Investigator-assessed Objective Response Rate Research Articles

Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02.

DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n=202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results used for study enrollment. This phase 2, open-label study evaluated T-DXd (5.4mg/kg once every 3weeks) for HER2-expressing (IHC 3+/2+by local or central testing) locally advanced or metastatic disease after≥1 systemic treatment or without alternative treatments. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival. In total, 111 (41.6%) and 151 (56.6%) patients were enrolled with IHC 3+and IHC 2+tumors, respectively. In patients with IHC 3+tumors, investigator-assessed confirmed ORR was 51.4% [95% confidence interval (CI) 41.7, 61.0], and median DOR was 14.2months (95% CI 10.3, 23.6). In patients with IHC 2+tumors, investigator-assessed ORR was 26.5% (95% CI 19.6, 34.3), and median DOR was 9.8months (95% CI 4.5, 12.6). Safety was consistent with the known profile of T-DXd. In line with previously reported results, T-DXd demonstrated clinically meaningful benefit in patients with HER2-expressing tumors, with the greatest benefit in patients with IHC 3+tumors. These data support the antitumor activity of T-DXd in HER2-expressing solid tumors, irrespective of whether patients are identified by local or central HER2 IHC testing.

Savolitinib in patients in China with locally advanced or metastatic treatment-naive non-small-cell lung cancer harbouring MET exon 14 skipping mutations: results from a single-arm, multicohort, multicentre, open-label, phase 3b confirmatory study.

Savolitinib has been approved in China for advanced or metastatic non-small-cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations in previously treated patients and those unable to receive platinum-based chemotherapy. We report results from a treatment-naive cohort of a phase 3b study that was designed to evaluate the efficacy and safety of savolitinib in locally advanced or metastatic METex14-mutated NSCLC. This single-arm, multicohort, multicentre, open-label, phase 3b study was done at 48 hospitals in China in adult (≥18 years) patients with locally advanced or metastatic METex14-mutated NSCLC who had not received previous systemic antitumour therapy. Patients with a bodyweight of 50 kg or more and those with a bodyweight of less than 50 kg received savolitinib once daily at 600 mg or 400 mg, respectively, in 21-day cycles. The primary endpoint was objective response rate assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumours, version 1.1. The full analysis set comprised all patients who received at least one dose of study medication, which was used to assess the efficacy endpoints and baseline and safety data. This study is registered with ClinicalTrials.gov (NCT04923945) and is closed to accrual. Between Aug 31, 2021, and Oct 20, 2023, 125 treatment-naive patients were assessed for eligibility, of whom 87 were enrolled and received savolitinib. The median age of patients was 70·0 years (IQR 65·2-75·8) and 51 (59%) of 87 patients were male and 36 (41%) were female. In the full analysis set, the IRC-assessed objective response rate was 62% (95% CI 51-72) and the investigator-assessed objective response rate was 60% (49-70), showing a high concordance rate (84%). Treatment-related adverse events were reported in 85 (98%) of 87 patients, with peripheral oedema (54 [62%]) being the most common. Two of these treatment-related adverse events led to death (cardiac failure n=1, unknown reasons n=1). Savolitinib showed manageable toxicity and promising efficacy in treatment-naive patients with advanced or metastatic METex14-mutated NSCLC. HUTCHMED and AstraZeneca.

Phase 2 dose-ranging study to evaluate the efficacy and safety of liposomal irinotecan (LY01610) as a second-line treatment for patients with relapsed small cell lung cancer

This was a multicenter, single-arm dose-ranging phase 2 study aimed to assess the efficacy and safety of LY01610, a liposomal irinotecan, at various doses for patients with relapsed small cell lung cancer (SCLC). This study (NCT04381910) enrolled patients with relapsed SCLC at 10 hospitals across China, who have failed with previous platinum-based treatments. LY01610 was administered at doses of 60mg/m2, 80mg/m2, and 100mg/m2. Primary endpoints were investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DoR). Secondary endpoints included investigator-assessed disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. From September 3, 2020 to March 3, 2022, a total of 66 patients were enrolled, with 6, 30, and 30 allocated to the 60mg/m2, 80mg/m2, and 100mg/m2 dose groups, respectively, with 68% (45/66) having a chemotherapy-free interval <90 days. In all 66 patients, the ORR was 32% (21/66, 95% confidence interval [CI], 21-44), with a median DoR of 5.2 months (95% CI, 3.0-8.3). Median PFS and OS were 4.0 (95% CI, 2.9-5.5) and 9.7 (95% CI, 7.2-12.3) months, respectively. The ORR of 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 33% (2/6), 33% (10/30), and 30% (9/30), respectively. The median DoR of 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 4.2 (95% CI, 2.8-not reached), 6.9 (95% CI, 2.5-9.9), and 4.0 (95% CI, 2.7-6.8) months, respectively. The incidence of ≥ grade 3 treatment-related adverse events (TRAEs) in the 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 33% (2/6), 47% (14/30), and 50% (15/30), respectively. Themost common≥grade 3 TRAEs of all 66 patients were neutropenia (27%), leukopenia (24%) and anemia (15%). LY01610 exhibited promising clinical efficacy and manageable safety profiles in patients with relapsed SCLC, the 80mg/m2 dose group had the best benefit-risk ratio. This study was supported by Luye Pharma Group Ltd.

Erdafitinib in Asian patients with advanced solid tumors: an open-label, single-arm, phase IIa trial

BackgroundFGFR genomic aberrations occur in approximately 5–10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer.MethodsPatients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics.ResultsThirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7–63.6); the median progression-free survival was 5.6 months (95% CI, 3.6–12.7) and median overall survival was 40.2 months (95% CI, 12.4–not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5–57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%).ConclusionsErdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals.Trial registrationThis trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

7 A Phase 1 study of fianlimab (anti–LAG-3) in combination with cemiplimab (anti–PD-1) in patients with advanced ccRCC

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

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study

BackgroundIndoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%.MethodsECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsTarget enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35–48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67–29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent.ConclusionsEpacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted.Trial registrationClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study

BackgroundIndoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC.MethodsECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1).ResultsA total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46–55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33–43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%).ConclusionsTreatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted.Trial registrationClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.

A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679/ECHO-302)

BackgroundImmunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC.MethodsKEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1.ResultsOne-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2–14.3) and 10.3 months (2.7–13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2–44.1] and sunitinib/pazopanib (29.2% [18.6–41.8]). Grade 3–5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects.ConclusionsORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab.Clinical trial registrationClinicalTrials.gov; NCT03260894.

A phase II study of osimertinib in patients with NSCLC harboring EGFR exon 20 insertion: A multicenter trial of the Korean Cancer Study Group (LU17-19)

BackgroundEpidermal growth factor receptor (EGFR) exon 20 insertions account for up to 10% of all EGFR mutations. Clinical outcomes in patients receiving approved EGFR exon 20 insertion–specific inhibitors have been variable. Although osimertinib has demonstrated antitumor activity in clinical trials, its clinical efficacy and translational potential remain to be determined in non-small cell lung carcinoma (NSCLC) with EGFR exon 20 insertion. MethodsIn this multicenter phase II study, patients with advanced NSCLC harboring EGFR exon 20 insertions for whom the standard chemotherapy failed received 80 mg osimertinib once daily. The primary endpoint was the investigator-assessed objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety profile. ResultsAmong 15 patients enrolled at stage 1, the best response was most commonly disease stabilization (73.3 %), which did not meet the stage 1 threshold (objective response ≥ 2/15). As of data cutoff, two patients remained on the treatment. The median PFS and OS were 3.8 (95 % confidence interval [CI] = 1.7–5.5) months and 6.5 (95 % CI = 3.9–not reached) months, respectively. Adverse events (≥grade 3) were anemia, hypercalcemia, and pneumonia (13.3 % each), and asthenia, femur fracture, increased alkaline phosphate, hyperkalemia, bone pain, and azotemia (6.7 % each). Pre-existing EGFR C797S mutation detected in plasma limited the efficacy of osimertinib. ConclusionOsimertinib at 80 mg once daily had limited efficacy and mostly showed disease stabilization with an acceptable safety profile in advanced NSCLC harboring EGFR exon 20 insertions.ClinicalTrials.govIdentifier: NCT03414814.

Entrectinib in ROS1-positive advanced non-small cell lung cancer: the phase 2/3 BFAST trial

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552.

FS-1502 in patients with HER2 high expression, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: An open-label, multicenter, phase II study.

e15000 Background: FS-1502 is an antibody-drug conjugate composed of an anti-HER2 antibody, linker, and Monomethylauristatin F. In this study, we conducted an open-label, multicenter, two-cohort phase II trial to evaluate the efficacy and safety of FS-1502 in HER2- positive locally advanced or metastatic gastric or gastroesophageal junction cancer. Methods: Pts with HER2-positive (IHC 3+ or 2+/FISH+) who had received ≥1 prior treatment regimens were eligible and received FS-1502 2.3 mg/kg alone every 3 weeks. The study consists of Cohort 1 for pts received ≥2 lines of previous therapy and Cohort 2 for pts only received first-line of previous therapy, respectively. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of response, disease control rate, and safety. Results: At data cutoff (Dec 24,2023), 46 pts were enrolled (intent-to-treat [ITT]), 35 pts were confirmed HER2-positive (IHC 3+ or IHC 2+/ISH+, Efficacy Evaluable Set [ES]) by central laboratory. In the ES, the median age was 58.3 years, 48.6% were IHC3+ and primary tumor location in 77.1% of pts was GC. 45.7% (16/35) pts had assigned to cohort 1 and 54.3% (19/35) pts had assigned to cohort 2. In cohort 1, median study follow-up time was 10.1 months, the investigator-assessed ORR was 37.5% (95% CI, 15.2-64.6), median PFS and OS were 4.3 months (95% CI, 1.5-5.8 months) and 10.0 months (95% CI,5.1-NA months), respectively. In cohort 2, median study follow-up time was 12.5 months, the investigator-assessed ORR was 52.6% (95% CI, 28.9-75.6). PFS and OS were 4.4 months (95% CI, 3.0-7.3 months) and 14.6 months (95% CI, 8.7-NA months), respectively. Grade≥3 treatment-related TEAEs were reported in 12 (26.1%) pts, ≥5% were hypokalemia (6.5%) and fatigue(6.5%). No adverse events leading to drug discontinuation or death. Efficacy and safety data are shown in table. Conclusions: FS-1502 showed promising activity with tolerable and manageable safety profile, which warrants further development in HER2-postive, advanced gastric or gastroesophageal junction adenocarcinoma who had received ≥1 prior treatment regimens. [Table: see text]

Dual immune checkpoint inhibition with nivolumab and ipilimumab (N+I) in patients with advanced anaplastic thyroid carcinoma (ATC).

e18075 Background: There are no standard of care therapies in advanced incurable setting for BRAF wild type (WT) ATC, &amp; after dabrafenib and trametinib (D+T) for BRAF V600E mutant ATC. We previously showed promising clinical activity of dual inhibition with N+I in exploratory cohort of 10 patients (pts) with advanced ATC in a single arm phase II clinical trial, with objective response rate (ORR) of 30% (NCT03246958, Lorch ASCO 2020). Here, we present efficacy and safety outcomes from a real-world cohort of pts with advanced ATC treated with N+I regimen. Methods: We conducted a retrospective cohort study of pts with advanced ATC (unresectable or with distant metastases, DM) who were seen at the Dana-Farber Cancer Institute (DFCI) thyroid cancer center from July 2021 to Jan 2024, received at least one dose of N+I with palliative intent &amp; completed at least one response assessment (data cutoff, 1/31/24). Pts on the DFCI clinical trial were not included. Investigator-assessed ORR (for the first N+I based treatment regimen) and immune-related adverse events (irAEs, collected till cutoff regardless of ongoing treatment) were evaluated. Results: 19 pts with advanced ATC (5: unresectable disease, 14: DM) were included, BRAF WT 12/19 (63%). Median age was 70y (range, 34-81), 68% female. ECOG PS at start was 0-1 in 14/19 (74%), 2 in 4 (21%) &amp; 3 in 1 (5%) pts. 5/19 (26%) pts received N+I concurrently with D+T; 4/5 (80%) in 2nd line after either mixed response or progressive disease (PD) on D+T. Best overall response (BOR) in N+I+D+T group was partial response (PR, 1/5, 20%) &amp; stable disease (SD, 4/5, 80%); ORR 20%. 14/19 (74%) pts received N+I, 12/14 (86%) as 1st line palliative therapy. 5 pts in N+I group (all with DM) received local therapies concurrently (1: debulking thyroid surgery, 3: radiation therapy (RT) to thyroid, &amp; 1: palliative RT to bone DM). BOR in N+I group were: complete response, CR (4/14, 28.6%); PR (3, 21.4%); SD (4, 28.6%); &amp; PD (3, 21.4%); ORR 50%. Excluding 5 pts with concurrent local therapies, ORR was 33.3% (1/9 CR, 2/9 PR).PD-L1 TPS was available for 12/19 pts (4: N+I+D+T, 8: N+I) and ≥1 in all tumors (range, 1-100). In 8 pts in N+I group, ORR stratified by PD-L1 TPS: TPS &lt;50 (range, 1-30): 0% (0/2: 1 SD, 1 PD), &amp; TPS ≥50 (range, 80-100): 83.3% (5/6: 3 CR, 2 PR, 1 PD). Any grade irAEs were observed in 16/19 (84.2%) pts. ≥Grade 3 irAEs occurred in 11/19 (57.9%) pts, most frequent were colitis (5, 26.3%), dermatitis/pruritus (3, 15.8%), myocarditis (2, 10.5%), &amp; adrenal insufficiency (2, 10.5%). There were no treatment-related deaths. Conclusions: In this largest real-world cohort study of pts with advanced ATC, N+I therapy showed high ORR of 50% (congruent with DFCI trial), albeit with high rates of iRAEs. High ORR was seen with PD-L1 TPS ≥50. Survival outcomes and genomic biomarkers, currently under investigation, will be presented at the meeting. N+I merit further investigation in an ATC focused clinical trial.

Disitamab vedotin combined with fruquintinib in patients with HER2-expressing or HER2 mutation/amplified metastatic colorectal cancer refractory to at least two standard regimens: A prospective, exploratory, single-arm study.

e15003 Background: Human epidermal receptor growth factor 2 (HER2) -expressing or amplified has been identified in 2-6% of patients with stage 3/4 colorectal cancer (CRC), and is associated with poor prognosis, however there are currently no approved HER2-targeted therapies for CRC in China. Herein, we aimed to study the antitumor activity and safety of Disitamab vedotin (RC48), a novel humanized anti-HER2 antibody conjugated to MMAE via a cleavable linker, combined with fruquintinib in patients with HER2-expressing or -amplified metastatic colorectal cancer. Methods: In this prospective, exploratory, single-arm study, patients diagnosed pathologically with mCRC, 18-75 years old harboring HER2 expression or HER2 mutation/amplification, and received at least two lines of treatment. HER2 expression was defined as a score of 1+, 2+ or 3+ on immunohistochemical [IHC] analysis, or mutation/amplification by NGS. Patients received RC48 2.5mg/kg intravenously every 2 weeks. Meanwhile, fruquintinib 3mg was administered orally once daily on days until disease progression, death, intolerable toxicity, withdrawal of consent. The primary endpoint was objective response rate (ORR) per RECIST v1.1; the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 12 patients were enrolled from November 25, 2022 to June 6, 2023. The results of baseline molecular profiling revealed 4 with IHC 1+, 4 with IHC 2+, 2 with IHC 3+, and 2 with HER2 amplification. In the metastatic setting, patients had received a median of 4 (range, 3-6) lines of prior systemic therapy. In the per-protocol set, the investigator-assessed ORR was 18.2% (2/11) and DCR was 90.9% (10/11). Median PFS was 5.5 months (95% CI: 2.7-8.2) and the median OS was 12.3 months (95% CI: 5.3-19.3). During the study process, 11 (91.7%) patients experienced adverse events (AEs), among which, 4 (33.3%) experienced grade 3 treatment-related AEs (TRAEs). The most common grade 3 TRAEs were neutropenia (25%), leukopenia (16.7%), and hypertension (8.3%). Moreover, no grade 4 or 5 TRAEs were observed. In addition, 4 (33.3%) patients experienced a dose reduction. No patients experienced dose interruption or discontinuation due to TRAEs. Conclusions: RC48 combined with fruquintinib has shown promising efficacy and a manageable safety profile for HER2-expressing or -amplified mCRC patients refractory to at least two standard treatment failures. Clinical trial information: NCT05661357 .

A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

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

6038 Background: Concurrent blockade of LAG-3 may enhance efficacy of anti–PD-1 therapies. We present safety and clinical activity data from a Phase 1 study in patients (pts) with head and neck squamous cell carcinomas (HNSCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Two expansion cohorts of adult pts with recurrent and/or metastatic HNSCC with no curative options who were anti–PD-1/PD-L1-naïve (cohort 11) or anti–PD-1/L1-experienced with most recent dose within 3 months (mos) prior to screening (cohort 12) were enrolled. All pts received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks (wks) for up to 24 mos. Tumor measurements were performed every 6 wks for 24 wks, then every 9 wks. Results: 15 pts each in cohort 11 and 12 (total N=30; median age: 69 years) were enrolled and treated with fianlimab + cemiplimab as of 04 Oct 2023 data cutoff.For cohorts 11 and 12 respectively, 80% and 87% of pts were male, and 53% and 80% were White. All pts had prior cancer-related systemic therapy. 33% (5/15) and 87% (13/15) of pts in cohorts 11 and 12 had ≥2 lines of prior therapies, respectively. For cohorts 11 and 12, median treatment duration was 12 wks (mean: 41 wks) and 13 wks (mean: 24 wks), and median follow-up was 12 mos and 10 mos, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 47% of pts each in cohorts 11 and 12. Serious TEAEs occurred in 13% and 20% of pts in cohorts 11 and 12, respectively. Treatment-related TEAEs (TRAEs) were reported in 67% of pts in cohorts 11 and 53% of pts in cohort 12. The most common TRAEs (any grade) were hypothyroidism (33%) in cohort 11; and fatigue (20%) and pneumonitis (20%) in cohort 12. Grade ≥3 TRAEs occurred in 7% of pts in cohorts 11 and 13% of pts in cohorts 12. Treatment-related immune-related AEs were reported in 47% and 40% of pts in cohorts 11 and 12, respectively. Treatment was discontinued due to any TEAE in 2 pts in cohort 12. In cohort 12, there was one death due to grade 5 respiratory failure attributable to aspiration pneumonia. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 33% (5 partial responses [PRs]) in cohort 11 and 7% (1 PR) in cohort 12. The disease control rate (DCR) was 47% and 67% in cohorts 11 and 12, respectively. Kaplan–Meier estimation of median progression-free survival was 2 mos (95% CI, 1–14) in cohort 11 and 4 mos (95% CI, 1–7) in cohort 12 pts. Duration of responses were 17, 10, 20, 22, and 20 mos in 5 responders in cohort 11; and 32 mos in 1 responder in cohort 12. Estimated event-free probability at 12 month was 33% (95% CI, 12–56) in cohort 11 and 16% (95% CI, 3–40) in cohort 12 pts. Conclusions: Fianlimab + cemiplimab in pts with HNSCC showed signs of clinical activity with durable responses among pts with anti–PD-1/PD-L1-naïve (cohort 11) and anti–PD-1/L1-experienced (cohort 12), with an acceptable safety profile which warrants further investigation. Clinical trial information: NCT03005782 .

A phase I/Ib study of the aurora kinase A inhibitor alisertib in combination with osimertinib in advanced osimertinib-resistant EGFR-mutated lung cancer.

8572 Background: The third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is effective for the treatment of advanced EGFR-mutated lung adenocarcinoma (LUAD), however treatment resistance invariably occurs. We previously identified Aurora Kinase A (AURKA) activation as a mechanism of resistance to osimertinib. Alisertib is an oral, selective, small-molecule inhibitor of AURKA. We evaluated the combination of alisertib with osimertinib in a phase I/Ib study of patients with advanced EGFR-mutated LUAD who experienced disease progression on prior treatment with osimertinib monotherapy. Methods: 21 total patients were treated in an open-label, single-center phase I trial (NCT04085315). 10 patients were treated in a 3+3 dose escalation phase with alisertib using an intermittent dosing strategy of 30 mg (n = 6) or 40 mg (n = 4) twice daily (BID) on days (d) 1-3, 8-11, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily. 11 additional patients were treated at the 30 mg alisertib intermittent dosing schedule in combination with osimertinib 80 mg daily in a Phase Ib dose expansion. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of the alisertib and osimertinib combination. Secondary endpoints were investigator-assessed objective response rate (ORR) by RECIST 1.1 criteria, depth of response (DoR), disease control rate (DCR) for at least 12 weeks, progression-free survival (PFS) and overall survival (OS). Results: 21 patients with stage IV EGFR-mutated LUAD (76.1% exon 19 deletion; 14.3% L858R; 9.5 % L861Q) who had progressed on osimertinib were enrolled. 10 (47.6%) patients had received only first-line osimertinib, while 11 (52.3%) had received ≥ 2 lines of prior therapy. Common treatment-related adverse events were neutropenia (42.9%), anemia (42.9%), and diarrhea (38.1%). 2 patients had dose limiting toxicities from grade 4 neutropenia at the alisertib 40mg BID dose level. 2 patients had serious adverse events related to the study drugs, including grade 3 constipation and grade 4 anemia. There were no treatment-related deaths. Intermittent alisertib 30 mg BID with osimertinib 80 mg daily was the MTD and R2PD. ORR for all enrolled patients was 9.5% (95% CI: 1.2% to 30.4%), DCR was 81% (95% CI: 58.1% to 94.6%), and median DoR was -4 % (95% CI: -15% to 10%). The median PFS was 5.5 months (95% CI: 3.7 – 13.2 months) and median OS was 23.5 months (95% CI: 11.9 months – NR). Conclusions: Intermittent dosing of alisertib 30 mg BID in combination with osimertinib 80 mg daily demonstrated no dose limiting toxicities and was identified as the RP2D. While ORR was &lt; 10%, DCR was &gt; 80% and the median PFS was 5.5 months. These results are comparable to other emerging therapies for patients with advanced osimertinib resistant EGFR-mutated LUAD and warrants further exploration. Clinical trial information: NCT04085315 .

A multi-center, open-label phase 1/1b dose finding, safety, and pharmacokinetic study of MBRC-101, an Anth-EphA5 monomethyl auristatin (MMAE) antibody drug conjugate, in advanced refractory solid tumors.

TPS3161 Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .

REZILIENT2: Phase 2 study of zipalertinib in patients with advanced non-small cell lung cancer (NSCLC) with exon 20 insertions (ex20ins) and other uncommon epidermal growth factor receptor (EGFR) mutations.

TPS8670 Background: Patients with NSCLC harboring uncommon EGFR mutations, including ex20ins, have limited treatment options. Zipalertinib (CLN-081/TAS6417) is an oral tyrosine kinase inhibitor of EGFR with broad activity against EGFRmutations (including ex20ins) and increased selectivity for ex20ins versus wild-type EGFR. Zipalertinib has shown preclinical activity against a wide spectrum of EGFR ex20ins mutations and other uncommon EGFR mutations. In a phase 1/2a study (REZILIENT1), encouraging antitumor activity and an acceptable safety profile were observed in heavily pretreated patients with EGFRex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation from the U.S. Food and Drug Administration. The aim of REZILIENT2 is to evaluate the efficacy and safety of zipalertinib in patients with NSCLC harboring EGFRex20ins and other uncommon single or compound EGFR mutations, including patients with brain metastases and leptomeningeal disease (LMD). Methods: In this global, phase 2b, open-label, multicohort study (NCT05967689), adult patients with locally advanced or metastatic NSCLC will be assigned to one of four cohorts depending on prior treatment and type of EGFR mutation: A) patients with EGFR ex20ins mutations who have progressed on or after first-line platinum-based chemotherapy and prior therapy targeting ex20ins (administered together or separately) for advanced disease; B) patients with EGFR ex20ins mutations who have not received prior treatment for advanced disease; C) patients with ex20ins or other uncommon single or compound EGFR mutations and active central nervous system metastases (including LMD) who may or may not have received prior treatment for advanced disease; and D) patients harboring other uncommon non-ex20ins single or compound EGFR mutations who have progressed on or after standard systemic therapy. Patients will receive zipalertinib at a starting dose of 100 mg orally twice daily, which will continue on a 21-day cycle until progression, unacceptable toxicity, or other discontinuation criteria are met. The primary endpoint is investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumours, version 1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, intracranial efficacy per Response Assessment in Neuro-Oncology Brain Metastases (cohort C), safety and tolerability, and pharmacokinetics. Estimated enrollment is 40 patients per cohort (total 160), with potential expansion to ~100 patients per cohort if predefined threshold criteria of efficacy are met. Enrollment began in July 2023. Clinical trial information: NCT05967689 .

Efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, and pembrolizumab in patients with immune checkpoint inhibitor-naive unresectable or metastatic melanoma: Updated results from IOV-COM-202 cohort 1A.

9505 Background: Immune checkpoint inhibitors (ICI) are front-line standard-of-care treatment (tx) for advanced (unresectable or metastatic) melanoma. Despite recent advances in front-line tx, a majority of patients (pts) do not achieve long-term benefit. Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, potentially induces durable responses in pts with advanced melanoma previously treated with ICI. This study evaluates lifileucel combined with anti-PD-1 therapy in front-line advanced melanoma. Methods: IOV-COM-202 (NCT03645928) Cohort 1A assesses the efficacy and safety of lifileucel and pembrolizumab (pembro) in pts with ICI-naive unresectable or metastatic melanoma. Pts may have received BRAF/MEK inhibitor tx if BRAF mutation-positive. Eligible pts must have ≥1 resectable lesion (≥1.5 cm diameter) for 22-day cryopreserved lifileucel manufacturing, and ≥1 measurable lesion for response assessment per RECIST v1.1. The tx regimen consists of pembro, nonmyeloablative lymphodepletion (cyclophosphamide and fludarabine), a single lifileucel infusion (1 × 109 – 150 × 109 cells), ≤6 doses of IL-2 (600,000 IU/kg IV), and continued pembro until disease progression, or unacceptable toxicity for ≤24 months. The endpoints are investigator-assessed objective response rate (ORR) and incidence of grade ≥3 treatment-emergent adverse events (TEAE). Results: As of 22-Dec-2023, 22 pts with a median (range) age of 48.5 (18–68) years received lifileucel and pembro. At baseline, the median (range) target lesion sum of diameters was 54.5 (14–355) mm; 7 (31.8%) pts had liver lesions. Metastatic staging at study entry was as follows: 4 (18.2%) had M1a, 2 (9.1%) had M1b, 10 (45.5%) had M1c, and 2 (9.1%) had M1d. Eight (36.4%) pts had V600 BRAF mutations; 3 (13.6%) pts had prior BRAF/MEK inhibitor tx. Confirmed ORR was 63.6% (14/22), including 22.7% (5/22) CR and 40.9% (9/22) PR; 6 pts (27.3%) had SD. Median time to initial response was 2.5 months. All response evaluable pts demonstrated regression of target lesions. At a median follow-up of 17.2 months, median duration of response was not reached. Responses deepened over time; 10/14 (71.4%) pts had ongoing response and 8/14 (36.4%) pts had response ≥12 months. TEAEs were consistent with the underlying disease and known safety profiles of pembro, nonmyeloablative lymphodepletion, and IL-2. Most common grade ≥3 TEAEs were thrombocytopenia (68.2%), neutropenia (50.0%), and anemia (45.5%). Conclusions: These results demonstrate encouraging efficacy and durability for the combination of lifileucel and pembro and support its further evaluation in pts with untreated advanced melanoma in the phase 3 study TILVANCE-301 (NCT05727904). Clinical trial information: NCT03645928 .

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 .