Investigator-assessed Objective Response Rate Research Articles

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250mg orally, once daily) plus toripalimab (240mg intravenously, once every threeweeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥  3 treatment-related adverse events occurred in 28 (46.7%) patients. Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. gov NCT04169672.

Phase II study to determine the anti-tumor activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in esophageal cancer.

Reported here are results from the esophageal squamous cell carcinoma (SCC) cohort of a Phase II, non-comparative, basket study, evaluating the anti-tumor activity and safety of FAP-IL2v plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor naive. Patients received FAP-IL2v 10 mg plus atezolizumab 1200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks, then every 2 weeks, plus atezolizumab 840 mg intravenously every 2 weeks. Primary endpoint was investigator-assessed objective response rate (ORR). In the response-evaluable population (N=34), best confirmed ORR was 20.6% (95% confidence interval [CI]: 10.4-36.8) with a complete response (CR) seen in one patient and partial responses (PR) in six patients. Disease control rate was 44.1% (CR=2.9%; PR=17.6%; stable disease [SD]=23.5%) and median duration of response was 10.1 months (95% CI: 5.6-26.7). Median progression-free survival was 1.9 months (95% CI: 1.8-3.7). Analysis of response by PD-L1 expression (Ventana SP263) resulted in an ORR of 26.7 % for patients with PD-L1-positive tumors (tumor area positivity [TAP] cut-off ≥1%; n=15) and 7.1% for patients with PD-L1-negative tumors (TAP cut-off <1%; n=14). Overall, the treatment combination was tolerable and adverse events were consistent with the known safety profiles of each drug. FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.

Abstract PO2-19-09: INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer

Abstract Background The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2-positive breast cancer (HER2+ BC) and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line induction treatment in patients with PIK3CA-mutated, HER2+, advanced BC (aBC). Trial design INAVO122 is a multicenter, randomized, international, double-blind, placebo-controlled study. Patients will be enrolled for: first-line induction treatment if they are receiving/will receive PH + a taxane; or maintenance treatment completing induction treatment. In the maintenance phase, patients will be randomized 1:1 to receive inavolisib (9 mg orally once daily; Days 1–21 of 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression, unacceptable toxicity, death, consent withdrawal, or at the investigator’s discretion. ELIGIBILITY Enrolled patients must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥ 6 months from completion of neoadjuvant/adjuvant systemic non-hormonal treatment. They must not have received any treatment for aBC prior to induction, and, at screening, fasting glucose must be &amp;lt; 126 mg/dL and HbA1c &amp;lt; 6.4%. To be randomized, patients must have completed induction therapy per standard of care without progression of disease and show left ventricular ejection fraction ≥ 50%. AIMS The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints are overall survival; investigator-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. STATISTICAL METHODS The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. ACCRUAL Target randomization is ~230 patients; recruitment began in July 2023. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05894239. Citation Format: Sandra Swain, Carlos Barrios, Reva Basho, Giuseppe Curigliano, Nadia Harbeck, Chiun-Shen Huang, Sherene Loi, Nicholas Turner, Jessica Chen, Volkmar Henschel, Simon Warburton, Fabiola Amair-Pinedo, Javier Cortés. INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-09.

Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Abstract Background The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy. Methods This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization. Results Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, &amp;gt; 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE &amp;gt;= Grade 4 were reported. No patient discontinued treatment due to TEAE. Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study. Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-08.

Tabelecleucel for EBV+ PTLD after allogeneic HCT or SOT in a multicenter expanded access protocol

AbstractPatients with Epstein-Barr virus (EBV)–positive posttransplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months after allogeneic hematopoietic cell transplant (HCT) and 4.1 months after solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV–specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD after HCT or SOT. We now report outcomes from a multicenter expanded access protocol in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory (R/R) to rituximab with/without chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates were both 70.0% (95% confidence interval [CI], 46.5-84.7) overall, both 61.5% (95% CI, 30.8-81.8) in HCT, and both 81.5% (95% CI, 43.5-95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than nonresponders (0%). Treatment was well tolerated, with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for R/R EBV+ PTLD after HCT or SOT. This trial was registered at www.ClinicalTrials.gov as #NCT02822495.

Abstract CT286: TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma

Abstract Introduction: Novel early-line therapies for advanced (unresectable or metastatic) melanoma are needed to improve the rate of deep and durable responses and increase the proportion of patients with long-term benefit. TILVANCE-301 will evaluate the efficacy and safety of lifileucel autologous TIL cell therapy plus pembrolizumab in patients with untreated advanced melanoma. Methods: TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group study that will randomize ~670 patients (1:1; Day 0) to Arm A: lifileucel plus pembrolizumab (Day 3: tumor tissue resection for TIL manufacturing; Day 5: pembrolizumab 200 mg; Day 26: pembrolizumab 400 mg; Day 28-29: cyclophosphamide 60 mg/kg; Day 28-32: fludarabine 25 mg/m2; Day 33: lifileucel; Day 34-37: ≤6 doses of high-dose IL-2; Week 10: pembrolizumab 400 mg Q6W) or Arm B: pembrolizumab alone (same pembrolizumab dosing as Arm A). Patients in Arm B with confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel monotherapy as immediate next treatment and may continue pembrolizumab until start of nonmyeloablative lymphodepletion. Eligible adults have histologically confirmed advanced melanoma, Eastern Cooperative Oncology Group performance status of 0-1, estimated life expectancy &amp;gt;6 months, ≥1 resectable lesion to generate lifileucel, and ≥1 remaining measurable lesion. Prior neoadjuvant or adjuvant treatment including immune checkpoint inhibitors may be allowed. Prior therapy for metastatic disease, symptomatic untreated brain metastases, organ allograft or prior cell therapy, uveal/ocular melanoma, and chronic systemic steroid therapy are not permitted. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) objective response rate (ORR) and progression-free survival (PFS). Key secondary efficacy endpoint is overall survival. Additional secondary efficacy endpoints include BIRC-assessed complete response (CR) rate, duration of response (DOR), and event-free survival (EFS); investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of treatment-emergent adverse events and relationship to study drug. Exploratory endpoints include in vivo T-cell persistence (unique CDR3 sequences in peripheral blood mononuclear cell [PBMC] over time) and correlative biomarkers (eg, lifileucel phenotypic and functional characteristics; lifileucel, tumor, and PBMC gene expression profiles; tumor mutational landscape). The study will enroll globally, with initial sites in Europe, North America, and Australia. Trial registration: NCT05727904 Citation Format: Sajeve Thomas, Young Ki Hong, Yazan Samhouri, James Larkin, David J. Olson, Gino K. In, Victoria Atkinson, Philip Lammers, Andrew J. Furness, Juan Martin-Liberal, Patrick Terheyden, Andrew S. Poklepovic, Ryan H. Nguyen, Idit Peretz, Marcus Butler, Adnan Khattak, Lavinia Spain, E.M. Gaughan, Melissa Wilson, John W. Dubay, Anja Williams, Stephanie Goff, Gary C. Doolittle, Jason Chesney, Friedrich Graf Finckenstein, Jeffrey Chou, Xiao Wu, Giri Sulur, Wen Shi, John Haanen. TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT286.

Abstract CT032: Promotive clinical effects of pembrolizumab with necitumumab in patients having advanced non-small cell lung cancer with PD-L1 expression of 50% or higher in a phase II study (K-TAIL-202)

Abstract Background: Pembrolizumab is the standard of care for advanced non-small cell lung cancer (NSCLC) with high programmed death-1 ligand 1 (PD-L1) expression. However, combination therapies comprising pembrolizumab and ipilimumab, tiragolumab, or lenvatinib have not demonstrated superior efficacy in this patient group. This study explored the effectiveness of the novel combination of pembrolizumab and necitumumab as first-line therapy in patients having advanced NSCLC with PD-L1 expression of 50% or higher. Methods: Patients with untreated advanced NSCLC with PD-L1 expression of 50% or higher received pembrolizumab and necitumumab every 3 weeks up to 35 cycles. The primary endpoint was investigator-assessed objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. The sample size was calculated using 80% power with a one-sided alpha error of 10%, a threshold ORR of 39.0%, and an expected ORR of 54.8%. Results: From December 2020 to March 2023, 50 patients were enrolled. Patient characteristics were as follows: male/female patients: 38/12; median age: 72 years (range: 51-90 years); histology, adenocarcinoma/squamous cell carcinoma/other: 35/15/5; and PS, 0/1: 20/30. At the time of the primary analysis, the ORR was 76.0% (95% CI: 61.9%-86.9%), with 2.0%, 74.0%, 10.0%, and 8.0% of the patients showing complete response, partial response, stable disease, and progressive disease, respectively. The median PFS was 15.7 months (95% CI, 10.3 to not reached) and the median OS was not reached. Common toxicities included rash (86%) and hypomagnesemia (60%). Grade 3 interstitial lung disease was noted in 5 patients (10%) and grade 5 cardiac arrest in 1 patient (2%). Conclusion: Combination therapy comprising pembrolizumab and necitumumab demonstrated a 76.0% ORR, meeting the primary endpoint, with manageable toxicities. The regimen showed promising clinical activity in patients with NSCLC and high PD-L1 expression, warranting further investigation. Clinical trial ID: jRCT2031200248. Citation Format: Atsushi Horiike, Hiroshi Wakui, Shunichi Sugawara, Yuji Minegishi, Sadatomo Tasaka, Sojiro Kusumoto, Toshio Sakatani, Hiroyuki Suzuki, Yukio Hosomi, Yuichi Tambo, Tsuneo Shimokawa, Hiroo Ishida, Eisaku Miyauchi, Katsuhiko Naoki, Tatsuro Fukuhara, Emiko Mura, Toshiaki Tsurui, Risako Suzuki, Nana Iriguchi, Tomoyuki Ishiguro, Yuya Hirasawa, Ryo Manabe, Masahiro Shimokawa, Ryotaro Ohkuma, Hirotsugu Ariizumi, Yutaro Kubota, Kazuyuki Hamada, Sachiko Takenoshita, Kakei Ryu, Takehiko Sambe, Eisuke Inoue, Satoshi Wada, Kiyoshi Yoshimura, Hironori Sagara, Shinichi Kobayashi, Takuya Tsunoda. Promotive clinical effects of pembrolizumab with necitumumab in patients having advanced non-small cell lung cancer with PD-L1 expression of 50% or higher in a phase II study (K-TAIL-202) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT032.

Abstract CT003: Initial results from an open-label phase 1b/2 study of RP1 oncolytic immunotherapy in solid organ transplant recipients with advanced cutaneous malignancies (ARTACUS)

Abstract Background: Skin cancers are common post-transplant malignancies in solid organ transplant (SOT) recipients. The use of immune checkpoint inhibitors has improved outcomes in the general patient (pt) population but is associated with a high risk of allograft rejection in transplant recipients. RP1 is an oncolytic immunotherapy that expresses a fusogenic glycoprotein (GALV-GP-R−) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The purpose of this study is to assess the safety and efficacy of single-agent RP1 in SOT recipients with skin cancer (NCT04349436). Methods: The trial will enroll up to 65 transplant recipients with histologically confirmed advanced cutaneous squamous cell carcinoma (CSCC) and up to 10 pts with advanced non-CSCC skin cancer in 2 parts. Part A (completed) enrolled kidney and liver transplant recipients until safety was established, and Part B is enrolling kidney, liver, heart, and lung transplant recipients. Pts must have stable allograft function and ECOG performance status ≤1. Pts with visceral metastases are excluded. Pts receive an initial RP1 dose at 1 × 106 plaque-forming units (PFU)/mL followed by 1 × 107 PFU/mL after 2 weeks and continuing every 2 weeks until prespecified study endpoints are met. Tumor biopsies are collected for biomarker analyses and HSV-1 serostatus is monitored. Results: At the data cutoff (Sept 18, 2023), 27 transplant recipients were enrolled (kidney, n = 22; liver, n = 4; lung, n = 1) with a median (range) age of 68 (48-86) years; 24 pts had CSCC and 3 had Merkel cell carcinoma. Nearly half of pts (44%) had metastatic disease at study baseline. The investigator-assessed objective response rate (ORR) for efficacy-evaluable pts was 35% (8/23); 22% of pts (5/23) had complete response (CR). Most responses were ongoing. The most common (&amp;gt;20%) treatment-emergent adverse events were fatigue (33%), chills (26%), and pyrexia (26%). There was no evidence of allograft rejection. Eight deaths were reported; none were related to RP1. Immunohistochemistry from tumor biopsies indicated influx of CD8+ T cells and upregulation of PD-L1 expression after RP1 treatment. Additional biomarker data from gene expression analysis will be presented. Conclusions: This is the first trial assessing single-agent RP1 activity in solid organ transplant recipients with advanced cutaneous malignancies. RP1 monotherapy showed compelling antitumor activity (ORR 35%; 22% CR) in evaluable pts. Additionally, RP1 monotherapy was well tolerated, and the safety profile was similar to non-immunocompromised pts with advanced skin cancers (IGNYTE study). Citation Format: Michael R. Migden, Wanxing Chai-Ho, Gregory A. Daniels, Theresa Medina, Trisha M. Wise-Draper, Meenal Kheterpal, Jennifer C. Tang, Sherrif F. Ibrahim, Diana Bolotin, Claire Verschraegen, Nathalie C. Zeitouni, Katy K. Tsai, Laxminarasimha Donthireddy, Praveen K. Bommareddy, Jeannie W. Hou, Walter Hong, Diwakar Davar. Initial results from an open-label phase 1b/2 study of RP1 oncolytic immunotherapy in solid organ transplant recipients with advanced cutaneous malignancies (ARTACUS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT003.

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair–Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D

BackgroundThe phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). Patients and MethodsPatients with MSS/pMMR mCRC received pembrolizumab 200 mg every 3 weeks plus mFOLFOX7 (previously untreated; cohort B) or FOLFIRI (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate (ORR) per RECIST v1.1 was secondary and biomarker analysis was exploratory. ResultsThirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3/4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3/4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. ORR was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than non-responders. No association between tumor mutational burden and response was observed. ConclusionsPembrolizumab plus mFOLFOX7/FOLFIRI demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. ClinicalTrials.gov IdentifierClinicalTrials.gov; NCT03374254

Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1–2, open-label, multicohort trial

In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. Bristol Myers Squibb and Ono Pharmaceutical.

Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study

The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein. This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032. Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event. Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile. Pfizer and Celcuity.

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3–11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

Short-term efficacy and safety of neoadjuvant pyrotinib plus taxanes for early HER2-positive breast cancer: a single-arm exploratory phase II trial.

The effectiveness and safety of pyrotinib have been substantiated in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC). However, the role of pyrotinib as a single HER2 blockade in neoadjuvant setting among BC patients has not been studied. The objective of this study was to evaluate the efficacy and tolerability of pyrotinib plus taxanes as a novel neoadjuvant regimen in patients with HER2-positive early or locally advanced BC. In this single-arm exploratory phase II trial, patients with treatment-naïve HER2-positive BC (stage IIA-IIIC) received pyrotinib 400 mg once daily and taxanes [docetaxel 75 mg/m2 or nanoparticle albumin-bound (nab)-paclitaxel 260 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly] for a total of four 21-day cycles before surgery. Efficacy assessment was based on pathological and clinical measurements. The primary endpoint of this study was the total pathological complete response (tpCR) rate. The secondary endpoints included breast pCR (bpCR) rate, investigator-assessed objective response rate (ORR) and adverse events (AEs) profiles. From 1 September 2021 to 30 December 2022, a total of 31 patients were enrolled. One patient was withdrawn due to unbearable skin rash after the second cycle of neoadjuvant therapy. The majority of the intention-to-treat (ITT) population was premenopausal (54.8%), had large tumors (90.3%) and metastatic nodes (58.1%) at diagnosis and hormone-receptor positive tumors (64.5%). Most participants used nab-paclitaxel (74.2%) and received mastectomy (67.7%) after neoadjuvant treatment. The tpCR and bpCR rates were 48.4% [95% confidence interval (CI): 30.8-66%] and 51.6% (95% CI: 34-69.2%), respectively. Grade ≥3 treatment-related AEs were observed in 16.1% (5/31) of the ITT population, including diarrhea (n=2, 6.5%), hand and foot numbness (n=1, 3.2%), loss of appetite (n=1, 3.2%), and skin rash (n=1, 3.2%). AE related dose reduction or pyrotinib interruption was not required. In female patients with HER2-positive non-metastatic BC, neoadjuvant pyrotinib monotherapy plus taxanes appears to show promising clinical benefit and controllable AEs [Chinese Clinical Trial Registry (ChiCTR2100050870)]. The long-term efficacy and safety of this regime warrant further verification.

Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial

Regorafenib has anti-tumor activity in patients with unresectable hepatocellular carcinoma (uHCC) with potential immunomodulatory effects, suggesting that its combination with immune checkpoint inhibitor may have clinically meaningful benefits in patients with uHCC. The multicenter, single-arm, phase 2 RENOBATE trial tested regorafenib–nivolumab as front-line treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). ORR per RECIST version 1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells showed that long-term responders exhibited T cell receptor repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67+ proliferating CD8+ T cells and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib–nivolumab combination as front-line treatment for uHCC and provide preliminary insights on immune biomarkers of response. ClinicalTrials.gov identifier: NCT04310709.

CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial.

C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8-2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%-48.2% (cycle 1) and 37.5%-44.2% (cycle 2) and occurred within 6-12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925).

Nivolumab monotherapy or combination with ipilimumab with or without cobimetinib in previously treated patients with pancreatic adenocarcinoma (CheckMate 032)

BackgroundPancreatic cancer is one of the deadliest cancer types and represents a major unmet medical need. CheckMate 032 investigated safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without...

A phase 1 study of fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) in patients with advanced ccRCC.

434 Background: Concurrent blockade of lymphocyte-activation gene 3 (LAG-3) may enhance efficacy of anti–programmed cell death protein 1 (PD-1) therapies. We present safety and clinical activity data from a Phase 1 study in patients with clear cell renal cell carcinoma (ccRCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Patients with advanced or metastatic ccRCC who had received no more than 2 previous regimens of anti-angiogenic therapy who were anti–PD-1/PD-L1-naïve (cohort 3) or anti–PD-1/L1-experienced with most recent dose within 3 months prior to screening (cohort 4) were eligible. All patients were to receive fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for up to 24 months. Tumor measurements were performed by RECIST 1.1 every 6 weeks for 24 weeks, then every 9 weeks. Results: 15 patients (median age: 64 years) each in cohort 3 and 4 (total N=30) were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff.For cohorts 3 and 4 respectively, 80% and 87% of patients were male, and 40% and 87% were White. All patients had prior cancer-related systemic therapy. 60% (9/15) and 93% (14/15) of patients in cohorts 3 and 4 had ≥2 lines of prior therapies, respectively. For cohorts 3 and 4, median treatment duration was 27 weeks and 18 weeks, and median follow-up was 13 months and 24 months, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 53% and 33% of patients in cohorts 3 and 4, respectively. Serious TEAEs occurred in 33% and 13% of patients in cohorts 3 and 4, respectively. Treatment-related TEAEs (TRAEs) were reported in 80% of patients in cohorts 3 and 60% of patients in cohort 4. The most common TRAEs (any grade) were rash (27%) and infusion related reaction (grade 1 and 2) (27%) in cohort 3 and fatigue (20%) in cohort 4. Grade ≥3 TRAEs occurred in 27% of patients in cohorts 3. Treatment was discontinued due to any TEAE in 3 patients in cohort 3 and 1 patient in cohort 4. In cohort 3, there was one death. The patient was a 79-year-old woman with a history of antiphospholipid syndrome who died from complications of biopsy-proven ischemic colitis attributed to study treatment. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 20% (3 partial responses [PRs]) in cohort 3 and 7% (1 PR) in cohort 4. The disease control rate (DCR) was 60% and 73% in cohorts 3 and 4, respectively. Kaplan–Meier estimation of median progression-free survival was 4 months (95% confidence interval [CI], 1–10) in cohort 3 and 4 months (95% CI, 1–7) in cohort 4 patients. Duration of responses were 4, 7, and 26 months in 3 responders in cohort 3; and 6 months in one responder in cohort 4. Conclusions: Fianlimab + cemiplimab demonstrated promising signs of clinical activity with durable responses among patients with anti–PD-1/PD-L1-naïve (cohort 3) and anti–PD-1/L1-experienced (cohort 4), with an acceptable safety profile. Clinical trial information: NCT03005782 .

ZSAB-TOP: A phase 2 trial of tislelizumab (TIS) and ociperlimab (OCI) combined with gemcitabine and cisplatin (GemCis) as the first-line treatment for advanced biliary tract cancer (BTC).

475 Background: GemCis has long been the standard-of-care for advanced BTC, however the prognosis remains poor. Combinations with immunotherapy and GemCis are being explored in BTC. This study aimed to evaluate the efficacy and safety of TIS (an anti-PD-1 antibody) and OCI (a TIGIT inhibitor) combined with GemCis as the first-line treatment for advanced BTC. Herein, the primary analysis results of this study were reported. Methods: In this open-label, single-arm, multicenter phase 2 study, systematic treatment-naïve pts with unresectable advanced BTC received TIS (200 mg, day1, Q3W), OCI (900 mg, day1, Q3W), and GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on days 1 and 8 Q3W, up to 8 cycles). The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. A binomial exact test with a one-sided α of 0.05 was performed in the analysis of the primary endpoint to test the historical ORR of 25% with GemCis. If p≤0.05, the statistical superiority of the study treatment would be claimed. Results: A total of 45 pts were enrolled, with 75.6% having intrahepatic cholangiocarcinoma and 60.0% metastatic disease. As of 24 Aug 2023 (median follow-up, 8.0 months), 24.4% (11/45) pts remained on study treatment. Among the 41 pts in efficacy analysis set, confirmed ORR (cORR) was 48.8% (20/41, 95% CI, 32.9-64.9, p=0.0009), with 1 complete response. The statistical superiority was achieved. The subgroups of TIGIT+ pts tended to have numerically higher cORR (Table). Median PFS was 7.7 months, with 6-month PFS rate of 67.6%. Median OS was not reached, and 6-month OS rate was 86.2%. Grade ≥3 treatment-related adverse events rate was 60% (27/45). Immune-mediated adverse events rate was 37.8% (17/45), which were mostly grade 1 and 2. Conclusions: The combination of TIS and OCI plus GemCis showed promising anti-tumor activity with manageable safety as the first-line treatment for advanced BTC. Clinical trial information: NCT05023109 . [Table: see text]

Phase 2 study of nab-sirolimus in patients with well-differentiated and advanced/metastatic neuroendocrine tumors of the gastrointestinal tract, lung, or pancreas.

TPS601 Background: Neuroendocrine tumors (NETs; ~2% of all malignancies) commonly arise from the gastrointestinal (GI) tract, pancreas, and lung, often presenting as metastatic disease. The PI3K/Akt/mTOR pathway is implicated in the pathogenesis and progression of NETs. Everolimus, an oral mTOR inhibitor (mTORi), is an option for treatment of NETs of the GI tract, lung, or pancreas but response rates observed in the RADIANT -3 and -4 studies were modest at 4–10%. nab-Sirolimus is a mTORi that utilizes nanoparticle technology to preferentially target tumors and is approved in the USA for malignant perivascular epithelioid cell tumor. In preclinical animal models, nab-sirolimus demonstrated higher intratumoral drug accumulation, improved target suppression, and stronger antitumor activity relative to equal weekly doses of sirolimus and everolimus, warranting further exploration of nab-sirolimus. This study will evaluate efficacy/safety of nab-sirolimus in patients with advanced/metastatic NETs. Methods: This phase 2, multicenter, open-label, single-arm study (NCT05997056) will enroll approximately 21 adults (≥18 years) with functional or non-functional, well-differentiated, locally advanced unresectable or metastatic NETs of the GI tract, lung, or pancreas who have received ≤2 prior lines of therapy, excluding somatostatin analogs (SSTa).Patients with functional NETS are eligible if they have been on a stable dose of SSTa for ≥12 weeks and had disease progression during SSTa treatment. Eligible patients must have ≥1 measurable target lesion (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), Eastern Cooperative Oncology Group performance status score 0 or 1, and adequate organ function/hematologic parameters.They are not permitted to have received prior mTORi, including nab-sirolimus, or to have tumors with known inactivating TSC1 or TSC2 alterations. Patients will receive nab-sirolimus 100 mg/m2 by intravenous infusion on days 1 and 8 of 21-day cycles. Treatment will continue until disease progression or unacceptable toxicity, or until discontinuation based on investigator or patient discretion.The primary endpoint is investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints include duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety. Exploratory endpoints include correlation of baseline molecular biomarkers with clinical outcomes. Analysis of study objectives will be descriptive. Study site activation is underway with the first patient on study anticipated for the 3rd quarter of 2023. Clinical trial information: NCT05997056 .

Comparison of efficacy and safety between PD-1 inhibitors and PD-L1 inhibitors plus platinum-etoposide as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, real-world analysis

BackgroundImmunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC.MethodsWe conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).ResultsBetween January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3–8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5–7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83–1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62–1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group.ConclusionsOur research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.