Blinded Independent Central Review Research Articles

Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Expanded efficacy analysis from CheckMate 8HW.

3503 Background: NIVO + IPI demonstrated superior progression-free survival (PFS) vs chemo in patients (pts) with previously untreated MSI-H/dMMR mCRC in the randomized phase 3 CheckMate 8HW study (NCT04008030). We report expanded efficacy analysis from the prespecified interim analysis of NIVO + IPI vs chemo in the 1L setting. Methods: Pts with unresectable or mCRC and MSI-H/dMMR status by local testing were enrolled across different lines of therapy and randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms) or for up to 2 years (NIVO ± IPI arms). In pts with blinded independent central review (BICR)–documented progression with chemo, crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) was a key exploratory endpoint. Results: Among 303 pts randomized to NIVO + IPI (n = 202) or chemo (n = 101), 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR. At 31.5-months (mo) median follow-up (range 6.1–48.4), NIVO + IPI demonstrated superior PFS vs chemo (HR 0.21; 97.91% CI 0.13–0.35; P < 0.0001). Subsequent systemic therapy was received by 20 (12%) and 57 (68%) pts in the NIVO + IPI and chemo arms, respectively. In the chemo arm, 56 (67%) pts received subsequent immunotherapy (39 [46%] crossed over to NIVO + IPI on study; 17 [20%] received non-study immunotherapy). Median PFS2 was not reached (NR) with NIVO + IPI and 29.9 mo with chemo (HR 0.27; 95% CI 0.17–0.44; Table). Any grade and grade 3/4 treatment-related adverse events (TRAEs) are presented (Table). Treatment-related deaths were reported for 2 pts in the NIVO + IPI arm. Conclusions: Clinical benefit with 1L NIVO + IPI vs chemo was maintained after subsequent therapy, as shown by improved PFS2 in pts with centrally confirmed MSI-H/dMMR mCRC. No new safety concerns were identified with NIVO + IPI. These results further support NIVO + IPI as a standard-of-care 1L treatment option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]

REJOICE-Ovarian01: A phase 2/3 study of raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (OVC).

TPS5625 Background: Platinum resistance develops in most patients with OVC. Prognosis is poor and therapeutic options are limited, illustrating the significant unmet need in these patients. R-DXd is an antibody–drug conjugate comprising a humanized immunoglobulin G1 antibody targeting cadherin 6 (CDH6), a stable linker selectively cleaved within tumor cells, and a membrane-permeable topoisomerase I inhibitor (DXd) payload. In the first-in-human study of R-DXd (NCT04707248) in patients with advanced/metastatic OVC who had prior systemic therapy, doses of 4.8–8.0 mg/kg showed an objective response rate (ORR) of 46% (95% confidence interval [CI]: 32, 61) and a median duration of response (DOR) of 11.2 months (95% CI: 3.0, not estimable). At doses currently being evaluated for RP2D (or dose optimization), R-DXd exhibited a positive benefit/risk profile, with manageable toxicities for further clinical development. Given these promising data, a Phase 2/3 study in patients with platinum-resistant OVC is underway. Methods: REJOICE-Ovarian01 (NCT06161025; ENGOT-ov77; GOG-3096) is a global, randomized, open-label Phase 2/3 study in patients with platinum-resistant OVC who have not been selected for CDH6 expression. Eligible patients are adults with high-grade serous or endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer with acquired platinum resistance and 1–3 prior systemic lines of therapy (LOT) including prior bevacizumab treatment (unless ineligible) and prior mirvetuximab soravtansine treatment for patients whose tumors are folate receptor alpha-positive (unless ineligible or not available). Patients with primary platinum-refractory disease are not eligible. In the Phase 2 dose-optimization part, approximately 105 patients will be randomized 1:1:1 to receive R-DXd at 4.8, 5.6, or 6.4 mg/kg intravenously every 21 days. In the Phase 3 part, approximately 450 patients will be randomized 1:1 to receive either R-DXd or treatment of physician’s choice (TPC: paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan). Randomization will be stratified by number of prior LOT (1 vs 2–3) and tumor CDH6 expression (high vs low) in both parts, and additionally by TPC (paclitaxel vs others) in the Phase 3 part. The Phase 2 primary endpoint is ORR by blinded independent central review (BICR). Key secondary endpoints include investigator-assessed ORR and DOR. No hypothesis testing will be performed in the Phase 2 part. The dual primary endpoints in Phase 3 are ORR and progression-free survival (PFS) by BICR; key secondary endpoints are OS and quality of life (QoL). ORR will be analyzed using a Cochran-Mantel-Haenszel test at a 2-sided 1% alpha level, and PFS will be analyzed using a stratified log-rank test at a 2-sided 4% alpha level. OS and one QoL subscale will be tested hierarchically after PFS. Study enrollment is planned to start in February 2024. Clinical trial information: NCT06161025 .

BELLWAVE-010: A phase 3 study of nemtabrutinib plus venetoclax versus venetoclax plus rituximab (VR) in previously treated patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

TPS7089 Background: VR is a standard of care option for pts with CLL/SLL who have relapsed after ≥1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton tyrosine kinase (BTK) plays an important role in the pathogenesis of CLL. Nemtabrutinib is a BTK inhibitor that targets both wild type and C481-mutant forms of BTK. In the ongoing BELLWAVE-001 study, nemtabrutinib demonstrated manageable safety and durable antitumor activity in pts with R/R CLL/SLL with and without C481 mutations. The randomized, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to evaluate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line or later treatment for pts with R/R CLL/SLL. Methods: Eligible pts are aged ≥18 years with active R/R CLL/SLL after ≥1 prior therapy per iwCLL 2018 criteria and an ECOG PS of 0-2. Approximately 720 pts will be enrolled in 2 parts. Part 1 is an open-label, nonrandomized dose escalation and confirmation phase to evaluate safety and determine the optimal dose of nemtabrutinib + venetoclax. Part 1 will enroll 30 pts to establish the dose of nemtabrutinib using a modified toxicity probability interval design. Pts will receive nemtabrutinib at 2 dose levels (45 mg PO QD starting dose, escalating to 65 mg PO QD) for 28 days, followed by nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks). Part 2 is an open-label, parallel-group, randomized phase comparing the efficacy and safety of nemtabrutinib + venetoclax with VR. In part 2, approximately 690 pts will be randomly assigned 1:1 to receive either nemtabrutinib at the recommended dose for 28 days followed by the nemtabrutinib + venetoclax or venetoclax + rituximab (or rituximab biosimilar; 375 mg/m2 at week 6, followed by 500 mg/m2 every 4 weeks starting at week 10 until week 26 [total 6 doses]). Study treatment will continue for approximately 2 years or until unacceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be stratified by BTK-C481 mutation status (detected vs not detected), geographic region (US/Canada vs Europe vs rest of world) and risk (high risk [del(17p) and/or TP53-mutated and/or IGHV-unmutated] vs low risk [absence of high-risk factors]). The primary end point for part 2 is progression-free survival by blinded independent central review (BICR) per iwCLL 2018 criteria. Secondary end points for part 2 are undetectable minimal residual disease in bone marrow at month 14 by central laboratory assessment, objective response rate (ORR), and duration of response by BICR per iwCLL 2018 criteria, overall survival, and safety. Exploratory end points are ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life. Recruitment is ongoing. Clinical trial information: NCT05947851 .

Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05.

8593 Background: Brain metastases (mets) occur frequently in pts with NSCLC, particularly pts with certain AGAs, and indicate poor prognosis. For pts with AGAs, treatment options are limited once targeted therapy and platinum-based chemotherapy (Pt-CT) become ineffective. The phase 2 TROPION-Lung05 trial (NCT04484142) of Dato-DXd has demonstrated systemic efficacy and a manageable safety profile in heavily pretreated pts with a/m NSCLC with AGAs who progressed following targeted therapy and Pt-CT; here we report an exploratory analysis of intracranial (IC) efficacy. Methods: Pts were treated with Dato-DXd 6 mg/kg IV Q3W. Pts with clinically stable brain mets were eligible. IC responses were assessed by blinded independent central review (BICR) of cranial CT/MRI (CNS BICR; per CNS RECIST) at baseline (BL) and Q6W. Systemic objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR, defined as CR+PR+SD or non-CR/non-PD lasting ≥6 mo), progression-free survival (PFS) by BICR per RECIST 1.1 and treatment-related adverse events (TRAEs) were determined in pts with and without BL brain mets. Results: In total 53/137 (39%) treated pts had BL brain mets; 29/53 (55%) had an EGFRmutation. Pts with BL brain mets had a median (range) of 3 (2–6) prior systemic therapies in the a/m setting, including targeted therapy and Pt-CT with/without immune checkpoint inhibitors; 15/53 (28%) had untreated brain mets. At data cutoff (Dec 14, 2022), median (range) study and treatment durations among pts with BL brain mets were 14.8 (9.7–20.5) and 3.2 (0.7–17.2) mo, respectively. Of these pts, 18/53 (34%) had measurable IC target lesions (3 untreated) and 35/53 (66%) had only non-target IC lesions. In 18 pts with target lesions, IC ORR was 22% (95% CI, 6–48), including 1 of 3 pts with untreated target lesions; IC DCR was 72% (95% CI, 47–90); IC CBR was 44% (95% CI, 22–69). Reduction in the sum of diameters of brain lesions was seen in 10/18 (56%). Median time to IC response was 1.5 (range, 1.3–5.4) mo; median duration of IC response was 5.5 (95% CI, 3.4–NE) mo Systemic efficacy and safety were similar in pts with and without BL brain mets (Table). Conclusions: Dato-DXd showed encouraging IC activity consistent with systemic responses in pts with a/m NSCLC with AGAs, supporting further investigation of Dato-DXd in pts with brain mets. Clinical trial information: NCT04484142 . [Table: see text]

Double reading performance and the impact of adjudication on progression-free survival estimations: Findings from a lung clinical trial.

e23010 Background: The FDA recommends Blinded Independent Central Review (BICR) with double read for clinical trials with imaging. However, inter-reader variability is a concern in these trials. While studies have investigated the variability of RECIST, the primary response criteria, little attention has been given to the optimal association of readers. The evaluation of therapeutic response in phase III trials relies on the Date of first Progressive Disease (DoPD), with the Discrepancy Rate (DR) as the preferred index for measuring inter-reader variability in DoPD evaluation. Another important index measures readers' bias, assessing their tendency to over or under-estimate diagnoses. In cases of discrepancies, a third reader is brought in for adjudication. However, the impact of adjudication on trials' Progression-Free Survival (PFS) is not well-documented. Our study examines the variability in a lung clinical trial using RECIST, analyzing double reading performance, reader association prediction, and the impact of adjudication on PFS estimations. Methods: We retrospectively analyzed five phase III lung clinical trials using the RECIST 1.1 criteria in BICR with double reads. The trials involved 7 readers organized into 11 teams, each reader having participated in multiple trials and performed over 50 reads, resulting in 1017 patients' reviews. Our analysis included: Calculation of DR and bias for each team, and testing the correlation between DR and bias. Computation of the signed bias for each individual reader. Evaluation of a probabilistic model to predict the DR for each team and the bias for each reader. Comparison of PFS between single and double reads after adjudication and endorsement of one of the readings. Results: A multiple comparisons test did not reveal any difference between teams’ DR (Marascuilo test; q > 0.05). The average DR across all teams was 39.9% [95%CI; 37.8; 41.9]. However, we did find significant differences in bias when comparing 9/55 pairs of teams (Marascuilo test; q < 0.05). The range of absolute bias values was 20% to 100%. We did not find a correlation between bias and DR (p = 0.64). Additionally, when comparing the average bias value per reader, no differences were observed (Marascuilo test; q < 0.05). We failed to predict teams DR and readers' bias. The endorsement rate of readers ranged [18%; 82%]. After adjudication, we found that 27% of the PFS were lower than the minimum value obtained from the single readers, in one case 20.6% shorter. Conclusions: Significant readers' bias has a notable impact on double readings, independent of the DR values. The performance of one reader cannot be generalized based on others. Additionally, adjudication significantly affects the PFS of clinical trials. These findings emphasize the importance of considering readers' bias and the potential consequences of adjudication in clinical trial assessments.

Pembrolizumab plus Abiraterone Acetate and Prednisone in Patients with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Results from KEYNOTE-365 Cohort D

Background and objectiveAbiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC. MethodsIn cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-naïve, had disease progression ≤6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3–modified RECIST v1.1 by BICR and overall survival (OS). Key findings and limitationsFor the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26–31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1–measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2–22) and median OS was 30 mo (95% confidence interval 23–not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3–5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design. ConclusionsPembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-naïve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents. Patient summaryFor patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety.

Evaluation of elranatamab vs EPd, PVd, or Kd in patients with relapsed or refractory multiple myeloma and prior anti-CD38–directed therapy: MagnetisMM-32.

TPS7576 Background: Elranatamab (ELRA), a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, has shown efficacy and manageable safety as a monotherapy in patients with relapsed or refractory multiple myeloma (RRMM). This study will evaluate ELRA monotherapy vs elotuzumab-pomalidomide-dexamethasone (EPd), pomalidomide-bortezomib-dexamethasone (PVd), or carfilzomib-dexamethasone (Kd) in patients with RRMM to determine whether ELRA can provide superior clinical benefit. Methods: MagnetisMM-32, a phase 3, open-label, multicenter, randomized study, will enroll ≈492 patients. Patients will receive ELRA (Arm A) or investigator’s choice of EPd, PVd or Kd (Arm B), until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Patients treated with ELRA will receive 2 step-up priming doses followed by weekly doses in a 28-day cycle. Patients who achieve a PR or better for ≥2 months will be eligible for reduced dosing frequency. Patients will be randomized 1:1 (stratified by prior line of therapy [1 vs 2 vs 3/4] and International Staging System disease stage [1/2 vs 3]). Key inclusion criteria include age of ≥18 years, prior multiple myeloma diagnosis with measurable disease (per IMWG criteria), evidence of progressive disease or failure to achieve a response to last line of multiple myeloma therapy, 1 to 4 prior lines of therapy including an anti–CD38 antibody–containing regimen (for ≥2 consecutive cycles) and a lenalidomide-containing regimen (for ≥2 consecutive cycles), adequate bone marrow function, and an ECOG performance status of ≤2. Key exclusion criteria include stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior BCMA-directed or CD3-redirecting therapy; and unable to receive EPd, PVd, or Kd. The primary and key secondary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per IMWG criteria and overall survival (OS), respectively. Other secondary endpoints include PFS by investigator, objective response rate, duration of response, time to response by BICR, PFS on next line of therapy per IMWG criteria, MRD negativity rate, safety, pharmacokinetics of ELRA, immunogenicity, and health-related quality of life outcomes. The primary endpoint and OS will be compared statistically between treatment arms by stratified log-rank tests. Clinical trial information: NCT06152575 .

A phase 2/3 study of fianlimab plus cemiplimab versus cemiplimab in patients with advanced non-small cell lung cancer with tumors expressing PD-L1 ≥50%.

TPS8663 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, IgG4 monoclonal antibodies. In patients (pts) with advanced non-small cell lung cancer (aNSCLC) and programmed cell death-ligand 1 (PD-L1) expression ≥50% with no actionable mutations, first-line cemiplimab monotherapy showed significantly prolonged overall survival (OS) and progression-free survival (PFS) versus chemotherapy, with a safety profile consistent with previous reports for cemiplimab monotherapy. Despite pts’ selection by PD-L1 expression, only ~50% of pts respond to PD-1 therapy, thus there is a need for immune-oncology combinations like anti–LAG-3 plus anti–PD-1 to potentially improve outcomes. Methods: This is a randomized, double-blind, Phase 2/3 study (NCT05785767) to evaluate fianlimab + cemiplimab versus cemiplimab monotherapy as first-line treatment in pts with aNSCLC and tumors expressing PD-L1 ≥50%. The study will be conducted globally at ~210 sites. Key inclusion criteria: ≥18 years old; histologically confirmed squamous or non-squamous stage IIIB/C (not candidates for surgical resection or definitive chemoradiation) or stage IV NSCLC (no prior systemic treatment for recurrent or metastatic NSCLC); PD-L1 expression in ≥50% of tumor cells; ≥1 radiographically measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1; Eastern Cooperative Oncology Group performance status ≤1; adequate organ and bone marrow function. This study has Phase 2 and Phase 3 parts and is expected to enroll ~850 pts. Pts will be treated for up to 108 weeks. In Phase 2, 150 patients will be randomized 1:1:1 into three treatment arms (Q3W IV): Arm A, fianlimab high dose + cemiplimab 350 mg; Arm B, fianlimab low dose + cemiplimab 350 mg; Arm C, cemiplimab 350 mg + saline/dextrose placebo. Based on findings from Phase 2, the dose of fianlimab (low or high) will be selected for Phase 3. In Phase 3, 700 patients will be randomized 1:1 into either experimental Arm A or B, and comparator Arm C (cemiplimab + placebo). In Phase 2, the primary endpoint is objective response rate (ORR) per blinded independent central review (BICR). The secondary endpoints are safety, ORR per investigator assessment, disease control rate (DCR), time to tumor response (TTR), duration of response (DOR), PFS, OS, patient-reported outcomes, pharmacokinetics, and immunogenicity. In Phase 3, the primary endpoint is OS in patients receiving fianlimab + cemiplimab versus cemiplimab monotherapy. Secondary endpoints are safety, ORR, DCR, TTR, DOR, and PFS, per BICR and investigator assessment, patient-reported outcomes, pharmacokinetics, and immunogenicity. This study is open for enrollment along with a second study of fianlimab + cemiplimab + chemotherapy in aNSCLC. Clinical trial information: NCT05785767 .

Characterization of complete responders to nivolumab + gemcitabine-cisplatin vs gemcitabine-cisplatin alone and patients with lymph node–only metastatic urothelial carcinoma from the CheckMate 901 trial.

4509 Background: In the CheckMate 901 trial, combination nivolumab (NIVO) + gemcitabine-cisplatin (GC) demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with compelling objective response rates (ORR; 57.6% with NIVO+GC vs 43.1% with GC alone) and deep, durable complete responses (CR; 21.7% with NIVO+GC vs 11.8% with GC alone) in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC). Lymph node (LN)-only metastatic disease is a favorable prognostic factor in pts with mUC and a subset of pts achieve durable disease-free, treatment-free survival with GC +/- surgical consolidation. We conducted a post hoc analysis to characterize the subset of pts with CR, with further analysis of pts with LN-only mUC. Methods: In the global, open-label, randomized, phase 3 CheckMate 901 (NCT03036098) trial, cisplatin-eligible pts received NIVO 360 mg + GC every 3 wk for ≤6 cycles followed by NIVO 480 mg every 4 wk until disease progression/unacceptable toxicity or up to a maximum of 2 yrs, or GC every 3 wk for ≤6 cycles. Primary endpoints were OS and PFS by blinded independent central review (BICR). ORR per BICR and safety were exploratory endpoints. These post hoc analyses evaluated treatment outcomes in complete responders and in pts with LN-only disease. Results: Of the 608 pts randomized, 102 (16.8%) achieved a CR. Baseline disease characteristics of these pts are shown in the Table. As pts with LN-only mUC were enriched in the CR group, additional analysis of this subgroup was performed. Of all randomized pts, 54 treated with NIVO+GC and 56 treated with GC had LN-only mUC. In these pts, the ORR and CR rate was 81.5% (95% CI 68.6-90.7) and 63.0% versus 64.3% (50.4-76.6%) and 33.9% for NIVO+GC and GC, respectively. Median OS (95% CI) in LN-only pts was 46.3 (24.0-NE) mos with NIVO+GC vs 24.9 (21.4-29.9) with GC (HR, 0.58, 95% CI 0.34-1.00), and median PFS (95% CI) was 30.5 (9.6-NE) mos with NIVO+GC vs 8.8 (7.5-10.9) mos with GC (HR 0.38, 95% CI 0.22-0.66). Conclusions: NIVO+GC generated deep responses in CheckMate 901 with a fixed duration of chemotherapy and up to 2 years NIVO. Exploratory characterization of pts with CR identified a group of pts enriched with LN-only disease.In pts with LN-only mUC, NIVO+GC induced durable disease control and clinically meaningful improvements in OS and PFS vs GC alone. These results provide additional support for NIVO plus cisplatin-based chemo as a first-line treatment option for pts with mUC. Clinical trial information: NCT03036098 . [Table: see text]

DeLLphi-301: Tarlatamab phase 2 trial in small cell lung cancer (SCLC)—Efficacy and safety analyzed by presence of brain metastasis.

8015 Background: Brain metastases affect 40%–70% of patients with SCLC. Tarlatamab, a BiTE (bispecific T-cell engager) immunotherapy targeting delta-like ligand 3, demonstrated durable responses and promising survival outcomes in patients with previously treated SCLC (10 mg Q2W) (DeLLphi-301; NCT05060016; Ahn M-J, N Engl J Med 2023). Here, tarlatamab efficacy and safety in patients with baseline brain metastases from DeLLphi-301 are reported. Methods: The DeLLphi-301 study design has been published. Patients with treated, stable, asymptomatic brain metastases were included. Subgroup analyses for efficacy (blinded independent central review [BICR] assessments) and safety by presence or absence of baseline brain metastases were performed. Intracranial activity was assessed. Post enrollment, brain imaging was performed if clinically indicated. Results: As of 27 June 2023, 186 patients had received tarlatamab (ECOG PS: 0–1; median prior lines of therapy: 2; median follow-up: 13.6 months). 29% of patients (54/186) had treated and stable brain metastases at baseline. Most patients (91%) with brain metastases had received prior local radiotherapy; 6% each had received surgery only or both radiotherapy and surgery. Overall systemic objective response rate (ORR; RECIST 1.1) was 45.3% in patients with brain metastases and 32.6% in patients without brain metastases (Table). Any grade immune effector cell associated neurotoxicity syndrome and associated neurological events occurred in 24.1% of patients with brain metastases and in 13.6% of patients without brain metastases; grade ≥ 3 events occurred in the 100 mg group only: 9.4% and 1.8%, respectively, and did not lead to tarlatamab discontinuation in any patient with brain metastases. Analysis of intracranial activity will be presented. Conclusions: Tarlatamab showed promising efficacy and a favorable benefit-risk profile in patients with previously treated SCLC and stable brain metastases. Clinical trial information: NCT05060016 . [Table: see text]

Bireociclib plus fulvestrant for advanced HR+/HER2- breast cancer progressing after endocrine therapy: Interim analysis of a phase 3 trial (BRIGHT-2).

1058 Background: Bireociclib is a new selective inhibitor of CDK4/6 which showed promising clinical activity and manageable tolerability both as monotherapy and in combination with endocrine therapy (ET). This phase III study (BRIGHT-2, NCT05077449) was to evaluate the efficacy and safety of Bireociclib plus fulvestrant in HR+/HER2- advanced breast cancer (ABC) that progressed on or after previous ET. Methods: BRIGHT-2 study was a multicenter, randomized, double-blinded, phase 3 trial in patients with HR+/HER2- ABC who had progressed on or after prior ET. Eligible patients were randomized 2:1 to receive Bireociclib (360 mg po bid) or placebo with fulvestrant (500 mg im, cycle1 d1, d15, then d1) on each 28-day cycle. The primary endpoint was PFS based on investigator’s assessment per RECIST v1.1. The interim analysis was conducted when 70% PFS events occurred. Results: A total of 305 Chinese female patients were randomly allocated to receive Bireociclib plus fulvestrant (BF, n = 204) or placebo plus fulvestrant (F, n = 101). 208 (68.2%) patients had visceral metastases, 78 (25.6%) patients with primary resistance to ET and 73 (23.9%) patients had received chemotherapy in metastatic setting. As of March 28, 2023, with a median follow-up of 8.7 mo, BF significantly prolonged the PFS per investigator with 12.94 (95%CI, 11.07-NR) mo compared to 7.29 (95%CI, 5.45-11.04) mo in the F group (HR, 0.561; 95%CI, 0.393-0.799; P= 0.0012). The median PFS assessed by blinded independent central review (BICR) were no-reached (95%CI, NR-NR) in BF group and 7.46 (95%CI, 5.49-NR) mo in F group (HR, 0.461; 95%CI, 0.312-0.683; P<0.0001) which were consistent with the investigator’s assessment. The subgroup analyses revealed that in BF group, PFS was improved compared across all subgroups with HRs < 1. For patients with primary resistance to ET, with liver metastases and with bone-only metastases, the HRs were 0.254 (95%CI: 0.128-0.503), 0.381 (95%CI: 0.226-0.644) and 0.234 (95%CI: 0.070-0.787) respectively. In BF group, the most common TEAEs were diarrhea [92.6% (all grades); 5.4% (≥grade 3)], neutropenia [87.3%; 31.4%], leukocytopenia [83.3%; 18.6%] and anemia [66.7%; 10.8%]. Most of AEs were grade 1 or grade 2 and could be alleviated or cured by dose adjustment or symptomatic treatment. Treatment discontinuation due to TEAE was reported in 3 (1.5%) patients with BF. As of March 28, 2023, 120(58.8%) patients in BF were receiving treatment and the trail were ongoing. Conclusions: Bireociclib plus fulvestrant showed superior efficacy for pretreated HR+/HER2- ABC, especially in patients with primary resistance to ET, liver metastases or bone-only metastases. The toxicity of Bireociclib plus fulvestrant were well tolerated and manageable with no new safety signal. Clinical trial information: NCT05077449 .

Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202).

TPS8653 Background: The 5-year progression free survival (PFS) rate of patients with metastatic, PD-L1 negative, non-small cell lung cancer (NSCLC) remains poor, ranging from approximately 2% to 10% with standard immunotherapy-based treatment regimens. Based on promising anti-tumor activity in the phase 1 CodeBreaK 101 study, with partial responses observed in 62% (8/13) of PD-L1 negative patients in the first-line setting, we hypothesize that sotorasib plus platinum doublet chemotherapy will demonstrate durable clinical response and improved outcomes in this population. CodeBreaK 202 (NCT05920356) is a global phase 3 randomized study evaluating the efficacy of sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC. Methods: Patients will be randomized 1:1 to either sotorasib 960 mg once daily or pembrolizumab administered in combination with carboplatin and pemetrexed for 4 cycles, followed by maintenance treatment with sotorasib or pembrolizumab administered in combination with pemetrexed. Key eligibility criteria include treatment-naïve metastatic or locally advanced stage IIIB/C disease that is not amenable to definitive chemoradiation, PD-L1 <1% expression, presence of KRAS G12C mutation, non-squamous tumor histology, and absence of actionable genomic alterations such as EGFR mutations and ALK rearrangements. Patients with both treated and untreated brain metastases are eligible if clinically asymptomatic. The primary endpoint is PFS per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints include overall survival and objective response rate. Exploratory endpoints include intra-cranial PFS per RANO-BM criteria. Approximately 750 patients are planned to be enrolled and recruitment began on November 18, 2023. Contact Amgen Medical Information for more information: medinfo@amgen.com . Clinical trial information: NCT05920356 .

A phase 3 trial of fixed dose combinations of fianlimab (anti–LAG-3) + cemiplimab (anti–PD-1) versus relatlimab + nivolumab in patients with unresectable or metastatic melanoma.

TPS9611 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. Concurrent LAG-3 blockade may enhance the efficacy of anti–PD-1 therapies. Relatlimab (anti–LAG-3) + nivolumab (anti–PD-1) monoclonal antibodies demonstrated benefit in progression-free survival (PFS) in advanced melanoma (Mel) patients compared with nivolumab alone in the RELATIVITY-047 study. In a multicohort Phase 1 study (NCT03005782), fianlimab + cemiplimab demonstrated reproducibly high clinical activity (objective response rate [ORR]: 61%, N=98) in three independent cohorts of advanced PD-(L)1–naïve metastatic Mel patients with an acceptable safety profile. Methods: This is a randomized, open-label, multicenter Phase 3 study (NCT06246916) comparing the fixed dose combination (FDC) of fianlimab + cemiplimab to the FDC of relatlimab + nivolumab in patients with unresectable or metastatic Mel. The primary objective is to demonstrate superiority of fianlimab + cemiplimab compared with relatlimab + nivolumab as measured by ORR assessed by blinded independent central review (BICR). This study will be conducted at approximately 80 sites across North America. Key inclusion criteria are: (1) aged ≥18 years; (2) histologically confirmed unresectable stage III or IV (metastatic) Mel; (3) no prior systemic therapy for unresectable or metastatic Mel; patients with adjuvant and/or neoadjuvant systemic therapies are eligible with a treatment-free and disease-free interval of >6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) Eastern Cooperative Oncology Group performance status of ≤1; (6) adequate bone marrow, hepatic, and kidney function. Approximately 560 patients will be randomized in a 1:1 ratio to two treatment arms: Arm A: FDC of fianlimab (Dose 1) + cemiplimab (Dose 2) every 3 weeks intravenously (IV); Arm B: FDC of relatlimab 160 mg + nivolumab 480 mg every 4 weeks IV. All patients will be stratified based on metastatic stage (stage III vs M1a–b vs M1c–d), baseline lactate dehydrogenase level (≤ vs > upper limit of normal), and prior adjuvant and/or neoadjuvant systemic therapy. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, a study withdrawal criterion is met, or the sponsor terminates the study. The primary endpoint is ORR and key secondary endpoints are PFS and overall survival. Additional secondary endpoints are duration of response, disease control rate, investigator-assessed ORR and PFS, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT06246916 .

FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations (FURMO-002).

TPS8666 Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor ( EGFR) inhibitor engineered for broad activity and selectivity across EGFRmutations (mts) (1). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the progression-free survival benefit observed in the Phase 3 study versus gefitinib (FURLONG). Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC harboring EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) and a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (2) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Robichaux et al., 2021. Clinical trial information: NCT05364073 .

Phase I/II trial of healthy donor fecal microbiota transplant (hdFMT) in PD-1 relapsed/refractory (R/R) non-small cell lung cancer (NSCLC).

TPS8648 Background: A significant portion of patients (pts) with advanced NSCLC either do not respond or become refractory to immune checkpoint inhibitor (ICI) therapy administered alone or in combination with platinum chemotherapy. In addition to tumor-intrinsic mechanisms supporting resistance to anti-PD-1, the gut microbiome is a major tumor-extrinsic regulator of responses to anti-PD-1. In mice, gut microbiota modulate therapeutic activity of anti-PD-1 ICI, and administration of gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key bacterial species are associated with favorable response, although limited concordance among the identified species has been reported across studies. We and others have previously demonstrated that microbiome modulation reversed anti-PD-1 resistance in anti-PD-1 R/R melanoma, and augmented benefit of anti-PD-1 monotherapy in ICI-naïve melanoma. We hypothesize that intestinal dysbiosis mediates anti-PD-1 resistance in anti-PD-1 R/R NSCLC, and that hdFMT may resensitize NSCLC to PD-1 blockade. Methods: This is an investigator-initiated, phase II trial of hdFMT with pembrolizumab (P) in pts with R/R NSCLC progressed on prior anti-PD-1 based therapy alone or in combination with platinum chemotherapy. Pts must have measurable disease per RECIST v1.1, no untreated CNS metastases, and no contraindications to FMT administration. hdFMT is derived from non-obese, healthy, adults aged ≥18 to <70, with no chronic diseases, and no recent antibiotic exposure. Donors are screened broadly for transmissible agents including SARS-CoV-2 using bookend screening. hdFMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts receive P 200mg every 3 weeks (Q3W). hdFMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo tumor biopsies at baseline and at W8, with optional post-progression biopsy. Primary endpoint: overall response rate (ORR) assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 5% will be tested versus a 1-sided alternative hypothesis of ≥25%, using Simon’s minimax two-stage design (type I error 0.04, power 0.9, when true response rate is 0.25). PFS and OS will be estimated via Kaplan-Meier method. Enrollment has commenced. Clinical trial information: NCT05669846 .

ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN).

3016 Background: PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, Phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adult (≥18 y) and pediatric (2-17 y) pts with inoperable NF1 PN causing significant morbidities. Methods: Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for pediatrics. Ptscould continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline (BL) in target PN volume, pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. Results: All114 pts (58 adult, 56 pediatric) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P<.001 vs null) in adults and 52% (95% CI, 38-65; P<.001 vs null) in pediatric pts. Two adult pts and 1 pediatric pt also had a confirmed response in the ongoing LTFU. Median (min, max) target PN volumetric best response from BL was -41% (-90, 13) and -42% (-91, 48) in adult and pediatric pts, respectively. As of the DCO, median treatment duration was 22 mo for each cohort and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adult pts and 7.9 (4-19) mo in pediatric pts. Adult and pediatric pts had statistically significant improvements from BL to cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in pediatric pts. 16% and 25% of adult and pediatric pts, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. Conclusions: In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1 PN pts across all ages. Clinical trial information: NCT03962543 .

Avelumab + axitinib vs sunitinib in patients (pts) with advanced renal cell carcinoma (aRCC): Final overall survival (OS) analysis from the JAVELIN Renal 101 phase 3 trial.

4508 Background: The JAVELIN Renal 101 (NCT02684006) phase 3 trial compared first-line treatment with avelumab + axitinib vs sunitinib in aRCC. The trial previously met one of its primary objectives by showing significantly longer progression-free survival (PFS) with avelumab + axitinib vs sunitinib in pts with PD-L1+ tumors; longer PFS, higher objective response rate (ORR), and an acceptable safety profile were also observed in the overall population. OS data were immature. Here we report the final analysis. Methods: Pts with untreated aRCC (any IMDC risk score) were randomized 1:1 to avelumab + axitinib or sunitinib. OS and PFS (by blinded independent central review) in pts with PD-L1+ tumors (SP263 assay) were independent primary endpoints. OS and PFS in the overall population were key secondary endpoints; response and safety were also analyzed. Results: Of 886 pts randomized, 560 (63.2%) had PD-L1+ tumors. At data cutoff (August 31, 2023), median follow-up in the avelumab + axitinib and sunitinib arms was 73.7 and 73.6 months, respectively (≥68 months in all pts). Final efficacy data are shown in the Table. In the avelumab + axitinib and sunitinib arms, grade ≥3 TRAEs occurred in 66.8% vs 61.5%, respectively. Second-line therapy was received by 58.1% vs 69.4%, including a PD-(L)1 inhibitor in 18.8% vs 53.6%, respectively. Conclusions: The JAVELIN Renal 101 trial provides the longest follow-up for immune checkpoint inhibitor + tyrosine kinase inhibitor combination treatment from a phase 3 trial reported to date. OS analyses favored avelumab + axitinib vs sunitinib but did not reach statistical significance. PFS was longer with avelumab + axitinib vs sunitinib, and responses were durable in a subset of pts. Final analysis results confirm the long-term efficacy and manageable safety profile of avelumab + axitinib treatment in pts with aRCC. Clinical trial information: NCT02684006 . [Table: see text]

A phase II trial of nivolumab plus axitinib in patients with anti-PD1 refractory advanced melanoma.

TPS9600 Background: A significant portion of patients (pts) with advanced melanoma (mel) either do not respond or become refractory to immune checkpoint inhibitor (ICI) therapy, with no established second line treatment regimen. A key ICI resistance mechanism includes formation of an immunosuppressive tumor microenvironment (TME). We have shown that high oxidative metabolism (OXPHOS) of mel tumor cells is associated with a hostile TME (1). Furthermore, this is associated with high intra-tumoral hypoxia (ITH). In mel tumor cells with high OXPHOS, CD8+ tumor infiltrating lymphocytes (TIL) display increased exhaustion and decreased functionality (decreased IFN-γ and TNF-α production). Pts with metastatic mel who progressed on ICI had tumor cells with high OXPHOS and ITH. Axitinib is a VEGFR small molecule tyrosine kinase inhibitor with high inhibitory activity for VEGFR 1-3. We previously showed that low dose axitinib reduces ITH in B16 murine mel, and our pre-clinical data show that axitinib synergizes with ICI to produce an improved tumor response (2). We hypothesize that axitinib will re-sensitize mel to ICI by modulating angiogenesis and reducing ITH and resultant T cell dysfunction. Methods: This is an investigator-initiated, single arm phase II trial of nivolumab plus axitinib for pts with unresectable stage III or IV cutaneous, acral, or mucosal mel who have progressed on prior anti-PD1 based therapy in the adjuvant or metastatic setting (NCT04493203). Pts previously treated with concomitant anti-CTLA4, anti-LAG3, BRAF/MEK inhibitors, and/or pts with brain metastases (asymptomatic or stable treated disease x 2 weeks) are eligible. Pts will receive nivolumab 480 mg IV every 4 wks with axitinib PO 5 mg twice daily for up to 2 years, or until progression or unacceptable toxicity. Pts will undergo biopsy at baseline and at 12 wks, with optional biopsy at progression. Pts will receive an oral dose of pimonidazole 0.5 mg/m2 prior to each biopsy to permit in-vivo evaluation of ITH. Staging scans (full body PET-CT or CT and MRI brain) will be obtained at baseline, with restaging scans at 12 week intervals. Primary endpoint: overall response rate (ORR) by RECIST 1.1. Responses are determined by Blinded Independent Central Review (BICR). Secondary endpoints: safety analysis, progression-free survival (PFS) and overall survival (OS). Extensive correlative translational analyses will focus on immunophenotypic changes in the TME, ITH, profiling of tumor cell metabolism, and TIL function. The null hypothesis that the true ORR is 10% will be tested versus a one-sided alternative hypothesis of ≥25%, using Simon’s minimax two-stage design. This design has a type I error rate 0.08 and power 0.81 when the true response rate is 0.25. PFS and OS will be estimated via Kaplan-Meier method. 31 of planned 31 pts have been enrolled in January 2024, with no data analysis yet available. 1. Najjar et al., JCI Insight 2019. 2. Scharping et al., Nat Immunol 2021. Clinical trial information: NCT04493203 .

Peak study: A phase 3, randomized, open-label multi-center clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST).

TPS11588 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. Bezuclastinib has a highly selective inhibition profile, leading to minimal off-target toxicities and allowing for combination with sunitinib. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations and may provide more durable responses. The early signs of clinical activity, tolerability, and safety observed with the combination thus far in Peak Part 1 (Somaiah et al. [presentation] CTOS 2023. Paper 62) are consistent with the completed Phase 1/2 study (PLX121-01). Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. Current Peak study sites are located in North America (3 countries), South America (3 countries), Europe (12 countries), and Asia-Pacific (4 countries). The lead-in portion to test a new formulation of bezuclastinib, (Part 1) completed enrollment in April 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: known PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated and circulating tumor DNA (ctDNA) will be collected and assessed. Clinical trial information: NCT05208047 .

OPERA-01: A randomized, open-label, phase 3 study of palazestrant (OP-1250) vs standard-of-care for ER+, HER2- advanced or metastatic breast cancer patients after endocrine therapy and CDK4/6 inhibitors.

TPS1135 Background: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC), endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) treatment in the first-line setting. However, patients develop resistance, most commonly due to acquired mutations in ESR1. Efficacy of available ET post CDK4/6i treatment is limited. Therefore, a significant unmet need exists for patients with ET-CDKi-resistant ER+, HER2– MBC to improve outcomes and delay time to chemotherapy. Palazestrant is an oral small molecule complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds ER and completely blocks ER-driven transcriptional activity, irrespective of ESR1 mutation status. In a phase 1/2 monotherapy study in heavily pretreated patients with ER+, HER2– advanced or MBC (NCT04505826), palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in patients with and without ESR1 mutation at the recommended Phase 2 dose of 120 mg once a day (qd) (1). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patients with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Eligible patients are adults who have a confirmed diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1-2 prior lines of ET, last ET duration for ≥6 months; must have received CDK4/6i with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC. No prior chemotherapy in the metastatic setting is permitted. In the dose selection part of the study, 120 patients are randomized to 90 mg qd or 120 mg qd palazestrant or SOC monotherapy. The dose selection will be conducted when 80 patients in both palazestrant arms have had an opportunity to be on treatment for16 weeks. Overall, 510 patients, including patients from the dose selection part, will be randomized to palazestrant or SOC ET. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in patients with and without ESR1mutations. The study started recruitment in November 2023. 1. Lin et al. ESMO 2023 MO382. Clinical trial information: NCT06016738 .