Interim Overall Survival Analysis Research Articles

Abstract GS03-12: Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis

Abstract Background: Patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant chemotherapy + HER2-targeted therapy have a high risk of recurrence and death. The standard of care when KATHERINE was designed was continuation of the same HER2-targeted therapy in the adjuvant setting for 1 year. The primary analysis of KATHERINE in 2018 showed that the risk of recurrence of invasive BC or death was 50% lower with adjuvant ado-trastuzumab emtansine (T-DM1) than with trastuzumab. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed, HER2-positive (immunohistochemistry 3+ or in situ hybridization-positive) primary BC (T1–4, N0–3, M0) who received neoadjuvant chemotherapy + HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg intravenously [IV] every 3 weeks [q3w]) or trastuzumab (6 mg/kg IV q3w) for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single vs dual neoadjuvant HER2-targeted therapy, and pathologic nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS). We report the final IDFS analysis, which was to occur after ~384 events had been reported, and the preplanned second interim analysis of overall survival (OS); specified to occur at the same time. Results: With a median follow-up of 8.4 years (101 months), T-DM1 sustained the improvement in IDFS over trastuzumab (unstratified hazard ratio [HR] 0.54; 95% confidence interval [CI] = 0.44, 0.66; p < 0.0001). Landmark 7-year IDFS rates were increased from 67.1% with trastuzumab to 80.8% with T-DM1; a difference of 13.7%. At clinical cutoff for the final IDFS analysis, 215 deaths had been reported. T-DM1 significantly reduced the risk of death by 34% compared with trastuzumab (unstratified HR 0.66; 95% CI = 0.51, 0.87; p = 0.0027). Deaths had occurred in 89/743 patients (12.0%) in the T-DM1 arm and 126/743 (17.0%) in the trastuzumab arm. Landmark 7-year OS rates were increased from 84.4% with trastuzumab to 89.1% with T-DM1; a difference of 4.7%. OS and IDFS benefits were seen across key subgroups. A low incidence of adverse events (AEs) related to study treatment or to study procedures was observed during the post-treatment period: Grade ≥3 related AEs occurred in 3/740 patients (0.4%) in the T-DM1 arm and 3/720 (0.4%) in the trastuzumab arm; serious related AEs, in 2/740 (0.3%) and 4/720 (0.6%), respectively. Related AEs classed as “cardiac disorders” were rare in both arms with extended follow-up. Conclusions: After 8.4 years (101 months) median follow-up, T-DM1 significantly improved OS in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. The IDFS benefit of T-DM1 was sustained in the intention-to-treat population with longer follow-up, and no new safety issues emerged. Cardiac toxicity was rare in both arms. T-DM1 is the first therapy to show improved survival post-surgery in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. Follow-up is ongoing for the final OS analysis. Citation Format: Sibylle Loibl, Max Mano, Michael Untch, Chiun-Shen Huang, Eleftherios Mamounas, Norman Wolmark, Adam Knott, Asna Siddiqui, Thomas Boulet, Beatrice Nyawira, Eleonora Restuccia, Charles Geyer. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis [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 GS03-12.

Abstract GS01-12: MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced breast cancer

Abstract Background: Abemaciclib is approved both for high-risk early breast cancer as well as advanced breast cancer (ABC) in the first- and second-line setting. In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- ABC with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) significantly improved PFS (HR, 0.540; 95% CI, 0.418-0.698; p=0.000002) as initial therapy in HR+, HER2- ABC. At the last interim OS analysis (~252 events, at 5.8 years follow-up [FU]), a numerically favorable median OS difference (12.6 months) was observed (HR, 0.754; 95% CI, 0.584-0.974; p=0.0301, non-significant [NS]). Here, we present the final OS analysis of MONARCH 3 (NCT02246621). Methods: MONARCH 3 is a randomized, double-blind, Phase 3 study of abemaciclib + NSAI (anastrozole or letrozole) vs placebo + NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. OS was a gated secondary endpoint and chemotherapy-free survival (CFS) an exploratory endpoint. Final OS analysis was planned after approximately 315 OS events had occurred in the intent-to-treat (ITT) population with a split alpha between the ITT population and the subgroup with visceral disease (sVD) according to a prespecified graphical testing scheme. Kaplan-Meier method and stratified Cox proportional hazards models were used for time-to-event analyses. All reported p-values are two-sided. Results A total of 493 women were randomized 2:1 to receive abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). After a median FU of 8.1 years, 7% of patients were still receiving treatment in the abemaciclib arm vs 3% in the placebo arm. In the ITT population, 314 OS events were observed (198 deaths among 328 patients [60%] in the abemaciclib arm and 116 among 165 [70%] in the placebo arm; HR, 0.804; 95% CI, 0.637-1.015; p=0.0664, NS). Median OS was 66.8 months in the abemaciclib arm and 53.7 months in the placebo arm, a numerical difference of 13.1 months in the ITT population. In the sVD, 178 events were observed (113 deaths among 173 patients [65%] in the abemaciclib arm and 65 among 90 [72%] in the placebo arm; HR, 0.758; 95% CI, 0.558-1.030; p=0.0757, NS). Median OS was 63.7 months in the abemaciclib arm and 48.8 months in the placebo arm, a numerical difference of 14.9 months in the sVD. Consistent OS differences were observed across prespecified subgroups. PFS benefit was sustained (median 29.0 vs 14.8 months; HR, 0.535; 95% CI, 0.429-0.668; nominal p<0.0001) with substantial difference in 6-year PFS rates (23.3% vs 4.3% for abemaciclib vs placebo). CFS was also improved with abemaciclib vs placebo (median 46.7 vs 30.6 months; HR, 0.693; 95% CI, 0.557-0.863; nominal p=0.0010). No new safety signals were observed with longer term use. Conclusion In patients with HR+, HER2- ABC, abemaciclib in combination with a NSAI resulted in numerically longer OS compared to NSAI alone; however, statistical significance was not reached after a median FU of 8.1 years. The clinically meaningful improvement in median OS (>13 months) combined with the sustained significant improvement in median PFS (>14 months) and substantial extension in median CFS (>16 months) continue to support the use of abemaciclib in combination with NSAI as first-line therapy in ABC. Citation Format: Matthew Goetz, Masakazu Toi, Jens Huober, Joo Hyuk Sohn, Olivier Trédan, Inhae Park, Mario Campone, Shin-Cheh Chen, Luis Manual Manso, Shani Paluch-Shimon, Orit C. Freedman, Valerie Andre, Abhijoy Saha, Gertjan van Hal, Ashwin Shahir, Hiroji Iwata, Stephen RD Johnston, Joyce O'Shaughnessy, Xavier Pivot, Sara Tolaney, Sara Hurvitz, Antonio Llombart. MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- 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 GS01-12.

Overall survival and long-term safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Final analyses from INTRIGUE.

748 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]

Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.

IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab vs best supportive care (BSC) following platinum-based chemotherapy in the PD-L1-positive and all stage II-IIIA non-small cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are here reported. The design, participants, and primary-endpoint DFS outcomes have been reported for this phase 3, open-label, 1:1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) vs BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC. Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay). At a median 45.3 months' follow-up on April 18, 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified HR was 0.995 (95% CI 0.78-1.28). The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n=882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 TC ≥1% (n=476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n=229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis (grade 3/4 in 53 [10.7%] and grade 5 in 4 [0.8%] of 495 patients, respectively). Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study

Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC.

The randomized, double-blinded, multi-center, phase III GEMSTONE-302 ( NCT03789604 ) study evaluated the efficacy and safety of sugemalimab versus placebo in combination with chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (NSCLC). In this study, 479 treatment-naive patients with stage IV squamous or non-squamous NSCLC without known EGFR sensitizing mutations, ALK, ROS1 or RET fusions were randomized (2:1) to receive 1,200 mg of sugemalimab (n = 320) or placebo (n = 159) every 3 weeks in combination with platinum-based chemotherapy for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC and sugemalimab or placebo plus pemetrexed for non-squamous NSCLC. Placebo-treated patients could cross over to receive sugemalimab monotherapy on disease progression. The primary endpoint was investigator-assessed progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and objective response rate. Sugemalimab plus chemotherapy has demonstrated significant PFS prolongation in the primary analysis as reported previously. As of 22 November 2021, the prespecified interim OS analysis showed significant improvement with the addition of sugemalimab to chemotherapy (median OS = 25.4 versus 16.9 months; hazard ratio = 0.65; 95% confidence interval = 0.50-0.84; P = 0.0008). Sugemalimab plus chemotherapy provided superior PFS and OS compared to placebo plus chemotherapy, supporting the use of sugemalimab as a first-line treatment option for metastatic NSCLC.

Overall survival and long-term safety in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Updated analyses from INTRIGUE.

11524 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the first interim analysis (IA) for overall survival (OS) in the INTRIGUE trial, data were immature (OS event rate, 22.3%), and median OS was not reached in either arm for the KIT exon 11 intent-to-treat (ITT) and all-patient (AP) ITT populations (S Bauer, et al. J Clin Oncol. 2022). Additionally, ripretinib had a more favorable safety profile with fewer grade 3/4 treatment-emergent adverse events (TEAEs) than sunitinib. Here, we present the second IA of OS and updated safety from INTRIGUE. Methods: INTRIGUE is a global, open-label, phase 3 study that enrolled adult pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint; data cutoff for the second IA was Sept 1, 2022. Results: Of 453 pts in the AP ITT population, 444 received treatment; 51 remain on treatment (33/223 [14.8%] with ripretinib and 18/221 [8.1%] with sunitinib). Common reasons for treatment discontinuation were progressive disease (PD) assessed by independent radiologic review (55.4%), PD assessed by investigator (10.6%), clinical PD (5.9%), withdrawal of consent (5.4%), and adverse event (AE; 4.5%); fewer pts discontinued due to an AE for ripretinib vs sunitinib (2.7% vs 6.3%). Following study treatment discontinuation, 58 pts (25.6%) from the sunitinib arm received ripretinib; 139 pts (61.5%) from the ripretinib arm later received sunitinib. There were 185 OS events (40.8%) in the AP ITT population; median duration of follow-up was 28.7 and 28.5 months for ripretinib and sunitinib, respectively. OS was similar with ripretinib vs sunitinib in the AP ITT (median 35.5 vs 30.9 months; HR 0.88, 95% CI 0.66 to 1.18; nominal P = 0.39) and KIT exon 11 ITT populations (median 34.0 vs 31.5 months; HR 1.05, 95% CI 0.75 to 1.48; nominal P = 0.77). The updated safety profile was consistent with the primary analysis; fewer pts had grade 3/4 TEAEs with ripretinib vs sunitinib (95 [42.6%] vs 149 [67.4%]). Dose interruptions and reductions were lower with ripretinib vs sunitinib. The median (range) treatment duration was 7.9 (0.2–38.2) months for ripretinib and 6.5 (0.2–38.3) months for sunitinib. Conclusions: In the second IA from INTRIGUE, OS was similar between treatment arms. The safety profile remained consistent with additional data, and results demonstrate favorable safety with ripretinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 .

Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC).

1003 Background: Treatment of HR+/HER2– mBC includes sequential endocrine therapy (ET) combined with targeted agents followed by sequential single-agent chemotherapy (CT), which is associated with poor outcomes and quality of life. SG is a Trop-2–directed antibody-drug conjugate approved in multiple countries for pts with metastatic triple-negative breast cancer who received ≥1 prior systemic therapy and in the US for pts with pretreated HR+/HER2- mBC. In the phase 3 TROPiCS-02 study, SG demonstrated a statistically significant OS benefit versus treatment of physician’s choice (TPC) in pts with pretreated, ET-resistant HR+/HER2– mBC at the 2nd planned interim OS analysis with 390 events (median, 14.4 vs 11.2 mo; HR, 0.79 [95% CI, 0.65-0.96]; P=0.02; Rugo HS, et al. ESMO 2022. LBA76); this is considered the final analysis per the protocol. Here, we report the results of an exploratory analysis of OS from TROPiCS-02 with a longer median follow-up (12.75 mo). Methods: Eligible pts withHR+/HER2– mBC who received prior taxane, ET, CDK4/6 inhibitor, and 2-4 prior lines of CT were randomly assigned 1:1 to receive SG (10 mg/kg IV d1 and 8, every 21 d) or TPC until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival by blinded independent central review per RECIST v1.1. Key secondary endpoints included OS and safety. In an exploratory analysis, we evaluated OS by HER2 immunohistochemistry (IHC). Results: In total, 543 pts (median prior CT for mBC, 3; visceral metastases, 95%) were randomized to receive SG (n=272) or TPC (n=271). At data cutoff (Dec 1, 2022), 437 OS events had occurred (median follow-up, 12.75 mo), with 47 (8.7%) new deaths in the SG versus TPC groups (22 [8.1%] vs 25 [9.2%]) since the 2nd planned interim analysis. With this extended follow-up, SG continues to demonstrate improved OS versus TPC (median, 14.5 vs 11.2 mo; HR, 0.79 [95% CI, 0.65-0.95]; nominal P=0.01). The OS rates (95% CI) for SG versus TPC were 60.9% (54.8-66.4) and 47.1% (41.0-53.0) at 12 months, 39.2% (33.4-45.0) and 31.7% (26.2-37.4) at 18 months, and 25.6% (20.4-31.1) and 21.1% (16.3-26.3) at 24 months. Overall, 92% of pts were evaluable for HER2 status by IHC (HER2 IHC0, n=217; HER2-low, n=283). SG demonstrated improved OS versus TPC in the HER2 IHC0 (median, 13.6 vs 10.8 mo; HR, 0.86 [95% CI, 0.63-1.13]) and HER2-low (median, 15.4 vs 11.5 mo, HR, 0.74 [95% CI, 0.57-0.97) groups. Updated safety will be reported at the time of presentation. Conclusions: The final OS analysis of the TROPiCS-02 study confirms the clinically meaningful OS benefit of SG over single-agent CT in pts with pretreated, endocrine-resistant HR+/HER2–mBC. This improvement was independent of HER2-low status. This analysis reinforces SG as an effective and safe treatment for this pt population with limited treatment options. Clinical trial information: NCT03901339 .

US Food and Drug Administration Approval Summary: Nivolumab Plus Platinum-Doublet Chemotherapy for the Neoadjuvant Treatment of Patients With Resectable Non-Small-Cell Lung Cancer.

On March 4, 2022, the US Food and Drug Administration (FDA) approved nivolumab plus platinum-doublet chemotherapy for the neoadjuvant treatment of patients with resectable non-small-cell lung cancer (NSCLC). We discuss the FDA's review of the key data and regulatory considerations supporting this approval. The approval was based on the results of CheckMate 816, an international, multiregional, active-controlled trial that randomly assigned 358 patients with resectable NSCLC, stage IB (≥4 cm) to IIIA (N2) per the American Joint Committee on Cancer seventh staging edition to receive either nivolumab plus platinum-doublet or platinum-doublet chemotherapy alone for three cycles before planned surgical resection. The major efficacy end point that supported this approval was event-free survival (EFS). At the first planned interim analysis (IA), the hazard ratio (HR) for EFS was 0.63 (95% CI, 0.45 to 0.87; P = .0052; statistical significance boundary = .0262) favoring the nivolumab plus chemotherapy arm; the median EFS was 31.6 months (95% CI, 30.2 to not reached) in the nivolumab plus chemotherapy arm versus 20.8 months (95% CI, 14.0 to 26.7) in the chemotherapy-only arm. At the time of a prespecified IA for overall survival (OS), 26% of patients had died, and the HR for OS was 0.57 (95% CI, 0.38 to 0.87; P = .0079; statistical significance boundary = .0033). Eighty-three percent of patients in the nivolumab-containing arm versus 75% in the chemotherapy-only arm received definitive surgery. This approval, the first for any regimen for the neoadjuvant treatment of NSCLC in the United States, was supported by a statistically significant and clinically meaningful improvement in EFS with no evidence of detriment in OS or negative impact on patients' receipt and timing of surgery or surgical outcomes.

Adjuvant olaparib in the subset of patients from Japan with BRCA1- or BRCA2-mutated high-risk early breast cancer from the phase 3 OlympiA trial

BackgroundThe efficacy and safety of olaparib compared with placebo in the subset of patients from Japan in the phase 3 OlympiA trial (NCT02032823) are reported here and contextualized with reference to the global OlympiA population.MethodsPatients with germline BRCA1 and/or BRCA2 pathogenic variants and HER2-negative, high-risk early breast cancer who had received neoadjuvant or adjuvant chemotherapy and completed local treatment were eligible. Patients were randomized 1:1 to receive olaparib or placebo for 1 year. Primary endpoint: invasive disease-free survival (IDFS). Secondary endpoints: distant disease-free survival (DDFS), overall survival (OS), and safety. Data are reported from the first pre-specified interim analysis (data cut-off [DCO] March 27, 2020) and the second, event driven, pre-specified interim analysis of OS (DCO July 12, 2021) in patients from Japan.Results140 patients were randomized in Japan (olaparib, n = 64; placebo, n = 76). At the first pre-specified interim analysis (median follow-up: 2.9 years), hazard ratios (HRs) for adjuvant olaparib compared with placebo were 0.5 for IDFS (95% confidence interval [CI] 0.18–1.24) and 0.41 for DDFS (95% CI 0.11–1.16). At the second pre-specified interim analysis of OS, three deaths occurred in the olaparib group versus six deaths in the placebo group (HR, 0.62 [95% CI 0.13–2.36]). Findings were consistent with those for the global population. No new safety signals were observed.ConclusionsWhile this analysis in a Japanese subset of patients was not powered to detect population-related treatment differences, efficacy and safety analysis results were consistent with the global OlympiA population, suggesting the findings from the global study are generalizable to clinical practice in Japan.

Abstract OT2-03-01: heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer

Abstract BACKGROUND Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader (SERD) that was found to be well tolerated and active as a monotherapy and in combination therapy in Phase I/II studies in early BC and pretreated locally advanced/metastatic BC (LA/mBC). Dual HER2 blockade with pertuzumab + trastuzumab (PH) + a taxane (induction therapy) followed by maintenance PH is the first-line standard of care for most patients (pts) with HER2+ LA/mBC. Despite HER2–ER blockade synergy, paucity of Phase III data evaluating maintenance PH + endocrine therapy (ET) vs. PH in pts with ER+/HER2+ LA/mBC leads to variable use of ET in this setting. Adding giredestrant to the maintenance phase could improve outcomes. TRIAL DESIGN This is a Phase III, randomized, two-arm, open-label, multicenter study evaluating the efficacy and safety of giredestrant + the fixed-dose combination of PH for subcutaneous injection (PH FDC SC) vs. PH FDC SC after induction therapy with PH FDC SC + a taxane in pts with ER+/HER2+ LA/mBC. In the induction phase, pts will receive 4–6 PH FDC SC cycles (1200 mg P/600 mg H in the first cycle, followed by 600/600 mg every 3 weeks) + a taxane (investigator choice of docetaxel/paclitaxel). Pts deriving clinical benefit may receive two additional cycles per investigator’s discretion. Pts completing ≥4 induction therapy cycles, achieving at least stable disease, and with a left ventricular ejection fraction (LVEF) ≥50% will be randomly assigned 1:1 to maintenance giredestrant 30 mg/day + PH FDC SC every 3 weeks or PH FDC SC only, until disease progression (PD). ET (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC-only arm. Study treatment will continue until PD, limiting toxicity, death, or consent withdrawal. ELIGIBILITY Enrolled pts must have ER+/HER2+ LA/mBC, disease-free interval from completion of (neo)adjuvant non-ET ≥6 months, Eastern Cooperative Oncology Group performance status 0/1, LVEF ≥50%, and adequate organ function. Pts with prior SERD treatment or presence of symptomatic central nervous system metastases will be excluded. All men and pre-/perimenopausal women must be eligible for a luteinizing hormone-releasing hormone agonist. AIMS The primary endpoint is investigator-assessed, maintenance progression-free survival. Secondary endpoints include overall survival (OS), objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned, and an independent data monitoring committee will be in place. ACCRUAL The study is open for enrollment. Approximately 812 pts will be enrolled in the induction phase, to allow for approximately 730 pts to be randomized in the maintenance phase. 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: NCT05296798. Citation Format: Sherko Küemmel, Catherine Harper-Wynne, Yeon H. Park, Fábio Franke, Michelino De Laurentiis, Eva Schumacher-Wulf, Daniel Eiger, Sarah Heeson, Mahesh Shivhare, Eleonora Restuccia, Joyce O’Shaughnessy. heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-03-01.

Abstract GS1-11: Sacituzumab Govitecan (SG) vs Treatment of Physician’s Choice (TPC): Efficacy by Trop-2 Expression in the TROPiCS-02 Study of Patients (Pts) With HR+/HER2– Metastatic Breast Cancer (mBC)

Abstract Background: HR+/HER2– mBC, the most common subset of breast cancer, is treated with sequential endocrine therapy + targeted agents followed by sequential single-agent chemotherapy (CT), with increasingly shorter benefit duration with each subsequent treatment. High Trop-2 expression is observed in breast cancer regardless of subtype. SG is a Trop-2-directed antibody-drug conjugate approved for pre-treated metastatic triple-negative breast cancer. In the phase 3 TROPiCS-02 study, SG showed both significant progression-free survival (PFS) benefit (HR, 0.66; P&amp;lt;0.001; median 5.5 vs 4.0 mo; JCO 2022) at the primary analysis and overall survival (OS) benefit (median 14.4 vs 11.2 mo; HR, 0.79; P=0.02; ESMO 2022) at the 2nd planned interim OS analysis vs TPC in pretreated HR+/HER2- mBC. Here we compare efficacy outcomes for SG and TPC by Trop-2 expression. Methods: Eligible pts had HR+/HER2- locally recurrent inoperable or mBC; received ≥1 prior taxane, endocrine therapy, a CDK4/6 inhibitor; and received 2-4 prior CT regimens for mBC. Pts were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (eribulin, gemcitabine, capecitabine, or vinorelbine) until disease progression or unacceptable toxicity. The primary endpoint was PFS by independent review per RECIST v1.1; OS and objective response rate (ORR) were key secondary endpoints. ORR was assessed by blinded independent central review per RECIST v1.1. Membrane Trop-2 expression on archival tumor tissue was assessed by immunohistochemistry and expressed as a histochemical score (H-score; range, 0-300); efficacy outcomes were assessed in H-score &amp;lt;100 and ≥100 groups. The H-score &amp;lt;100 group was further divided into H-score ≤10 and &amp;gt;10- &amp;lt;100 subgroups to assess the activity of SG in pts with very low Trop-2 expression. Results: Data cut-off was January 3, 2022 for PFS (median follow-up, 10.2 mo) and July 1, 2022 for OS (median follow-up, 12.5 mo). In total, 543 pts were randomized to receive SG (n=272) vs TPC (n=271). Pts had a median of 3 prior CT regimens for mBC; 95% had visceral metastases. There were 238 (88%) vs 224 (83%) Trop-2-evaluable pts in the SG vs TPC groups, respectively; of these, 95% had tumors with Trop-2 H-score &amp;gt;0. Of Trop-2-evaluable pts, 192 (42%) and 270 (58%) had H-scores &amp;lt;100 and ≥100, respectively. Demographics and baseline characteristics were generally consistent across H-score groups. PFS and OS benefit was observed for SG vs TPC across both Trop-2 groups (Table). Median PFS was 5.3 vs 4.0 mo (HR, 0.77; 95% CI, 0.54-1.09) and 6.4 vs 4.1 mo (HR, 0.60; 95% CI, 0.44-0.81) in the H-score &amp;lt;100 and ≥100 groups; median OS was 14.6 vs 11.3 mo (HR, 0.75; 95% CI, 0.54-1.04) and 14.4 vs 11.2 mo (HR, 0.83; 95% CI, 0.62-1.11), respectively. Disease response was observed in the 34 pts with H-score ≤10 who received SG. In pts who received SG, those with H-score ≤10, &amp;gt;10- &amp;lt;100, and ≥100 had ORRs of 24%, 18%, and 23%, respectively. The safety profile for SG by Trop-2 H-score was consistent with previous reports. Conclusions: In this TROPiCS-02 post-hoc analysis, improved efficacy with SG vs TPC was observed regardless of Trop-2 expression, and there was no clear level of Trop-2 expression at which a better treatment effect for SG was observed. These results support SG as an effective novel treatment option for patients with pretreated, endocrine-resistant HR+/HER2- mBC, and reinforce that Trop-2 testing is not required for SG treatment. Table Citation Format: Hope Rugo, Aditya Bardia, Frederik Marmé, Javier Cortés, Peter Schmid, Delphine Loirat, Olivier Trédan, Eva Ciruelos, Florence Dalenc, Patricia Gómez Pardo, Komal Jhaveri, Monica Motwani, Oh Kyu Yoon, Hao Wang, Wendy Verret, Sara Tolaney. Sacituzumab Govitecan (SG) vs Treatment of Physician’s Choice (TPC): Efficacy by Trop-2 Expression in the TROPiCS-02 Study of Patients (Pts) With HR+/HER2– Metastatic Breast Cancer (mBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-11.

C-reactive protein (CRP) as a predictive marker for outcomes with avelumab + axitinib (A + Ax) in patients with poor-risk advanced renal cell carcinoma (aRCC): Exploratory analysis from JAVELIN Renal 101.

670 Background: Analyses from the phase 3 JAVELIN Renal 101 trial (NCT02684006) suggested that CRP levels at baseline (BL) and early after treatment may predict outcomes with A + Ax in patients with aRCC. In addition, many patients with International Metastatic RCC Database Consortium (IMDC) poor risk who had prolonged progression-free survival (PFS) and overall survival (OS) were observed at the third interim analysis of OS. We analyzed the association between CRP levels and prolonged PFS/OS with A + Ax in patients with IMDC poor risk. Methods: CRP levels were assessed at screening and on day 1 of each 6-week cycle. Patients in the A + Ax arm with 3 or 4-6 IMDC risk factors were categorized into subgroups with CRP normal (BL CRP &lt;10 mg/L), normalized (BL CRP ≥10 mg/L and ≥1 CRP value decreased to &lt;10 mg/L during 6-week treatment), or non-normalized (CRP ≥10 mg/L at BL and during 6-week treatment). CRP levels were compared in patients with prolonged PFS/OS (PFS ≥24 months [mo] and OS ≥30 mo) or PFS &lt;24 mo (any OS duration). Results: In the A + Ax arm (N=442), 44 and 29 patients had 3 or 4-6 IMDC risk factors, of whom 7 and 5 had prolonged PFS/OS, and 26 and 20 had PFS &lt;24 mo, respectively (Table). Most patients with 3 or 4-6 risk factors with prolonged PFS/OS were in the normal or non-normalized CRP group, respectively. In patients with 3 risk factors with prolonged PFS/OS, CRP levels were generally low at BL and remained low for 24 mo. In patients with 4-6 risk factors with prolonged PFS/OS, CRP levels were high at BL and decreased markedly within 6 weeks, then maintained for 24 mo. Conclusions: In patients with poor-risk aRCC treated with A + Ax, a low CRP level at BL and during treatment or a rapid decrease in high CRP levels might predict favorable long-term outcomes, although CRP levels are unspecific and may increase/decrease with other diseases/comorbidities. Clinical trial information: NCT02684006 . [Table: see text]

First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial

First-line systemic therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) are limited. In this multicenter, double-blind phase 3 trial, a total of 551 patients with previously untreated, locally advanced or metastatic ESCC and PD-L1 combined positive score of ≥1 were randomized (2:1) to receive serplulimab (an anti-PD-1 antibody; 3 mg/kg) or placebo (on day 1), plus cisplatin (50 mg/m2) (on day 1) and continuous infusion of 5-fluorouracil (1,200 mg/m2) (on days 1 and 2), once every 2 weeks. The study met the primary endpoints. At the prespecified final analysis of progression-free survival (PFS) assessed by the blinded independent radiological review committee, serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy (median PFS of 5.8 months and 5.3 months, respectively; hazard ratio, 0.60; 95% confidence interval, 0.48–0.75; P < 0.0001). At the prespecified interim analysis of overall survival (OS), serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy (median OS of 15.3 months and 11.8 months, respectively; hazard ratio, 0.68; 95% confidence interval, 0.53–0.87; P = 0.0020). Grade 3 or higher treatment-related adverse events occurred in 201 (53%) and 81 (48%) patients in the serplulimab plus chemotherapy group and the placebo plus chemotherapy group, respectively. Serplulimab plus chemotherapy administered every 2 weeks significantly improved PFS and OS in patients with previously untreated, PD-L1-positive advanced ESCC, with a manageable safety profile. This study is registered with ClinicalTrials.gov (NCT03958890).

123P IMpower010: Exploratory overall survival (OS) with adjuvant atezolizumab (atezo) vs best supportive care (BSC) in stage II-IIIA NSCLC with high PD-L1 expression

IMpower010 (NCT02486718) showed a statistically significant benefit in primary-endpoint disease-free survival (DFS) with adjuvant atezo vs BSC in resected stage II-IIIA PD-L1 tumour cell (TC) ≥1% (SP263) NSCLC after platinum-based chemotherapy. This finding led to the approval of atezo in this setting in the US, China, Japan and other countries and to its approval for stage II-IIIA PD-L1 TC ≥50% NSCLC in the EU and other countries. At the first pre-specified interim analysis (IA) of OS (cutoff 18 Apr 2022), the secondary endpoint of OS in the ITT population was not mature, but OS is of clinical interest in this curative setting; in pts with stage II-IIIA and stage II-IIIA PD-L1 ≥1% NSCLC, the respective OS HRs were 0.95 (95% CI: 0.74, 1.24) and 0.71 (95% CI: 0.49, 1.03) (Wakelee JTO 2022; 17:S2).

62MO Naxitamab pivotal clinical trial planned interim analysis of PFS and OS in patients with relapsed or refractory high-risk neuroblastoma

Naxitamab (NAX) is a humanized GD2-binding monoclonal antibody approved in the US with granulocyte-macrophage colony-stimulating factor (GM-CSF) under accelerated approval based in part on ad hoc analysis of data from the registrational phase II 201 trial (NCT03363373). We report progression free (PFS) and overall survival (OS) results of prespecified interim analyses.

Transfusion Independence Response As a Potential Surrogate for Overall Survival in Jaki-Experienced Patients with Myelofibrosis from Momentum

Introduction: Momelotinib (MMB), an oral ACVR1, JAK1 and JAK2 inhibitor, has previously demonstrated clinical activity on symptoms, anemia and spleen volume in JAK inhibitor (JAKi)-naïve and JAKi -experienced patients with myelofibrosis (MF). A commonly used anemia endpoint, transfusion independence response (TI-R), is defined as the absence of transfusions and no hemoglobin (Hgb) measurements below 8 g/dL during the 12 weeks preceding Week 24 (W24). As previously reported from the SIMPLIFY-1 Phase 3 study of JAKi-naïve patients with MF, patients receiving MMB who achieved TI-R experienced prolonged overall survival (OS) compared to those who were non-TI-R. Hence, TI-R can provide a surrogate for long-term clinical benefit (Mesa et al. Leukemia. 2022). The TI-R endpoint, however, does not fully describe transfusion burden outcomes for patients not meeting the definition of TI-R. Dynamic and time-to-event analyses have previously demonstrated MMB can reduce overall transfusion burden compared to ruxolitinib (RUX) in JAKi-naïve patients including in those who do not achieve TI-R (Mesa et al. Leuk Lymphoma. 2022). To better understand the impact of MMB on TI-R, OS and transfusion burden in JAKi-experienced patients, similar analyses were applied to the ongoing Phase 3 MOMENTUM study which is investigating MMB vs danazol (DAN) in anemic, symptomatic patients with MF who have previously been treated with a JAKi. Methods: MOMENTUM is a double-blind, randomized (2:1) study of MMB 200 mg daily (130 patients) vs DAN 600 mg daily (65 patients) with a randomized treatment (RT) period of 24 weeks, after which patients could receive open-label (OL) MMB. Eligible patients had primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1 MF; MFSAF total symptom score ≥10; Hgb <10 g/dL; prior JAKi for ≥90 days or ≥28 days with RBC transfusions ≥4 units in 8 weeks or Grade 3/4 thrombocytopenia, anemia, or hematoma; and palpable spleen ≥5 cm. Anemia benefit was evaluated by TI-R, Kaplan-Meier (KM) estimates of the proportion of patients who required zero units transfused during RT, hazard ratio (HR) of RBC units transfused as recurrent events, HR of time to 1st, 3rd and 5th transfusion unit and odds ratio (OR) of having zero units transfused estimated by a zero-inflated negative binomial model. Survival was estimated using KM analysis. Transfusion dependence (TD) was defined as requiring ≥4 units of RBC transfusions in the 8 weeks immediately prior with each transfusion in response to a Hgb assessment of ≤9.5 g/dL. Transfusion requiring (TR) was defined as neither TD nor TI. Results: Mean duration of prior JAKi therapy was 139 weeks in the MMB arm and 125 weeks in the DAN arm. The study population was highly anemic with a mean Hgb of 8.1 g/dL in the MMB arm and 7.9 g/dL in the DAN arm; 48% and 49% of MMB and DAN patients respectively had baseline Hgb <8 g/dL. At baseline, 13% and 15% of MMB and DAN patients were TI, respectively, whereas a majority (49% MMB; 52% DAN) were TD. The rate of W24 TI-R was 31% and 20% for the MMB and DAN arms, respectively (non-inferiority p=0.0064). Over the 24-week RT period, 35% of MMB patients had zero units transfused compared to 17% of DAN patients (OR=2.7; p=0.0107). Regardless of baseline transfusion status (TD, TI, or TR), patients randomized to MMB received fewer mean cumulative RBC units during RT compared to those randomized to DAN. Time-to-event-analyses showed median days to 1st, 3rd, and 5th transfusion on MMB was >2 times that on DAN (MMB:40, 106 and not reached; DAN:15, 52, 109). Of the 63 MMB patients with baseline TD, 9 (14%) were TI at the end of W24 and 19 (30%) were TR. Of the 34 DAN patients with baseline TD, 9% were TI at the end of W24 and 9% were TR. Interim OS analysis of both study arms shows that patients who achieve W24 TI-R have prolonged OS compared to those who were non-TI-R; MMB arm shown in Figure 1 (HR=0.15; p=0.0364). Discussion: Anemia is a major unmet need in MF that is associated with poor prognosis and frequently managed with recurrent transfusions, which are costly in terms of reduced quality of life and OS as well as increased healthcare resource utilization. The analyses presented herein demonstrate that patients receiving MMB benefitted from increased likelihood of becoming TI and lower transfusion burden compared with patients receiving DAN. These findings are consistent with previously reported data from the SIMPLIFY studies of MMB and suggest that TI-R at W24 is a potential surrogate for improved OS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P= 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI-0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Overall survival (OS) with first-line atezolizumab (A) or placebo (P) in combination with vemurafenib (V) and cobimetinib (C) in BRAFV600 mutation-positive advanced melanoma: Second interim OS analysis of the phase 3 IMspire150 study.

9547 Background: Primary analysis of the phase 3 IMspire150 study (NCT02908672) demonstrated improved investigator-assessed progression-free survival (PFS) with first-line A + V + C vs P + V + C in patients (pts) with BRAFV600 mutation–positive advanced melanoma (hazard ratio [HR] 0.78; 95% CI, 0.63-0.97; P= 0.025). With median follow-up of 18.9 months at primary analysis, OS data were immature; interim analysis of OS at the time of the primary analysis demonstrated a trend in favor of A + V + C over P + V + C (estimated 2-year OS rate, 60.4% vs 53.1%) (Gutzmer et al. Lancet 2020;395:1835-1844). Herein, we present results from the second interim OS analysis of the IMspire150 study. Methods: IMspire150 enrolled previously untreated pts with stage IV or unresectable stage IIIc BRAFV600 mutation-positive melanoma (n = 514). Pts were randomized 1:1 to receive 28-day cycles of A + V + C (n = 256) or P + V + C (n = 258). Pts received V + C in cycle 1; A or P was added on days 1 and 15 from cycle 2 onwards. The second interim OS analysis was planned after ̃270 OS events were recorded, and was projected to have a minimally detectable difference of HR of 0.74 with a P value boundary of 0.0140. OS was estimated using the Kaplan-Meier method. Results: At data cutoff (Sept 8, 2021), 273 OS events had occurred. Median follow-up was 29.1 months (range, 1-54) for A + V + C and 22.8 months (range, 0-54) for P + V + C. A continued trend toward OS benefit in favor of A + V + C over P + V + C was observed with median OS of 39.0 vs 25.8 months, but the difference did not reach statistical significance (HR, 0.84; 95% CI, 0.66-1.06; P= 0.1432). A delayed treatment effect was observed, with landmark OS rates for A + V + C vs P + V + C of 76.1% vs 76.5% at 12 months and 61.5% vs 53.3% at 24 months. With additional follow-up, A + V + C continued to show PFS benefit over P + V + C (HR, 0.79; 95% CI, 0.64-0.97; P= 0.0224); overall response rates (66.7% vs 65.0%) and median duration of response (21.0 vs 12.6 months) remained consistent with those reported at primary analysis. No new safety signals were observed with additional follow-up. Conclusions: With further follow-up, A + V + C demonstrated a consistent, but not statistically significant, improvement in OS and continued benefit in duration of response versus P + V + C in previously untreated pts with BRAFV600 mutation–positive advanced melanoma. Clinical trial information: NCT02908672.

Final progression-free survival, interim overall survival, and biomarker analyses of CHOICE-01: A phase 3 study of toripalimab versus placebo in combination with first-line chemotherapy for advanced NSCLC without EGFR/ALK mutations.

9028 Background: Toripalimab (anti-PD-1) in combination with chemotherapy showed significant improvement in progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced NSCLC regardless of tumor PD-L1 expression. Whole exome sequencing (WES) was performed to identify correlative biomarkers for survival. Methods: Patients (n = 465) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomized 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) in combination with chemotherapy for 4-6 cycles, followed by maintenance of toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors included PD-L1 expression status, histology, and smoking status. The primary endpoint was PFS by investigator per RECIST v1.1. Secondary endpoints included PFS by a blinded independent review committee (BIRC), OS and safety. Results: At the prespecified final PFS analysis (cutoff date Oct 31, 2021), a significant improvement in PFS as assessed by investigator was observed for the toripalimab arm over the placebo arm: HR = 0.49 (95% CI: 0.39-0.61), two-sided p &lt; 0.0001, median PFS 8.4 vs 5.6 months. The 1-year PFS rates were 36.7% vs 17.2%. PFS as assessed by BIRC was also significantly longer in the toripalimab arm. The improvements of PFS were observed across key subgroups, including histology and PD-L1 expression. At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm: HR = 0.69 (95% CI: 0.52-0.92), two-sided p = 0.0099, median OS not reached vs 17.1 months. The incidence of Grade ≥3 adverse events (AEs) (78.6% vs 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs 3.2%) and fatal AEs (5.5% vs 2.6%) were more frequent in the toripalimab arm. WES results from 394 available patients revealed that patients with high tumor mutational burden (TMB) (≥10 mutations per million base pairs) were associated with significantly better PFS in the toripalimab arm over the placebo arm (median PFS 13.1 vs 5.5 months) (interaction P = 0.026). In addition, patients with mutations in the FAK-PI3K-Akt pathway or IL-7 signaling pathways achieved significantly better PFS and OS from the toripalimab chemotherapy combination (interaction P values ≤ 0.01). Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided superior PFS and OS when compared to chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as 1st line therapy for advanced NSCLC patients without EGFR/ALK mutations. Clinical trial information: NCT03856411.