Interim Overall Survival Analysis Research Articles

Adjuvant Pertuzumab and Trastuzumab in Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the APHINITY Trial: Third Interim Overall Survival Analysis With Efficacy Update.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The APHINITY trial (ClinicalTrials.gov identifier: NCT01358877) previously demonstrated that pertuzumab added to adjuvant trastuzumab and chemotherapy improved invasive disease-free survival (iDFS) for patients with early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Here, we report the preplanned third interim analysis of overall survival (OS) and a descriptive updated iDFS analysis with 8.4 years of median follow-up of 4,804 patients in the intent-to-treat population. The 8-year OS was 92.7% in the pertuzumab versus 92.0% in the placebo group (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .078, above the 0.006 significance threshold). The HR was 0.80 [95% CI 0.63 to 1.00] in the node-positive cohort and 0.99 [95% CI, 0.64 to 1.55] in the node-negative cohort. Updated results of 8-year iDFS in the node-positive cohort showed an absolute improvement of 4.9% favoring pertuzumab (86.1% v 81.2%; HR, 0.72 [95% CI, 0.60 to 0.87]). The node-negative cohort did well without adding pertuzumab (8-year iDFS and OS in the placebo group were 93.3% and 96.4%, respectively). The iDFS benefit was seen in the hormone receptor-negative (HR, 0.82 [95% CI, 0.64 to 1.06]) and HR+ cohorts (HR of 0.75 [95% CI, 0.61 to 0.92]). Despite improvement in overall iDFS, the addition of pertuzumab did not improve OS at this third interim analysis.

Ide-cel vs standard regimens in triple-class–exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses

AbstractOutcomes are poor in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.

Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial

At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. F Hoffmann-La Roche.

Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC (‘EC alone’; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607.

Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: Primary results of the phase 3 LAURA study.

LBA4 Background: EGFR mutations occur in up to one-third of pts with unresectable stg III NSCLC. Consolidation durvalumab is standard of care (SoC) for pts who do not progress after concurrent CRT (cCRT), yet the benefit of consolidation immunotherapy specifically for EGFRm NSCLC remains uncertain, with limited data available. Osi, a 3rd-generation CNS-active EGFR-TKI, is recommended for EGFRm advanced/metastatic NSCLC and as adjuvant therapy for resectable EGFRm NSCLC. We report primary results from the global, double-blind, placebo (PBO)-controlled Phase 3 LAURA study (NCT03521154), assessing efficacy/safety of osi in unresectable stg III EGFRm NSCLC without progression after definitive CRT. Methods: Eligible pts: aged ≥18 years (≥20 in Japan), WHO PS 0/1, unresectable stg III EGFRm (Ex19del/L858R) NSCLC, had received definitive platinum-based cCRT/sequential CRT (sCRT) with no progression. Pts were stratified (cCRT vs sCRT; stg IIIA vs IIIB/IIIC; Chinese vs non-Chinese) and randomized 2:1 to receive osi 80 mg or PBO QD until progression (blinded independent central review [BICR]-confirmed)/discontinuation. Imaging, including brain MRI, was mandated at baseline, every 8 wks to wk 48, then every 12 wks, until progression by BICR. Open-label osi was offered after progression by BICR. Primary endpoint: progression-free survival (PFS; RECIST v1.1) assessed by BICR. Secondary endpoints included overall survival (OS) and safety. Data cut-off: January 5, 2024. Results: Overall, 216 pts were randomly assigned: osi n=143, PBO n=73. Baseline characteristics were generally balanced across osi/PBO arms: female 63/58%, stg IIIA 36/33%, IIIB 47/52%, IIIC 17/15%, Ex19del 52/59%. Osi significantly improved PFS by BICR vs PBO: HR 0.16; 95% CI 0.10, 0.24; p&lt;0.001. Median PFS was 39.1 mo (95% CI 31.5, not calculable) for osi vs 5.6 mo (95% CI 3.7, 7.4) for PBO; 12-mo PFS rate was 74% (osi) vs 22% (PBO); 24-mo PFS rate was 65% (osi) vs 13% (PBO). Investigator-assessed PFS (HR 0.19; 95% CI 0.12, 0.29; nominal p&lt;0.001) was consistent with PFS by BICR. PFS benefit was consistent across predefined subgroups. Interim OS analysis (20% maturity) showed a trend in favor of osi: HR 0.81; 95% CI 0.42, 1.56; p=0.530; 81% of pts (PBO arm) received osi after progression. All-causality AEs were reported in 98% vs 88% pts; ≥Grade 3 AEs in 35% vs 12%; serious AEs in 38% vs 15% for osi vs PBO, respectively. Radiation pneumonitis AEs (grouped term): 48% (osi) vs 38% (PBO), majority Grade 1/2. Any AEs leading to discontinuation were reported in 13% vs 5% for osi vs PBO, respectively. Conclusions: Osi after definitive CRT demonstrated a statistically significant and clinically meaningful improvement in PFS, for unresectable stg III EGFRm NSCLC, with no unexpected safety signals. These results establish osi as the new SoC for EGFRm NSCLC in this setting. Clinical trial information: NCT03521154 .

Correlation of therapy-induced neutropenia with survival in patients with metastatic pancreatic cancer treated with GSK-3 inhibitor elraglusib (9-ING-41) in combination with gemcitabine/nab-paclitaxel in the 1801 phase 2 study.

e16311 Background: Previously, elraglusib (9-ING-41), an inhibitor of Glycogen Synthase Kinase-3 (GSK-3), was shown to potentiate the anticancer effects of chemotherapeutic drugs in preclinical models of cancer. The combination of elraglusib and gemcitabine/nab-paclitaxel (GnP) is currently being investigated in a randomized, open-label 1801 phase 2 study as a first-line therapy for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Chemotherapy-induced neutropenia is a common dose-limiting toxicity resulting in dose reductions and/or treatment interruptions. Present evidence shows that therapy-induced neutropenia (TIN) grade 3-4 correlates with survival and is a potential marker for improved clinical outcome in elraglusib/GnP-treated patients. Methods: We correlated overall survival (OS) and time-to-treatment discontinuation (TTD) with TIN grade 3-4 in 72 (GnP arm) and 155 (elraglusib/GnP arm) mPDAC patients previously untreated for advanced disease (1801 Part 3 Arm B study; NCT03678883). TTD was defined as the date of first dose to the date of treatment discontinuation or death. The Kaplan-Meier log-rank test was used for statistical analysis. A p-value &lt; 0.05 was considered statistically significant. Results: The rate of grade 3-4 TIN was 22% (16/72 patients) and 47% (72/155 patients) in the GnP and elraglusib/GnP groups, respectively. Based on 28% of all recorded death events in elraglusib/GnP group and 36% in GnP group, we found that grade 3-4 TIN was significantly associated with improved OS in patients treated with elraglusib/GnP (median OS: 14.4 vs 5.9 months; P &lt; 0.05) but not in patients treated with GnP (median OS: 7.6 vs 7.2 months). In the elraglusib/GnP group, patients with grade 3-4 TIN stayed on treatment significantly longer (median TTD: 7.9 months; P &lt; 0.05) as compared to the patients who did not develop TIN grade 3-4 (median TTD: 1.7 months). Conclusions: Our preliminary results identified grade 3-4 TIN as a potential marker of improved clinical outcome for elraglusib/GnP therapy in previously untreated patients with mPDAC. Recruitment for the 1801 Part 3 Arm B phase 2 trial has been completed. Another interim analysis of OS and its correlation to grade 3-4 TIN will be available by April 2024 and will be included in the final presentation. Clinical trial information: NCT03678883 .

BEAT-SC: A randomized phase III study of bevacizumab or placebo in combination with atezolizumab and platinum-based chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC).

8001 Background: Atezolizumab combined with carboplatin and etoposide is approved as first-line treatment for patients with ES-SCLC, based on results from the Phase I/III IMpower133 trial (NCT02763579). The VEGF inhibitor bevacizumab (bev) is approved for the treatment of many tumor types and has synergistic effects when combined with atezolizumab, as demonstrated by the Phase III IMpower150 study (NCT02366143) in non-small cell lung cancer. BEAT-SC (jRCT2080224946) is evaluating the efficacy and safety of bev combined with atezolizumab and platinum-based chemotherapy in patients with ES-SCLC from Japan and China. Here, we report the primary analysis for progression-free survival (PFS) and the first interim analysis for overall survival (OS) from BEAT-SC. Methods: Eligible patients had measurable ES-SCLC, were aged ≥20 y (≥18 y for patients from China), had an ECOG performance status of 0 or 1 and had no prior systemic treatment for ES-SCLC. Patients were randomized 1:1 to receive 4 cycles (21 days/cycle) of induction therapy with bev combined with atezolizumab + cisplatin or carboplatin + etoposide (ACE) or placebo combined with ACE, followed by maintenance therapy with bev + atezolizumab or placebo + atezolizumab, respectively. The primary endpoint was investigator-assessed PFS (INV-PFS). Key secondary endpoints included OS and safety. Results: The ITT population comprised 333 patients with a median age of 65.0 y; 82.6% of the patients were male, 57.7% were from China, 91.8% received carboplatin and 87.6% were current or former smokers. At data cutoff (June 30, 2023; median follow-up, 10.2 mo), median INV-PFS was 5.7 mo for bev + ACE vs 4.4 mo for placebo + ACE (HR, 0.70; 95% CI: 0.54, 0.90; P=0.0060; 2-sided α boundary=0.05). Median OS was 13.0 mo for bev + ACE vs 16.6 mo for placebo + ACE (HR, 1.22; 95% CI: 0.89, 1.67; P=0.2212; 2-sided α boundary=0.0079). Among the safety analysis population (n=330), bev + ACE was well-tolerated and treatment-related adverse events (TRAEs) were generally similar between treatment arms (Table). Conclusions: BEAT-SC met its primary endpoint, demonstrating that the addition of bev to ACE significantly increased PFS vs placebo + ACE. OS data were immature at the first interim OS analysis, and the numerical OS improvement of bev + ACE was not shown vs placebo + ACE; OS follow-up will continue. No new safety signals were observed. Clinical trial information: jRCT2080224946 . [Table: see text]

Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): Results from the phase III OptiTROP-Breast01 study.

104 Background: TROP2 (trophoblast cell surface antigen 2) is highly expressed in TNBC and is associated with worse survival. Sacituzumab tirumotecan (SKB264/MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor with a drug-to-antibody-ratio (DAR) of 7.4. The hydrolytically linker permits both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release the membrane permeable payload enabling the “bystander effect”. Here, we report the results from a phase Ⅲ study of sacituzumab tirumotecan in pts with advanced TNBC (OptiTROP-Breast01, NCT05347134). Methods: In this randomized phase Ⅲ trial, SKB264 was compared with physician's choice of chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in pts with locally recurrent or metastatic TNBC who had received two or more prior therapies including at least one for metastatic setting. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). The TROP2 expression was determined by immunohistochemistry (IHC) using the semi-quantitative H-score method. Results: Pts were randomly assigned to receive SKB264 (n = 130) or chemotherapy (n = 133). The median age was 51 years; 87% had visceral metastases; 26% received prior PD-1/PD-L1 inhibitors; 48% received three or more prior lines of chemotherapy for advanced disease. The primary endpoint of PFS was met based on interim analysis (data cutoff: Jun 21, 2023) with a 69% reduction in risk of progression or death (HR 0.31; 95% CI, 0.22 to 0.45; P &lt;0.00001). The median PFS assessed by BICR was 5.7 months (95% CI, 4.3 to 7.2) with SKB264 and 2.3 months (95% CI, 1.6 to 2.7) with chemotherapy; PFS at 6 months was 43.4% vs 11.1%. In the subset of pts with TROP2 H-score &gt; 200, the median PFS was 5.8 months with SKB264 and 1.9 months with chemotherapy (HR 0.28; 95% CI, 0.17 to 0.48). At the first planned interim analysis for overall survival (OS) (data cutoff: Nov 30, 2023) with median follow-up of 10.4 months, OS was statistically significant in favor of SKB264 (HR 0.53; 95% CI, 0.36 to 0.78; P =0.0005); the median OS was not reached (95% CI, 11.2 to NE) with SKB264 and 9.4 months (95% CI, 8.5 to 11.7) with chemotherapy. The objective response rate assessed by BICR was 43.8% with SKB264 and 12.8% with chemotherapy. Most common grade ≥ 3 treatment-related adverse events (SKB264 vs chemotherapy) were neutrophil count decreased (32.3% vs 47.0%), anemia (27.7% vs 6.1%) and white blood cell count decreased (25.4% vs 36.4%). Conclusions: Sacituzumab tirumotecan monotherapy demonstrated statistically significant and clinically meaningful PFS and OS benefit over chemotherapy, with a manageable safety profile in pts with heavily pretreated advanced TNBC and limited treatment options. Clinical trial information: NCT05347134 .

Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study.

4110 Background: The phase 3 CARES-310 trial is the first to demonstrate significant progression-free survival (PFS) and overall survival (OS) benefits with immunotherapy plus an anti-angiogenic tyrosine kinase inhibitor (TKI) over standard TKI as first-line treatment for uHCC. In the primary analysis of PFS (data cut-off [DCO], May. 10, 2021) and interim analysis of OS (DCO, Feb. 8, 2022), significant improvements were observed with camrelizumab (C; anti-PD-1 antibody) + rivoceranib (R; VEGFR2-TKI) vs. sorafenib (S). Here, we report updated data at the final analysis (FA), after an additional follow-up of ~16 mo. Methods: In this international, randomized, open-label, phase 3 trial, 543 patients with uHCC who had not previously received systemic treatment were randomized 1:1 to receive either C (200 mg, iv, q2w) + R (250 mg, po, qd) or S (400 mg, po, bid). As of Jun.14, 2023, 351 (65%) deaths occurred, and a protocol-specified FA was performed. Results: 272 patients were allocated to C+R and 271 to S. At DCO of FA, median follow-up was 22.1 mo in C+R group and 14.9 mo in S group. After end of study treatment, 36% of patients in C+R group and 42% in S group received subsequent targeted therapy; 17% and 36% received immunotherapy, respectively. Median OS was significantly prolonged with C+R vs . S (23.8 mo [95% CI 20.6-27.2] vs. 15.2 mo [95% CI 13.2-18.5]; hazard ratio (HR) 0.64 [95% CI 0.52-0.79]; 1-sided p &lt;0.0001). OS rate with C+R vs.S was 49.0% vs. 36.2% at 24 mo, and 37.7% vs. 24.8% at 36 mo. OS benefits with C+R was generally consistent across subgroups, regardless of geographical region, race, and aetiology. Benefits in PFS, objective response rate (ORR) and duration of response (DoR) with C+R were also sustained after prolonged follow-up (Table). Safety data aligned with the interim OS analysis, with no new signals noted. Conclusions: At the protocol-specified FA, C+R continued to show clinically meaningful survival improvement compared with S, with manageable safety. The extended follow-up further confirmed the favorable benefit-to-risk profile of C+R, supporting it as a new first-line treatment option for uHCC. Clinical trial information: NCT03764293 . [Table: see text]

PionERA Breast Cancer (BC): Phase III study of first-line (1L) giredestrant vs. fulvestrant, both combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), in patients (pts) with estrogen receptor-positive (ER+), HER2– locally advanced/metastatic BC (LA/mBC) with resistance to prior adjuvant (adj) endocrine therapy (ET).

TPS1130 Background: Pts with ER+, HER2– LA/mBC who relapse on/after adj ET and who have endocrine resistance represent a population with a high unmet need; for pts who relapse on or &lt;12 months of adj aromatase inhibitors, fulvestrant + a CDK4/6i is 1L standard of care. However, fulvestrant has limited efficacy in pts with ESR1-mutated ( ESR1m) tumors and requires monthly intramuscular (IM) injections that negatively impact quality of life (QoL). New treatment (tx) options, such as combinations of an oral selective ER degrader (SERD) + a CDK4/6i (beyond palbociclib), are needed to improve survival, QoL, tolerability, and adherence. Giredestrant is a highly potent, nonsteroidal, oral selective ER antagonist and degrader that achieves robust ER occupancy and is active regardless of ESR1m status. Giredestrant was well tolerated with promising activity, as monotherapy and in combination with any approved CDK4/6i, in Phase I/II studies in ER+, HER2– BC. pionERA BC is the first study to investigate an oral SERD (giredestrant) + investigator’s (inv’s) choice of CDK4/6i in pts with 1L ET-resistant ER+, HER2– LA/mBC. Methods: pionERA BC (NCT06065748) is a Phase III, global, randomized, open-label, multicenter study in pts with ER+, HER2– LA/mBC with resistance to prior adj ET. Pts will be randomized 1:1 to oral daily 30 mg giredestrant or IM 500 mg fulvestrant (Days 1 and 15 of Cycle 1, then once monthly), both in combination with inv’s choice of CDK4/6i (palbociclib, abemaciclib, or ribociclib), stratified by: prior adj CDK4/6i (yes vs. no); choice of CDK4/6i; ESR1m status by central testing ( ESR1m vs. no ESR1 mutation detected [ ESR1nmd]); disease site (visceral vs. non-visceral). Pts will receive tx until disease progression, limiting toxicity, death, or consent withdrawal. Eligibility: Female/male pts with ER+, HER2– LA/mBC; resistance to prior adj ET (± CDK4/6i); no prior systemic tx for LA/mBC; documented ESR1m status by circulating tumor DNA. Enrollment of pts with ESR1nmd tumors will be capped at 60% of the total study population. Co-primary endpoints (EPs): Inv-assessed progression-free survival (PFS) in the ESR1m subgroup and in the full analysis set. Secondary EPs: PFS ( ESR1nmd subgroup); overall survival (OS); inv-assessed confirmed overall response rate; duration of response; clinical benefit rate; time to chemotherapy; safety; pt-reported outcomes. The co-primary EPs will be compared between tx arms using a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned at the time of the primary PFS analysis; an independent data monitoring committee will be in place for safety. Target enrollment: 1050 pts; recruitment ongoing. Clinical trial information: NCT06065748 .

An open-label, placebo-controlled, randomized phase II trial of camrelizumab combined with or without apatinib or capecitabine in the treatment of previously treated advanced pancreatic cancer.

e16324 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancer types that have essentially no clinical benefit from immune checkpoint inhibitors therapy, combined immunotherapy is expected to solve this dilemma. We conducted a randomized open-label, placebo-controlled phase II trial evaluating the efficacy of camrelizumab combined with apatinib or capecitabine in the treatment of patients with previously treated metastatic PDAC (ChiCTR1900024095). Methods: Eligible patients (n = 30) were randomized 1:1:1 to receive camrelizumab (200 mg q2w) combined with apatinib (250mg qd, d1-28, q4w) or capecitabine (1000 mg/m2, bid d1-14, q3w), or placebo plus capecitabine (1000 mg/m2, bid d1-14, q3w) until disease progression or unacceptable toxicity. Tumor response was assessed every 8 weeks according to RECISTv1.1. Primary endpoints were investigator-assessed 6-month overall survival (OS) rate. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Data cutoff date for the prespecified interim OS and final PFS analysis was Oct 30, 2022. Results: In the primary endpoint analysis, camrelizumab combined treatment showed improved 6-month OS rates, whether in the camrelizumab-apatinib arm (83.3% versus 33.3%, p = 0.1189) or in the camrelizumab-capecitabine arm (100% versus 33.3%, p = 0.0098), compared placebo-capecitabine, respectively. Median PFS was 5.4 months, HR 0.58, [95% confidence interval (CI), 0.21–1.59] in the camrelizumab-apatinib arm , 3.1 months HR 0.98, [95%CI, 0.35–2.77] in the camrelizumab-capecitabine arm , and 2.6 months in the placebo-capecitabine, respectively. The ORR and DCR were 0% and 66.7% in the camrelizumab-apatinib arm, 40% and 50% in the camrelizumab-capecitabine arm, 0% and 44.4% in the placebo-capecitabine, respectively. PR was observed in two patients receiving camrelizumab-capecitabine treatment. The median DoR were 5.3 months in the camrelizumab-apatinib arm, 4.3 months in the camrelizumab-capecitabine arm, and 2.1 months in the placebo-capecitabine arm. Treatment-related adverse event rates were slightly increased in camrelizumab combined arms. Incidences of grade ≥3 treatment-related adverse events were comparable between the three groups (20%、 10% vs 0%), with reactive cutaneous capillary endothelial proliferation (10%) as the most common one in Camrelizumab combinations. Conclusions: Camrelizumab combined treatment showed improved 6-month OS vs conventional capecitabine monotherapy, with a manageable safety profile. These analyses revealed combined immunotherapy could be used as a new option for posterior line treatment in previously treated metastatic PDAC. Clinical trial information: ChiCTR1900024095.

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 &amp;lt; 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&amp;lt;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 (&amp;gt;13 months) combined with the sustained significant improvement in median PFS (&amp;gt;14 months) and substantial extension in median CFS (&amp;gt;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.