Investigator-assessed Median Progression-free Survival Research Articles

Final analysis of the randomized phase 3 ESCORT-1st trial: Camrelizumab plus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma.

4055 Background: The ESCORT-1st trial (NCT03691090) was a randomized, double-blind, placebo-controlled, phase 3 trial that aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy compared to placebo plus chemotherapy in previously untreated patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Interim analysis of this trial showed significantly longer overall survival (OS) and progression-free survival (PFS) with camrelizumab plus chemotherapy compared to placebo plus chemotherapy (Luo et al., JAMA, 2021). In this report, we present the final analysis of the efficacy and safety outcomes from the ESCORT-1st study, with an additional 1.5-year follow-up. Methods: A total of 596 eligible patients with previously untreated advanced or metastatic ESCC were randomly assigned in a 1:1 ratio to receive either camrelizumab 200 mg or placebo for up to 2 years, in combination with up to 6 cycles of paclitaxel and cisplatin. All treatments were administered intravenously every 3 weeks. Randomization was stratified based on the presence of liver metastases and previous definitive chemoradiotherapy. The primary endpoints of the study were OS and PFS as assessed by an independent review committee. The data cutoff for this final analysis was April 30, 2022. Results: At the data cutoff, the minimum follow-up period was 24 months, and no patients remained on the study treatment. Among the patients, 214 (71.8%) in the camrelizumab plus chemotherapy group and 250 (83.9%) in the placebo plus chemotherapy group had died. The camrelizumab plus chemotherapy group demonstrated a longer median OS compared to the placebo plus chemotherapy group (15.6 months [95% CI 14.0–18.4] vs 12.6 months [95% CI 11.2–13.8], HR 0.70 [95% CI 0.58–0.84]; one-sided P<0.0001). The 1-year, 2-year, and 3-year OS rates were 62.4% vs 51.7%, 35.9% vs 23.8%, and 25.6% vs 12.8% in the camrelizumab plus chemotherapy group and the placebo plus chemotherapy group, respectively. The median investigator-assessed PFS was also longer with camrelizumab plus chemotherapy compared to placebo plus chemotherapy (7.6 months [95% CI 6.9–8.3] vs 5.8 months [95% CI 5.6–6.6]; HR 0.54 [95% CI 0.45–0.65]; one-sided P<0.0001). No new safety signals were identified during the extended follow-up period. Conclusions: The extended follow-up of the ESCORT-1st trial reaffirms that camrelizumab plus chemotherapy provides significant and clinically meaningful improvements in OS and PFS compared to placebo plus chemotherapy, with a manageable safety profile for patients with untreated advanced or metastatic ESCC. These findings further support the use of first-line camrelizumab plus chemotherapy as the standard of care for these patients. Clinical trial information: NCT03691090 .

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]

Abstract GS03-13: Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis

Abstract Background: More effective treatments for patients (pts) with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative breast cancer (HR+, HER2– BC) that prevent or overcome resistance are needed. Previous phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα) inhibitors have a limited therapeutic window. Inavolisib is a highly potent and selective inhibitor of the PI3K catalytic subunit α isoform protein (p110α; encoded by the PIK3CA gene). In addition, inavolisib promotes the degradation of mutated p110α, which may limit toxicity. Prior preclinical data suggested substantial synergy between PI3K and cyclin-dependent kinase 4/6 inhibition plus endocrine therapy. The inavolisib first-in-human study (NCT03006172) showed that the triplet had a manageable safety profile, lack of drug–drug interactions, and promising preliminary antitumor activity. Methods: The Phase III, randomized, double-blind INAVO120 trial (NCT04191499) recruited 325 pts with PIK3CA-mutated, HR+, HER2– locally advanced/metastatic BC (LA/mBC) who relapsed during or within 12 months of adjuvant endocrine therapy completion, and who had no prior therapy for advanced BC. PIK3CA mutations were identified by central circulating tumor DNA (ctDNA) or local tissue/ctDNA analysis. Pts were randomized to inavolisib (9 mg orally once a day [PO QD] on Days 1–28 of each cycle) or placebo (PO QD) in combination with palbociclib (125 mg PO QD on Days 1–21 of each cycle) and fulvestrant (500 mg intramuscularly on Cycle 1 Days 1 and 15, and on Day 1 of each subsequent cycle). This is the first study to assess the triplet combination at maximum dose (inavolisib) or per-label dose/schedule (palbociclib/fulvestrant). The primary endpoint was investigator-assessed progression-free survival (INV-PFS). Secondary endpoints included overall survival (OS) and confirmed objective response rate (ORR). Adverse events (AEs) were graded per NCI-CTCAE v5. Results: After 21.3 months median follow-up, median INV-PFS was 15.0 months (95% confidence interval [CI] = 11.3, 20.5) with inavolisib + palbociclib + fulvestrant, and 7.3 months (95% CI = 5.6, 9.3) with placebo + palbociclib + fulvestrant (hazard ratio 0.43; 95% CI = 0.32, 0.59). Landmark INV-PFS event-free rates at 6, 12, and 18 months were 82.9%, 55.9%, and 46.2% with inavolisib, and 55.9%, 32.6%, and 21.1% with placebo. OS showed a trend in favor of inavolisib (hazard ratio 0.64; 95% CI = 0.43, 0.97; p = 0.0338 [boundary 0.0098 or hazard ratio 0.592]), with follow-up ongoing. Landmark OS event-free rates at 12 and 18 months were 85.9% and 73.7% with inavolisib, and 74.9% and 67.5% with placebo. Confirmed ORRs were 58.4% with inavolisib and 25.0% with placebo. Rates of selected Grade 3–4 AEs with inavolisib and placebo were: neutropenia at 80.2% and 78.4%; hyperglycemia at 5.6% and 0%; diarrhea at 3.7% and 0%; stomatitis and mucosal inflammation at 5.6% and 0%; and rash at 0% and 0%. The rate of discontinuation due to AEs was 6.2% for inavolisib and 0.6% for placebo. There were no treatment-related Grade 5 AEs. Conclusions: Inavolisib + palbociclib + fulvestrant demonstrated a statistically significant and clinically meaningful improvement in INV-PFS vs. placebo + palbociclib + fulvestrant in this high-risk population, and a favorable OS trend in favor of the inavolisib combination at the first interim analysis. Inavolisib + palbociclib + fulvestrant had a manageable safety profile consistent with the known safety profiles of the individual drugs (reflective of α isoform selectivity of inavolisib), and no new safety signal was identified. Inavolisib + palbociclib + fulvestrant could represent a new standard of care for pts with PIK3CA-mutated, HR+, HER2– LA/mBC. Citation Format: Komal L. Jhaveri, Seock-Ah Im, Cristina Saura, Dejan Juric, Sibylle Loibl, Kevin Kalinsky, Peter Schmid, Sherene Loi, Eirini Thanopoulou, Noopur Shankar, Guiyuan Lei, Thomas Stout, Katherine E. Hutchinson, Jennifer Schutzman, Chunyan Song, Nicholas C. Turner. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary 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 GS03-13.

Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma

PurposeThere are limited and no standard therapies for recurrent glioblastoma. We herein report the antitumour activity and safety of sintilimab, bevacizumab and temozolomide (TMZ) in recurrent glioblastoma.MethodsWe retrospectively analysed eight patients with recurrent glioblastoma treated with sintilimab (200 mg) every three weeks + bevacizumab (10 mg/kg) every three weeks + TMZ (200 mg/m²orally) (5 days orally every 28 days for a total of four weeks). The primary objective was investigator-assessed median progression-free survival(mPFS). Secondary objectives were to assess the 6-month PFS, objective response rate (ORR) and duration of response (DOR) accroding to RANO criteria.ResultsThe mPFS time for 8 patients was 3.340 months (95% CI: 2.217–4.463), The longest PFS was close to 9 months. Five patients were assessed to have achieved partial response (PR), with an overall remission rate of 62.5%, Four patients experienced a change in tumour volume at the best response time of greater than 60% shrinkage from baseline, and one patient remained progression free upon review, with a DOR of more than 6.57 months. The 6-month PFS was 25% (95% CI: 5.0–55.0%). Three patients had a treatment-related adverse events, though no grade 4 or 5 adverse events occurred.ConclusionIn this small retrospective study, the combination regimen of sintilimab, bevacizumab and TMZ showed promising antitumour activity in treatment of recurrent glioblastoma, with a good objective remission rate.

A Phase II Study of Chidamide Plus R-GDP Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Transplantation: Efficacy and Safety Analysis

Background: A significant subset of Diffuse large B-cell lymphoma (DLBCL) patients (30%-40%) face treatment failure, necessitating effective salvage chemotherapy. We conducted a phase II study evaluating the efficacy and safety of chidamide plus R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin) in relapsed/refractory (r/r) DLBCL patients. Methods: This open-label, single-arm study included 27 patients with r/r DLBCL who were ineligible for autologous stem cell transplantation. Prior to the induction monotherapy phase, chidamide was administered orally at a dose of 30 mg twice a week for one week. The combination therapy phase consisted of oral chidamide at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period, along with intravenous administration of rituximab, gemcitabine, dexamethasone, and cisplatin on a 21-day cycle. Results: A total of 27 patients received at least one dose of Chidamide plus R-GDP and were evaluated for safety. The median follow-up period was 17.0 months (range: 3.5 to 55 months). Radiological response assessment was available for 24 patients, who constituted the efficacy population. Fourteen patients completed six cycles of chidamide plus R-GDP (per-protocol population), while 10 patients discontinued treatment at the data cutoff. The baseline characteristics of enrolled patients included a median age of 67 years, predominantly older than 65 years. Approximately half of the patients exhibited elevated lactate dehydrogenase levels. All patients had received prior therapy with R-CHOP or equivalent chemoimmunotherapy. The majority of cases were classified as stage III/IV and non-germinal center B-cell-like (non-GCB) type by immunohistochemistry. Refractory or relapsed DLBCL within 1 year since the last treatment was observed in 74.0% of patients. Efficacy Outcomes: The investigator-assessed best objective response rate (ORR) was 79.2% (95% CI: 75.1% to 83.3%), with a complete response (CR) rate of 45.8% (95% CI: 41.6% to 49.9%) and a partial response (PR) rate of 33.3% (95% CI: 29.3% to 37.4%). The median time to response was 1.2 months, and the median time to CR or CRu (unconfirmed complete response) was 3.9 months. The best disease control rate was 87.5%. Among the patients who completed six cycles of chidamide plus R-GDP, the best ORR was 100%, with 71.4% achieving CR and 28.6% PR. Kaplan-Meier plots reveal that the median investigator-assessed progression-free survival (PFS) for the efficacy population was 5.9 (95% CI, 3.1 to 12.4) months. The median overall survival was 48.3 (95% CI, 13.1 to not reach (NR)) months. Safety Outcomes: A total of 13 patients (48.1%) required treatment interruption, primarily due to adverse events (22.2%) and disease progression (18.5%). Among patients who completed six cycles of chidamide plus R-GDP, 57.1% required a chidamide dose reduction. The most frequent treatment-emergent adverse event was anemia, occurring in all patients. Thrombocytopenia was the most common grade ≥3 adverse event leading to treatment interruption or dose reduction, affecting 48.1% of patients. Non-hematologic events included hypocalcemia (59.3%), hyponatremia (55.6%), and hypokalemia (44.4%). Three patients experienced grade 3 pneumonitis, and one patient had grade 3 skin rash. Conclusion: Chidamide plus R-GDP salvage chemotherapy demonstrated promising efficacy (ORR: 79.2%; CR rate: 45.8%) in r/r DLBCL patients. Adverse events were manageable but necessitated monitoring. Larger trials are needed to validate these findings and establish chidamide plus R-GDP as a potential treatment option for this challenging population. Keywords: relapsed/refractory DLBCL, salvage chemotherapy, chidamide, R-GDP, efficacy, safety

Clinical Utility of Mobocertinib in the Treatment of NSCLC - Patient Selection and Reported Outcomes.

Mobocertinib is an oral tyrosine kinase inhibitor (TKI) that selectively targets epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations. It is a structural analog of the third-generation TKI osimertinib, which targets EGFR T790M mutant non-small cell lung cancer (NSCLC); however, mobocertinib gains selectivity for EGFRex20ins mutants over wild type (WT) by interacting with the C790 gatekeeper residue of EGFR. This is accomplished via a carboxylated isopropyl ester moiety at the C5-position of mobocertinib's central pyrimidine core. In Phase 1/2 dose-escalation and dose-expansion studies, mobocertinib was found to have an investigator-confirmed overall response rate (ORR) of 56% (9/16; 95% CI: 30-80%) and 25% (3/12; 95% CI: 5-57%) in patients without and with baseline brain metastasis, respectively. Median investigator-assessed progression-free survival (mPFS) was 10.2 months (95% CI: 5.6 - not reached) and 3.7 months (95% CI: 1.8-15.9) in patients without and with baseline brain metastasis, respectively. A third phase evaluated patients who had received pre-treatment with platinum-based chemotherapy (PPP) and included an extension cohort (EXCLAIM cohort) which evaluated patients treated previously with 1 or 2 lines of therapy. An Independent Review Committee (IRC) found both cohorts to have similar outcomes in terms of ORR, median time to response, mPFS, and disease progression or death. The treatment-emergent adverse events (TEAE) related to mobocertinib are similar to other EGFR inhibitors and are predominately gastrointestinal (eg diarrhea, nausea, vomiting) and cutaneous (eg rash). In September 2021, the FDA granted accelerated approval for mobocertinib in the treatment of patients with locally advanced or metastatic NSCLC with EGFRex20ins mutation whose disease progressed while on platinum-based chemotherapy. The present review describes data that led to the approval of mobocertinib.

Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma

BackgroundIn an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes.MethodsIn this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization.ResultsA total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P=0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival.ConclusionsAt a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.)

Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial.

1001 Background: Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in combination with ET has become a standard first-line treatment for pts with endocrine-sensitive, HR[+]/HER2[-] ABC. The optimal treatment after progression on a CDK4/6i remains unknown. This study aims to determine if P maintenance with an alternative ET improves the antitumor activity of second-line treatment in this patient population. Methods: A total of 198 pts with HR[+]/HER2[-] ABC who had disease progression to first-line P plus ET (aromatase inhibitor or fulvestrant) were included. Pts were eligible if they had clinical benefit to the first-line treatment defined as response or stable disease ≥24 weeks, or who had progressed on a P-based regimen in the adjuvant setting with disease progression after at least 12 months of treatment but no more than 12 months following P treatment completion. Pts were randomly assigned (2:1 ratio) to receive P plus second-line ET (letrozole or fulvestrant, based on prior ET) or second-line ET alone. Stratification factors were prior ET and the presence of visceral involvement. Primary endpoint was investigator-assessed progression-free survival (PFS) determined by RECIST v.1.1. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), overall survival, and safety. The 2-sided log-rank test (α = 0.05) had an 80% power to detect a hazard ratio ≤0.59 in favor of P maintenance. Results: Between April 2019 and October 2022, 136 and 62 pts were randomized to receive P+ET and ET, respectively. Pts characteristics were well balanced. Median age was 59 years (range: 33-85), 61.1% were ECOG 0, 61.1% had visceral disease, and 89.9% received aromatase inhibitor + P as first-line treatment for metastatic disease. At median follow-up of 8.7 months and 155 PFS events, median investigator-assessed PFS was 4.2 months (95% CI 3.5–5.8) in the P+ET vs. 3.6 months (95% CI 2.7–4.2) in the ET arm (hazard ratio 0.8, 95% CI 0.6–1.1, p=0.206). This result was consistent across all stratification subgroups. 6-month PFS rate was 40.9% and 28.6% for P+ET and ET, respectively. Among 138 pts with measurable disease, no significant differences were observed in ORR (6.4% vs. 2.3%) or CBR (33.0% vs. 29.5%) for P+ET and ET, respectively. Grade 3-4 adverse events were higher in pts treated with P+ET (45.2% vs. 8.3%) and no new safety signals were identified. No treatment-related deaths were reported. Conclusions: For HR[+]/HER2[-] ABC pts, maintaining P with a second-line ET beyond progression on prior P-based therapy did not significantly improve PFS compared with second-line ET alone. Planned biomarker analysis may help identify which pts are more likely to benefit from this therapeutic approach. Clinical trial information: NCT03809988 .

A phase 2 study of HLX07 as monotherapy or combination therapy in patients with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma.

4029 Background: Esophageal cancer is one of the most common cancers worldwide with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype. Most patients are diagnosed at the advanced stage, and the prognosis remains poor. About 40–84% of ESCC cases showed overexpression of EGFR which was related to shorter overall survival and disease-free survival, indicating that treatment targeting EGFR could be a new strategy. This study aimed to evaluate the efficacy and safety of HLX07, a novel recombinant humanized anti-EGFR monoclonal antibody (mAb), as monotherapy or combination therapy in patients with locally advanced, unresectable/metastatic ESCC. Methods: In this open-label, multicenter phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed locally advanced, unresectable/metastatic ESCC or esophageal adenosquamous carcinoma were enrolled. Patients with no prior systemic antitumor therapy were assigned to group A and given HLX07 1000 mg plus serplulimab 200 mg (anti-PD-1 mAb) and chemotherapy (5-FU 2400 mg/m2 + cisplatin 50 mg/m2), Q2W IV. Patients who had failed first-line immuno-chemotherapy combination or at least two lines of other systemic antitumor therapy were assigned to group B and given HLX07 monotherapy (1000 mg Q2W IV). The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) assessed by an independent radiological review committee and investigators per RECIST v1.1. Secondary endpoints included other efficacy measures, safety, pharmacokinetics, immunogenicity, and biomarker explorations. Results: As of February 4, 2023, 49 patients were enrolled in group A (n=30) and group B (n=19), with a median age of 64.5 and 59.0 years, respectively. 26 (86.7%) patients in group A and all patients in group B were male. The median follow-up duration was 2.9 months, and the preliminary efficacy was presented. Among the 42 efficacy evaluable patients (29 in group A and 13 in group B), investigator-assessed ORRs were 55.2% (95% CI 35.7–73.6%) and 23.1% (95% CI 5.0–53.8%) in the respective groups. Investigator-assessed median PFSs were not reached in group A and 1.5 months (95% CI 1.2–not evaluable) in group B. 15 (50.0%) patients in group A and 5 (26.3%) in group B had grade ≥3 treatment-emergent adverse events (AEs). AEs of special interest were observed in 16 (53.3%) and 11 (57.9%) patients, respectively, most commonly rash (43.3% vs 47.4%) and hypomagnesemia (33.3% vs 36.8%). No drug-related death was reported. Conclusions: The encouraging antitumor activity and manageable safety profile support further development of HLX07 as a new treatment option for patients with advanced ESCC, both in first-line and late-line settings. Clinical trial information: NCT05221658 .

Pertuzumab retreatment in patients with HER2-positive locally advanced/metastatic breast cancer: Overall survival results of a phase III randomized trial (JBCRG-M05: PRECIOUS).

1015 Background: We previously reported that pertuzumab (P) retreatment in combination with trastuzumab (T) + chemotherapy based on physician’s choice (C) (PTC) significantly improved investigator-assessed progression-free survival (PFS) compared with T + C (TC) in patients with HER2-positive locally advanced/metastatic breast cancer (LA/MBC) previously treated with P-containing regimens in the phase III PRECIOUS study. Here we report updated OS at the median follow-up of 27.4 mo. Methods: Patients previously treated with P-containing regimens as 1st/2nd-line treatment for LA/MBC were randomly assigned 1:1 to two groups, PTC group and TC group, stratified by estrogen receptor (ER) status, previous treatment duration of P, number of previous chemotherapy regimens, and presence or absence of visceral metastasis. The primary endpoint was investigator-assessed PFS. The key secondary endpoints included OS, independent reviewer assessed PFS and safety. Superiority of PTC to TC will be tested using a log-rank test and a one-sided P-value of less than 0.05 will be considered an indicator of superiority. The distribution of OS will be estimated using the Kaplan-Meier method. In addition, the hazard ratio and one-sided 95% CI of the therapeutic effect between the groups will be calculated using the Cox proportional hazard model. Results: Of the 219pts enrolled, 217 (108 PTC, 109 TC) were included in the intent-to-treat analysis. At the data cutoff (Dec 31, 2021), OS and PFS events were 138 (63.6%) and 190 (87.6%), respectively. Updated median OS was significantly longer in the PTC group (median OS 36.2 vs. 26.5 mo.; HR = 0.73 [one side 95%CI upper limit, 0.97]; log-rank test p = 0.0323). In a prespecified subgroup analysis for OS including ER, visceral metastases, number of previous chemotherapy regimen was broadly constant without disease-free interval. Updated median investigator-assessed PFS (5.5 vs. 4.2 mo.; HR = 0.81 [one side 95%CI upper limit, 1.03]; stratified log-rank test p = 0.019) were also significantly better in the PTC group. Median PFS by independent review did not show the difference between two groups (4.4 vs. 4.4 mo.; HR = 1.03 [one side 95%CI upper limit, 1.36]; log-rank test p = 0.561). The serious adverse event rate did not differ between the groups (19.0% vs. 23.1%). There were no new safety signals in the two groups. Conclusions: Retreatment of P in combination with TC demonstrated significantly improved OS compared to TC. HER2 dual blockade with PT can contribute to improve survival in patients previously treated with P-containing regimens as 1st/2nd-line treatment for LA/MBC. Clinical trial information: NCT02514681 .

Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial

BackgroundThe phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma.MethodsPatients with previously untreated stage III–IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients.ResultsSeventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18–1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy.ConclusionsMedian progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

Trifluridine–tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study

Trifluridine-tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer. We aimed to investigate first-line trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment. In this open-label, randomised, phase 3 study, we enrolled patients aged 18 years and older with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine-tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), primary tumour location (right vs left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs non-clinical condition). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomisation to radiological progression or death from any cause, in the intention-to-treat population. Safety was assessed in all patients having taken at least one dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of progression-free survival, conducted after 629 events had occurred. This study is registered with ClinicalTrials.gov, NCT03869892. Between March 21, 2019, and Sept 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine-tipiracil plus bevacizumab (n=426) or capecitabine plus bevacizumab (n=430). After a median follow-up of 16·6 months (95% CI 16·5-17·1), the hazard ratio for progression-free survival for trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0·87 (0·75-1·02; p=0·0464; protocol-defined significance level of p=0·021 not met). Investigator-assessed median progression-free survival was 9·4 months (95% CI 9·1-10·9) with trifluridine-tipiracil plus bevacizumab versus 9·3 months (8·9-9·8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine-tipiracil plus bevacizumab group vs six [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs four [<1%]), anaemia (60 [14%] vs 16 [4%]), and hand-foot syndrome (none vs 61 [15%]). Nine deaths (five in the trifluridine-tipiracil plus bevacizumab group and four in the capecitabine plus bevacizumab group) were treatment related. First-line trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab in this population. As expected, the safety profile differed between the two treatments, but there were no new safety concerns. Trifluridine-tipiracil plus bevacizumab represents a feasible alternative to capecitabine plus bevacizumab in this population. Servier International Research Institute, Suresnes, France.

Efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients with pretreated HER2-positive advanced metastatic breast cancer: results from a randomized, open-label, multicenter, phase II bridging study.

Trastuzumab is the recommended first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients in China, but therapeutic resistance to trastuzumab and other early-line treatments is common and late-line treatment options are limited. Derived from the same murine precursor antibody, margetuximab has enhanced anti-tumor activity compared with trastuzumab and may be an effective late-line treatment. However, data regarding the use of margetuximab in pre-treated Chinese patients are scarce. This study aimed to evaluate the efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients, and to determine whether the results are consistent with the clinical benefit of margetuximab observed in the pivotal global phase III study. In this randomized, open-label, multicenter, phase II bridging study, eligible Chinese patients pretreated with ≥2 lines of anti-HER2 therapies were randomized 1:1 by stratified block randomization to margetuximab (15 mg/kg over at least 120 minutes) or trastuzumab (6 mg/kg over at least 30 minutes), each administered intravenously once every 21-day cycle and plus chemotherapy. Disease assessment was conducted once every two treatment cycles (6 weeks ± 7 days). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), and the incidence and severity of treatment-emergent adverse events (TEAEs). Between February 4, 2020 and February 23, 2021, 123 patients were randomized to the margetuximab (n=62) and trastuzumab (n=61) arms. Among them, 15 and 7 patients, respectively, were still on study treatment as of data cut-off (September 3, 2021). Overall, 99.2% were female, median age was 53 years old. All patients were pretreated with trastuzumab, and 83.7% and 25.2%, respectively, were pretreated with tyrosine kinase inhibitors (TKIs) and pertuzumab. Baseline characteristics were numerically balanced between arms. BICR-assessed median PFS (mPFS) was 5.5 months in the margetuximab arm and 4.1 months in the trastuzumab arm, with a hazard ratio (HR) of 0.69 [95% confidence interval (CI): 0.43-1.12], which met the consistency criterion (HR <0.88) for bridging success. Median investigator-assessed PFS was 5.5 months in the margetuximab arm and 4.0 months in the trastuzumab arm (HR =0.63; 95% CI: 0.41-0.96). Median OS (mOS) was not yet reached. Both ORR and CBR were greater in the margetuximab arm (25.5% vs. 12.5%; 32.7% vs. 14.3%). Safety results were numerically comparable between the two arms. Anti-HER2 treatment-related infusion-related reactions (IRRs) were more common in the margetuximab arm than in the trastuzumab arm (12.9% vs. 1.7%). All IRRs could be resolved. Margetuximab was effective and well-tolerated in this study, supporting its clinical use in pretreated HER2-positive MBC patients in China. ClinicalTrials.gov Identifier: NCT04262804.

Long-Term Efficacy and Safety of Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Final Results of the Phase 1/2 and Randomized Phase 2 (ALTA) Trials

IntroductionWe report brigatinib long-term efficacy and safety from phase 1/2 and phase 2 (ALTA) trials in ALK–rearrangement positive (ALK+) NSCLC. MethodsThe phase 1/2 study evaluated brigatinib 30 to 300 mg/d in patients with advanced malignancies. ALTA randomized patients with crizotinib-refractory ALK+ NSCLC to brigatinib 90 mg once daily (arm A) or 180 mg once daily (7-d lead-in at 90 mg; arm B). ResultsIn the phase 1/2 study, 79 of 137 brigatinib-treated patients had ALK+ NSCLC; 71 were crizotinib pretreated. ALTA randomized 222 patients (n = 112 in arm A; n = 110 in arm B). Median follow-up at phase 1/2 study end (≈5.6 y after last patient enrolled) was 27.7 months; at ALTA study end (≈4.4 y after last patient enrolled), 19.6 months (A) and 28.3 months (B). Among patients with ALK+ NSCLC in the phase 1/2 study, median investigator-assessed progression-free survival (PFS) was 14.5 months (95% confidence interval [CI]: 10.8–21.2); median overall survival was 47.6 months (28.6–not reached). In ALTA, median investigator-assessed PFS was 9.2 months (7.4–11.1) in arm A and 15.6 months (11.1–18.5) in arm B; median independent review committee (IRC)-assessed PFS was 9.9 (7.4–12.8) and 16.7 (11.6–21.4) months, respectively; median overall survival was 25.9 (18.2–45.8) and 40.6 (32.5–not reached) months, respectively. Median intracranial PFS for patients with any brain metastases was 12.8 (9.2–18.4) months in arm A and 18.4 (12.6–23.9) months in arm B. No new safety signals were identified versus previous analyses. ConclusionsBrigatinib exhibited sustained long-term activity and PFS with manageable safety in patients with crizotinib-refractory ALK+ NSCLC.

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study

IntroductionBefotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. MethodsThis was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. ResultsA total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75–100 mg), respectively. At data cutoff (August 15, 2021), independent review committee–assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%–72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%–61.5%) in cohort A and 65.9% (95% CI: 60.1%–71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6–12.5) months in cohort A and 12.5 (95% CI: 11.1–13.8) months in cohort B. The median independent review committee–assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0–not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%–55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%–78.2%) and 55.9% (95% CI: 37.9%–72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6–NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8–NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. ConclusionsBefotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial

PurposePI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC).MethodsCohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).ResultsOverall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%).ConclusionAdding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects.Trial registration NCT03337724.

Veliparib monotherapy following carboplatin/paclitaxel plus veliparib combination therapy in patients with germline BRCA-associated advanced breast cancer: results of exploratory analyses from the phase III BROCADE3 trial

In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P= 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported. Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days-2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases. A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo). Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy.

Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor–Positive, ERBB2-Negative Advanced Breast Cancer

The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020. Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1. A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. ClinicalTrials.gov Identifier: NCT02491983.

Rucaparib maintenance treatment for recurrent ovarian carcinoma: the effects of progression-free interval and prior therapies on efficacy and safety in the randomized phase III trial ARIEL3

IntroductionIn ARIEL3 (NCT01968213), the poly(adenosine diphosphate-ribose) polymerase inhibitor rucaparib significantly improved progression-free survival versus placebo regardless of biomarker status when used as maintenance treatment for recurrent ovarian cancer. The aim...

Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: phase IIIb LUCY interim analysis

BackgroundIn the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. MethodsThis open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. ResultsOf 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). ConclusionOlaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842.