity responsible for the study

Eisai Inc., Woodcliff Lake, NJ, USA and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Eisai Inc., Woodcliff Lake, NJ, USA and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

J.C. Yang: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, GSK, Janssen, Merck, Novartis, Puma Biotechnology, Takeda Oncology; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, Merck Serono, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche, Takeda Oncology, Yuhan Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Pfizer, Roche, Takeda Oncology. S. Sugawara: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Kyowa Kirin, Lilly, MSD K.K., Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceuticals, Pfizer, Taiho Pharmaceuticals, and Yakult Honsha. N.S. Basappa: Financial Interests, Personal, Advisory Board, and Honoraria: Merck, Eisai, Pfizer, Bristol Myers Squibb, Roche, Ipsen, Janssen, AstraZeneca, EMD Serono, Bayer, Astellas. D. Moran Ortiz: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Astellas, AstraZeneca; Financial Interests, Personal, Research Grant: Roche, Bristol Myers Squibb, MSD, Covance. C.E. Okpara: Financial Interests, Personal, Full or part-time Employment: Eisai Ltd., Hatfield, UK. Z. Zimmer, A. Samkari, N. Bhagwati: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Kenilworth, NJ, USA. All other authors have declared no conflicts of interest.

Background

TIS is an anti-PD-1 antibody engineered to minimize FcγR binding, a mechanism of T-cell clearance and potential anti-PD-1 resistance. TIS demonstrated antitumor activity in NPC as a single agent in a Phase I/II study (CTR20160872). This randomized, double-blind, Phase III study evaluated TIS + GP vs placebo + GP as 1L treatment for RM-NPC (NCT03924986).

Methods

Eligible pts with RM-NPC were randomized 1:1 to receive TIS (Arm A) or placebo (Arm B) (200 mg IV D1) plus G (1 g/m² IV D1, D8) and P (80 mg/m² D1) every three weeks (Q3W) for 4–6 cycles followed by TIS or placebo Q3W until disease progression, unacceptable toxicity, or withdrawal. After disease progression, patients in Arm B could crossover to receive TIS monotherapy. The primary endpoint was independent review committee-assessed progression-free survival (PFS_IRC). Secondary endpoints included objective response rate (ORR_IRC), duration of response (DoR_IRC), investigator-assessed PFS (PFS_INV), and safety.

Results

A total of 263 pts were randomized to Arm A (n=131) and Arm B (n=132). At the interim analysis (data cut-off: Mar 26, 2021), median follow-up was 10.0 months (m). Median PFS_IRC was significantly longer for Arm A vs B (HR 0.52 [95% CI: 0.38, 0.73]; median PFS: 9.2 vs 7.4 m; p<0.0001). PFS benefit in Arm A was consistent across most subgroups. PFS_INV was consistent with PFS_IRC (HR 0.54 [0.38, 0.76]; median 9.8 vs 7.6 m). ORR_IRC and median DoR_IRC were 69.5% and 8.5 m (Arm A) and 55.3% and 6.1 m (Arm B), with 21 (16.0%) and 9 (6.8%) patients achieving complete response, respectively. The 12-month PFS_IRC event-free rate was 35.7% (Arm A) and 12.2% (Arm B). Safety is described in the table. Table: 121O

Summary of TEAEs

Conclusions

TIS + GP significantly prolonged PFS vs GP alone as 1L therapy for RM-NPC. ORR and DoR were increased for TIS + GP vs GP alone. The safety profile of TIS + GP was manageable and consistent with previous reports, with no new safety signals identified.

Clinical trial identification

NCT03924986.

Editorial acknowledgement

Editorial writing support for the development of this abstract, under direction of the authors, was provided by Jenny Feehan, BSc, of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene Ltd.

Legal entity responsible for the study

BeiGene Ltd.

Funding

BeiGene Ltd.

Disclosure

Y. Wu: Financial Interests, Personal, Full or part-time Employment: BeiGene. L. Zhang: Financial Interests, Personal, Invited Speaker: Hengrui Pharm; Financial Interests, Institutional, Research Grant: Hengrui Pharm; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal and Institutional, Proprietary Information: Hengrui Pharm. All other authors have declared no conflicts of interest.

Background

Neoadjuvant concurrent chemoradiotherapy with surgery is the standard treatment for esophageal squamous cell carcinoma (ESCC) in NCCN guidelines. But many patients refused or abandon radiotherapy because of the intolerable adverse effects. We designed a single-arm, open-label, phase II trial of pembrolizumab plus paclitaxel, cisplatin followed by Da Vinci robot surgery for locally advanced (stage III) ESCC. The purpose is to observe and evaluate the efficacy and safety.

Methods

The enrolled subjects are the locally advanced and resectable (stage Ⅲ，8^th, AJCC) ESCC patients, who will receive pembrolizumab (200mg, IV, D1, Q3W for 3 cycles), paclitaxel (135mg/m², IV, D2, Q3W for 3 cycles) ，and cisplatin (20mg/m², IV, D2-4, Q3W for 3 cycles), then will undergo Da Vinci robot-assisted McKeown surgery within 4-6 weeks after neoadjuvant treatment. If the pathology result is not a complete response, pembrolizumab alone as adjuvant therapy should be continued for at least 6 cycles with the same usage as before. Primary endpoints: major pathological response (MPR) rate; the safety. Secondary endpoints: pathological complete response (pCR) rate, objective response rate (ORR); 1, 3, 5-years OS and DFS, R0 resection rate and 30-day perioperative complications. Quality of life (EORTC QLQ-C30, OES18) and nutrition assessment (PG-SGA score).

Results

This trial has recruited 42 subjects (50 in plan), of which 29 have finished robot surgery. The results confirm that this new treatment is safe (no adverse events of grade 3 or higher), and did not cause a delay in surgery. Patients' nutritional status and QOL improved significantly. R0 resection rate is 100%, with MPR 21/29 (72.4%), pCR 12/29 (41.4%), and ORR 28/29 (96.6%). No perioperative death has occurred so far.

Conclusion

Pembrolizumab combined with paclitaxel and cisplatin as a neoadjuvant therapy was associated with few side effects, did not delay surgery, and induced a major pathological response in 72.4% of resected ESCC tumors. It may be better than the neoadjuvant concurrent chemoradiation recommended by NCCN guidelines.

Clinical trial identification

NCT 04389177, date of registration: 15 May 2020.

Disclosure

All authors have declared no conflicts of interest.