Modified RECIST V1 Research Articles

Updated results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine cancers (NEC).

8090 Background: Delta-like canonical Notch ligand 3 (DLL3) is highly expressed on the cell surface of neuroendocrine carcinomas, which have few approved treatment options in the refractory, metastatic setting. HPN328 is DLL3-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. Methods: Pts with relapsed/refractory, metastatic SCLC, neuroendocrine prostate cancer (NEPC) and other NEC associated with DLL3 expression are eligible. Primary objectives are safety, maximum tolerated dose (MTD) and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. Overall response rate (ORR) is determined using modified RECIST v1.1 to include extracranial response assessment for pts treated with radiotherapy for brain metastases while on treatment. HPN328 is administered IV QW or Q2W with priming dose preceding target dose in higher dose cohorts. Results: As of January 5, 2024, 86 pts received HPN328 doses of 0.015-24 mg across 14 cohorts (SCLC [n = 54;63%]; other NEC [n = 32;37%]). The median (range) number of prior regimens was 3 (1-7); 83% previously received a PD-1/PD-L1 blocker. Treatment is ongoing in 24 of 46 (52%) pts in the dose optimization cohorts (1 mg priming dose with 12 or 24 mg target doses QW or Q2W). Treatment-related AEs in ≥ 10% of pts included CRS (59% [30% G1, 26% G2, 3% G3+]), dysgeusia (36%), fatigue (34%), diarrhea (19%), nausea (17%), vomiting (14%), decreased appetite and decreased neutrophil count (13% each), and weight decreased (11%). No G3-4 CRS was seen at target doses. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9% of pts, all G1-2. The maximum tolerated priming dose was 1 mg; dose escalation of target dose continued up to 24 mg QW without reaching a maximum tolerated target dose. Among efficacy evaluable pts treated in dose optimization cohorts, the confirmed ORR in SCLC was 50% (12/24), with one complete response (CR). In NEC (other than NEPC) the confirmed ORR was 44% (4/9), with one CR. Four of eleven pts with NEPC had unconfirmed PRs in 1 mg priming dose cohorts, with 5 NEPC pts remaining on treatment > 20 weeks. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active in SCLC, NEC, and NEPC. Current dose optimization cohorts have completed enrollment and data continue to mature; selection of a recommended phase 2 dose will be made based upon complete mature data. Updated safety and efficacy results will be presented. Clinical trial information: NCT04471727 .

Safety, efficacy, and biomarker results from an open-label, multicenter, phase 1 study of RP2 alone or combined with nivolumab in a cohort of patients with uveal melanoma.

9511 Background: Uveal melanoma is the most common primary intraocular tumor in adults and has a high risk of liver metastasis. Effective treatments for metastatic uveal melanoma (MUM) are limited, as MUM responds poorly to immune checkpoint inhibition. RP2 is an enhanced-potency oncolytic HSV-1–expressing human GM-CSF, a fusogenic glycoprotein (GALV-GP-R−), and an anti–CTLA-4 antibody-like molecule. We present safety, efficacy, and biomarker data for RP2 monotherapy and RP2 +nivolumab (nivo; anti–PD-1) in patients (pts) with MUM (NCT04336241). Methods: Pts ≥18 years old with advanced or metastatic non-neurologic solid tumors (including MUM) who progressed on, or could not tolerate, standard therapy were included in the clinical trial; pts had ≥1 measurable and injectable tumor (≥1 cm). After determination of the recommended phase 2 dose of intratumoral RP2 (1×106 PFU/mL once, then ≤7 doses at 1×107 PFU/mL; ≤10 mL total/treatment day), pts received RP2 Q2W as monotherapy or in addition to nivo (240 mg Q2W/480 mg Q4W). Responses were assessed per modified RECIST v1.1.Tumor biopsies and peripheral blood mononuclear cells were collected pre-treatment and at day 43 and were analyzed by immunohistochemistry (IHC) and/or sequencing of the CDR3β region of the T-cell receptor (TCR) by immunoSEQ. Results: A total of 17 pts with MUM were enrolled (RP2 monotherapy, n = 3; RP2 + nivo, n = 14). Most pts had received both anti–PD-1 and anti–CTLA-4 therapy (12/17 [70.6%]), and 3/17 (17.6%) had received ≥3 prior lines of therapy. The ORR was 29.4% (5/17; all PRs; RP2 monotherapy, 1/3; RP2 + nivo, 4/14). The DCR (CR + PR + SD) was 58.8% (10/17). The median (range) duration of response at the data cutoff was 11.5 (2.8–21.2) months, with some responses and disease stabilizations ongoing. The most common overall grade 1–2 treatment-related AEs (TRAEs; ≥20% overall) were pyrexia, chills, fatigue, hypotension, and pruritus. The only grade 3 TRAE in > 1 pt was hypotension (2 pts receiving RP2 + nivo); no grade 4/5 TRAEs occurred. Evaluable baseline and post-treatment biopsies were used for IHC (n = 8) and TCR sequencing analyses. Paired biopsies from pts with clinical benefit (n = 5; 2 PR, 3 SD) showed an increase in tumor PD-L1 expression by IHC analysis, and 4 of these pts (2 PR, 2 SD) exhibited an increase in CD8+ T-cell infiltration into tumors. TCR sequencing following treatment with RP2 + nivo revealed expansion of pre-existing TCRs and generation of new T-cell clones. Conclusions: RP2 alone or combined with nivo demonstrated a favorable safety profile and meaningful antitumor activity in pts with previously treated MUM. Biomarker data indicated immune cell infiltration and increased PD-L1 expression in tumors and changes in the peripheral T-cell repertoire following RP2 ± nivo therapy. Based on these results, a randomized, controlled clinical development plan is being planned. Clinical trial information: NCT04336241 .

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.

Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09).

8084 Background: Transforming growth factor β (TGF-β) is involved in tumor immune evasion and epithelial–mesenchymal transition (EMT). As TGF-β upregulation and EMT are associated with resistance to anti-PD1 therapy, we evaluated the efficacy of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in malignant pleural mesothelioma (MPM). Methods: Patients with advanced MPM who were previously treated with platinum-based chemotherapy were enrolled and received bintrafusp alfa 1200mg/m2 every 2 weeks until progression or for a maximum of two years. The primary objective was to determine the progression-free survival (PFS) by modified RECIST v1.1. assessed by the investigators. The expected median PFS was 4.5 months. Secondary objectives were overall response rate, duration of response, overall survival (OS) and safety. Results: Between October 2021 to March 2023, 47 patients were enrolled. Mean age was 70 years (41-84) and 36 (78.3%) were males. Most patients had epithelioid histology (82.9%) and had received only 1 prior line of therapy (84.8%). With a median follow-up of 11.5 months, 43 patients had disease progression and 24 patients died. The median number of doses administered was 4 (1-21) and reasons for treatment discontinuation were disease progression (82.6%), toxicity (6.5%), investigator decision (4.4%) and death (6.5%) by tumor progression. The median PFS was 1.9 months (95% CI 1.7 – 5.4) and the 6 month-PFS rate was 15.9%. Disease control rate was 34.8% (95% CI 22.2-49.9) consisting of 2 patients with partial response and 13 patients with stable disease as best response. The median OS was 11.9 months (95% CI 4.4 – not reached) and 6, 12 and 18-month OS rate was 65.3%, 46.5% and 26.6%, respectively. No significant differences in OS and PFS were observed based on MPM histological subtype. Grade 3-4 treatment-related adverse events occurred in 16 (34%) patients, anemia being the most common (n = 5); skin toxicity (n = 3); colitis (n = 2); adrenal insufficiency, acute kidney injury, allergic reaction, lipase, and amylase increased (n = 1 each). Conclusions: Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy. Clinical trial information: NCT05005429 .

RTID-06. THE PIVOTAL METIS (EF-25) STUDY OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC) FOLLOWING RADIOSURGERY

Abstract INTRODUCTION: TTFields are electric fields that disrupt processes necessary for cancer cell survival and can stimulate an antitumor immune response in preclinical NSCLC models. TTFields therapy is a noninvasive and locoregional treatment approved for glioblastoma, which has recently demonstrated a survival benefit when applied to the thorax with standard of care (SOC) systemic therapy in patients with metastatic NSCLC that progressed on/after platinum. Here we describe the pivotal METIS study (EF-25, NCT02831959) evaluating the efficacy and safety of TTFields therapy applied to brain metastases from NSCLC. TRIAL DESIGN: Patients (270) with 1–10 brain metastases from NSCLC will receive stereotactic radiosurgery (SRS), followed by 1:1 randomization to TTFields (NovoTTF-200M [150 kHz] applied to the head ≥ 18 h/day) with best SOC, or best SOC alone. Key inclusion criteria are life expectancy ≥ 3 months, a new diagnosis of 1 inoperable or 2–10 supra and/or infratentorial brain metastases from NSCLC, that are amenable to SRS. Patients who had prior whole brain radiotherapy, or have single operable, leptomeningeal, or recurrent brain metastases, certain genetic mutations, or severe comorbidities or contraindications, are not eligible. The primary endpoint is time to first intracranial progression. Secondary endpoints include time to neurocognitive failure, overall survival, radiological response rate, time to second intracranial progression, time to first/second intracranial progression by modified RECIST v1.1, rate of intracranial progression, time to distant progression, rate of cognitive decline, quality of life, neurocognitive failure-free survival, and safety. The study is powered at 80% (2-sided alpha of 0.05) to detect a hazard ratio of 0.57. In July 2021, an independent Data Monitoring Committee reviewed the study data and recommended continuation. The study includes 128 sites in Europe, Israel, mainland China, North America, and Hong Kong. The final patient was enrolled in March 2023.

Safety, pharmacokinetics (PK), and clinical activity of bezuclastinib + sunitinib in previously-treated gastrointestinal stromal tumor (GIST): Results from part 1 of the phase 3 Peak study.

11537 Background: Patients with GIST often relapse after first line therapy with imatinib due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct and complementary, when combined they inhibit a broad spectrum of secondary KIT mutations. In a prior Phase 1b/2a study (NCT02401815), the combination of the original formulation (Form. A) of bezuclastinib + sunitinib had an acceptable safety profile and was associated with clinical activity at the RP2D (Wagner, JAMA Oncol 2021;7(9):1343-50). An optimized formulation (Form. B) of bezuclastinib with improved bioavailability was developed to reduce pill burden for GIST pts. PK and safety results from the Part 1a lead-in of Peak (NCT05208047) have been previously presented (Wagner, CTOS 2022, P320). Herein we intend to report comprehensive clinical results from Part 1a including duration of therapy, initial response assessment and updated safety. Methods: Peak, a randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in pts with imatinib-resistant or intolerant GIST. In Part 1a of the 3-part study, bezuclastinib (Form. B) dosing was escalated in serial cohorts based on PK results until the target exposure, comparable to those achieved at the RP2D established in the Phase 1b/2a study, was achieved. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Results: Part 1a enrolled 19 pts. Five pts (Cohort 1) received the starting dose of once daily (QD) bezuclastinib 300 mg+ sunitinib 37.5 mg; dose was escalated to 600 mg with 14 pts receiving bezuclastinib 600 mg + sunitinib 37.5 mg. Median age - 60 yrs (range: 42-77); 68% male; 95% ECOG PS 0-1; 95% metastatic and 5% locally advanced. As of Sept 2022 data cutoff, the median (range) treatment duration was 6 weeks (3.1, 23.9). Due to AEs, one pt required dose reduction of bezuclastinib (Gr 3 diarrhea) and 1 pt discontinued (Gr 2 rash). The majority of TEAEs were low grade, with no ≥ Gr4. Most common TRAEs were diarrhea (37%), neutropenia (37%), ALT (32%) and AST (26%) increases. One pt experienced SAEs of Gr 2 neutropenia and pyrexia and Gr 3 thrombocytopenia. Steady state exposure in pts receiving QD doses of bezuclastinib 600 mg + sunitinib 37.5 mg in this study were similar to that at the RP2D established in the prior Phase 1b/2a study. Conclusions: Initial data from Peak shows an encouraging safety and tolerability profile with no unique safety signals when compared to the known safety profile for sunitinib monotherapy. A dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was confirmed for use in Peak study Part 2, for which enrollment is ongoing. Updated data from Part 1a, including response data, will be presented. Clinical trial information: NCT05208047 .

A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases.

TPS745 Background: A SEER analysis from 2010 to 2013 demonstrated that the incidence of brain metastases(mets) at the diagnosis of renal cell carcinoma(RCC) is 1.51%, and around 12% of patients(pts) with advanced RCC (aRCC) also had mets to the brain. Brain mets confer a poor prognosis. Local management strategies for brain mets from RCC include surgical resection, stereotactic radiosurgery and whole brain radiation therapy. Although systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is a potent small molecule inhibitor of multiple tyrosine kinases that was approved by FDA for pts with aRCC alone or in combination with nivolumab. Cabozantinib has demonstrated activity in patients with intracranial tumors. A phase III trial (COSMIC-313) recently evaluated cabozantinib in combination with nivolumab and ipilimumab compared to nivolumab plus ipilimumab and demonstrated significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. The combination was found to be safe as frontline systemic treatment. The role of this combination in patients with aRCC with brain mets remains undefined. As such, we propose a study to assess the safety and efficacy of cabozantinib in combination with nivolumab/ipilimumab in RCC pts with untreated brain mets. We believe the results from this trial could provide additional treatment options for pts with RCC brain mets who are typically excluded from clinical trials. Methods: This is a phase II study to assess the safety and efficacy of the combination of nivolumab with ipilimumab and cabozantinib in pts with untreated brain mets from RCC until disease progression or intolerable toxicities or patient withdrawal. Planned accrual is 40 pts. Pts will be treated with nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily. Then pts will be treated with nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until progression or intolerable toxicities or patient’s withdrawal. A lead-in group of 6 pts will be closely monitored for dose limiting toxicities(DLT). If stopping criteria (>3 patients develop DLTs) is met, then treatment will be switched to nivolumab plus cabozantinib omitting ipilimumab. The primary objective is intracranial progression free survival(PFS). Secondary objectives include intracranial safety, objective response rate (intracranial + extracranial) by modified RECIST v1.1 and RECIST v1.1, extracranial PFS and overall survival. This phase II trial is currently enrolling pts. Clinical trial information: NCT05048212 .

A randomized Phase III trial of durvalumab with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib in newly diagnosed advanced ovarian cancer (DUO-O): Updated trial endpoint and inclusion of China cohort (329)

Objectives: Maintenance therapy with the PARP inhibitor olaparib (with or without the antiangiogenic agent bevacizumab) leads to significant progression-free survival (PFS) benefits in patients with newly diagnosed advanced ovarian cancer (OC) (with or without a BRCA’ and/or BRCA2 mutation [BRCAm]) (Moore et al. N Eng J Med 2018; Ray-Coquard et al. N Eng J Med 2019). Preclinical data have shown a potential synergistic antitumor effect when combining an immune checkpoint inhibitor with an antiangiogenic agent and a PARP inhibitor. The combination has shown promise as a treatment in platinum-sensitive relapsed non-germline BRCAm OC patients (Drew et al. ESMO 2020). The Phase III DUO-O trial (NCT03737643) began global enrollment in January 2019 and will evaluate the efficacy and safety of combinations of the standard of care platinumbased chemotherapy, bevacizumab, and the anti-PD-L1 antibody durvalumab, followed by maintenance bevacizumab, durvalumab, and olaparib in patients with newly diagnosed advanced OC (Harter et al. ASCO 2019). The China cohort will evaluate these combinations in a standalone analysis of patients with non-BRCAm tumors. Methods: Eligible patients must have newly diagnosed stage III or IV high-grade ovarian, epithelial, fallopian, or primary peritoneal cancer and have undergone upfront primary surgery or be planned to have interval debulking surgery. From sites in China, ~120 patients with a non-BRCAm tumor (using a China-based central laboratory to determine BRCAm status) will be randomized 1:1:1 to: chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + olaparib maintenance; chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + placebo maintenance; or chemotherapy + bevacizumab + placebo, followed by bevacizumab + placebo. Olaparib (300 mg bid) and durvalumab (1120 mg q3w) will be administered for up to 24 months, and bevacizumab (15 mg/kg q3w) for up to 15 months, or until disease progression. The primary endpoints are investigator-assessed PFS (modified RECIST v1.1) in all patients with a non-BRCA tumor and patients with a non-BRCA, homologous recombination deficiency-positive tumor. A key secondary efficacy endpoint is overall survival, and safety will be summarized descriptively. Local China protocol amendments are in progress, and relevant updates will be presented. Enrollment in China began in April 2021. Objectives: Maintenance therapy with the PARP inhibitor olaparib (with or without the antiangiogenic agent bevacizumab) leads to significant progression-free survival (PFS) benefits in patients with newly diagnosed advanced ovarian cancer (OC) (with or without a BRCA’ and/or BRCA2 mutation [BRCAm]) (Moore et al. N Eng J Med 2018; Ray-Coquard et al. N Eng J Med 2019). Preclinical data have shown a potential synergistic antitumor effect when combining an immune checkpoint inhibitor with an antiangiogenic agent and a PARP inhibitor. The combination has shown promise as a treatment in platinum-sensitive relapsed non-germline BRCAm OC patients (Drew et al. ESMO 2020). The Phase III DUO-O trial (NCT03737643) began global enrollment in January 2019 and will evaluate the efficacy and safety of combinations of the standard of care platinumbased chemotherapy, bevacizumab, and the anti-PD-L1 antibody durvalumab, followed by maintenance bevacizumab, durvalumab, and olaparib in patients with newly diagnosed advanced OC (Harter et al. ASCO 2019). The China cohort will evaluate these combinations in a standalone analysis of patients with non-BRCAm tumors. Methods: Eligible patients must have newly diagnosed stage III or IV high-grade ovarian, epithelial, fallopian, or primary peritoneal cancer and have undergone upfront primary surgery or be planned to have interval debulking surgery. From sites in China, ~120 patients with a non-BRCAm tumor (using a China-based central laboratory to determine BRCAm status) will be randomized 1:1:1 to: chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + olaparib maintenance; chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + placebo maintenance; or chemotherapy + bevacizumab + placebo, followed by bevacizumab + placebo. Olaparib (300 mg bid) and durvalumab (1120 mg q3w) will be administered for up to 24 months, and bevacizumab (15 mg/kg q3w) for up to 15 months, or until disease progression. The primary endpoints are investigator-assessed PFS (modified RECIST v1.1) in all patients with a non-BRCA tumor and patients with a non-BRCA, homologous recombination deficiency-positive tumor. A key secondary efficacy endpoint is overall survival, and safety will be summarized descriptively. Local China protocol amendments are in progress, and relevant updates will be presented. Enrollment in China began in April 2021.

Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

Pembrolizumab Plus Docetaxel and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort B Study

BackgroundPatients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments. ObjectiveTo evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC. Design, setting, and participantsThe trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening. InterventionPembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/m2 IV Q3W, and prednisone 5 mg orally twice daily. Outcome measurements and statistical analysisThe primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the 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 time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and overall survival (OS). Results and limitationsAmong 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3–5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size. ConclusionsPembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted. Patient summaryWe evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population.This trial is registered on ClinicalTrials.gov as NCT02861573.

Phase 2 LEAP-009: Lenvatinib (Lenva) With or Without Pembrolizumab (Pembro) vs. Chemotherapy (Chemo) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) That has Progressed on Platinum and Immunotherapy

<h3>Purpose/Objective(s)</h3> Pembro monotherapy and pembro plus platinum-based chemo are now standard-of-care options for the first-line treatment of R/M HNSCC. However, the optimal second-line regimen for R/M HNSCC that has progressed on or after immunotherapy or platinum-based chemo remains unclear. Pembro given in combination with the multikinase inhibitor lenva showed promising antitumor activity and acceptable safety in patients with metastatic HNSCC in the phase 1b/2 Study 111/KEYNOTE-146 trial. The open-label, randomized, phase 2 LEAP-009 (NCT04428151) study is designed to investigate the efficacy and safety of lenva ± pembro versus SOC chemo in patients with R/M HNSCC that has progressed after platinum-based chemo and a PD-1/PD-L1 inhibitor. <h3>Materials/Methods</h3> Key eligibility criteria include age ≥18 years; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; disease incurable by local therapy; measurable disease per RECIST v1.1 by BICR; ECOG performance status of 0 or 1; and no major blood vessel invasion/infiltration. Patients must have had disease progression on or after platinum-containing chemo ± cetuximab and have had disease progression on a PD-1/PD-L1 inhibitor (progression within 12 weeks of the last dose; must have received ≥2 doses). Patients will be randomly allocated 3:3:2 to lenva 20 mg PO QD + pembro 200 mg IV Q3W (≤35 pembro cycles), investigator's choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine), or lenva monotherapy 24 mg PO QD. Treatment will continue until centrally verified disease progression, unacceptable toxicity, or withdrawal from study. Randomization will be stratified by PD-L1 tumor proportion score (<50% vs ≥50%) and ECOG performance status (0 vs 1). Patients with disease progression in the chemo or lenva monotherapy arms may be eligible to cross over to pembro + lenva. The primary end point is ORR per modified RECIST v1.1 by BICR. Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. Imaging by CT or MRI will be performed every 6 weeks through year 1 and every 9 weeks thereafter. Safety will be monitored throughout the study and for 30 days after treatment end (90 days for serious AEs unless new anticancer treatment is initiated). An interim futility analysis will be conducted for the lenva monotherapy arm. Estimated enrollment is 400 patients. Recruitment is currently underway. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

KEYNOTE-365 cohorts E and F: Phase 1b/2 study of pembrolizumab + lenvatinib combination therapy in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC (t-NE).

TPS215 Background: Standard of care for noncurative adenocarcinoma mCRPC is docetaxel or the next-generation hormonal agents (NHAs) abiraterone and enzalutamide. However, approximately 20% of patients develop t-NE after treatment for adenocarcinoma mCRPC; t-NE is associated with shorter survival, and it has no standard of care beyond combination platinum chemotherapy. The vascular endothelial growth factor (VEGF)/fibroblast growth factor receptor (FGFR) inhibitor lenvatinib inhibits proliferation and angiogenesis in preclinical models of adenocarcinoma prostate cancer. The phase 2 KEYNOTE-199 trial showed some antitumor activity with pembrolizumab monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC. VEGF/FGFR inhibition combined with PD-1 inhibition may have enhanced benefit in mCRPC, for adenocarcinoma and possibly as a new treatment option for t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate different pembrolizumab combination therapies in several patient populations with mCRPC. Cohort E will enroll patients with confirmed adenocarcinoma of the prostate without small cell histology, per investigator. Cohort F will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort F requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within &lt; 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score of 0 or 1. Both cohorts will receive pembrolizumab 200 mg IV every 3 weeks + oral lenvatinib 20 mg once daily until disease progression, withdrawal of consent, prespecified alanine aminotransaminase or aspartate aminotransaminase level increase, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.

KEYNOTE-365 cohorts G and H: Phase 1b/2 study of pembrolizumab + vibostolimab combination therapy in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC (t-NE).

TPS204 Background: Treatment options are limited for patients with mCRPC that progresses after treatment with next-generation hormonal agents (NHAs)—such as enzalutamide and abiraterone acetate—or docetaxel. Approximately 20% of patients with adenocarcinoma mCRPC that progresses on androgen deprivation therapy develop t-NE mCRPC, which is associated with shortened overall survival (OS). The PD-1 inhibitor pembrolizumab showed antitumor activity as monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC in the phase 2 KEYNOTE-199 trial. The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor vibostolimab showed antitumor activity when combined with pembrolizumab in pretreated patients with several tumor types in a phase 1 dose-escalation study. Combining PD-1 and TIGIT inhibition might have enhanced benefit in mCRPC, potentially both adenocarcinoma and t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate the efficacy and safety of several pembrolizumab combination therapies in patients with mCRPC. Patients enrolled in cohort G will have confirmed adenocarcinoma of the prostate without small cell histology, per the investigator. Cohort H will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Enrollment in cohort H requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within &lt; 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score 0 or 1. Both cohorts will receive MK-7684A, a coformulation of pembrolizumab 200 mg and vibostolimab 200 mg, IV every 3 weeks. Treatment will continue until disease progression, withdrawal of consent, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and OS. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.

KEYNOTE-365 cohort I: Phase 1b/2 study of pembrolizumab combined with platinum-containing chemotherapy and chemotherapy alone for treatment-emergent neuroendocrine prostate carcinoma (t-NE).

TPS218 Background: In previously treated adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC), approximately 20% of patients develop t-NE PC, which is aggressive with short overall survival (OS). t-NE PC treatment includes platinum-containing chemotherapy because of t-NE’s histologic, biologic, and clinical similarity to small cell/NE lung cancer. In the open-label, multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573), pembrolizumab, when combined with several agents for treatment of adenocarcinoma mCRPC, showed clinical activity and acceptable safety. To identify new treatment options for t-NE mCRPC, cohort I will help to evaluate platinum-containing chemotherapy alone or combined with pembrolizumab for patients with t-NE. Methods: Cohort I of the KEYNOTE-365 study will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) and prior docetaxel treatment for mCRPC. Prior treatment with ≤2 next-generation hormonal agents (NHAs) for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort I requires previous prostate cancer progression within 6 months of starting an NHA (mHSPC or mCRPC) and within &lt; 6 cycles of docetaxel for mCRPC. Each arm will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Eligible patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2). Pembrolizumab treatment will continue for up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG PS score (0 vs 1). Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; duration of response (DOR) and disease control rate (DCR) per RECIST v1.1 by BICR; ORR, DOR, DCR, and radiographic progression-free survival per Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and OS. End points will be summarized for each arm without formal hypothesis testing. This cohort of KEYNOTE-365 is enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.

CA209-8YD: A phase I/II trial of rucaparib in combination with ramucirumab with or without nivolumab in previously treated advanced gastroesophageal adenocarcinoma (GEA) (RiME).

TPS377 Background: GEA is one of the leading causes of cancer-related deaths worldwide and in the US. In chemo refractory GEA, therapeutic options are limited with modest efficacy. About 35% of GC have DNA damage response (DDR) gene alterations and PARP inhibitors have shown to induce synthetic lethality and reduce tumor burden in in vitro and in vivo models of GEA. DDR deficient tumors have increased tumor mutational load, tumor infiltrating lymphocytes, and increased chemokines and PD-L1 expression in the tumor microenvironment. PARP inhibitors like rucaparib enhance antigen presentation, induce pro-inflammatory cytokines, influence PD-1/PD-L1 expression, and modulate T- and B- cell activity. Furthermore, results from multiple GEA early phase trials have supported the immune modulatory impact of VEGF targeted agents like ramucirumab. We hypothesize that modulation of the tumor microenvironment via PARP and VEGF inhibition will enhance anti-tumor immunity and lead to clinical synergy when combined with immune checkpoint inhibitors like nivolumab in this population. Methods: A safety lead in phase of 6-9 patients will be followed by an open label, two parallel cohorts phase II study. A total of 52 patients (26 in each cohort) will be enrolled. A starting rucaparib dose of 600 mg BID in combination with the standard doses of ramucirumab and flat doses of nivolumab will be used for the safety lead in. Rucaparib dose will be lowered for phase II if &gt; 1/6 patients experienced DLTs. Participants enrolled to cohort A will receive rucaparib at the recommended phase II dose (RP2D) PO twice daily + ramucirumab 8mg/kg IV q2w + nivolumab 480mg IV q4w (28-day cycles). Participants in cohort B will receive rucaparib at RP2D PO twice daily + ramucirumab 8mg/kg IV q2w (28-day cycles). Assessment of tumor response using modified RECIST v1.1 will be done every 2 cycles. 50% of Pts who will be enrolled in each of the 2 cohorts must have a deleterious tumor gene alteration in at least 1 gene in a screening 17-gene homologous recombination deficient (HRD) panel. Eligible Pts received ≥1 line of therapy, ECOG PS 0-1, adequate organ function, no prior PARP inhibitors, and have mismatch repair (MMR) proficient tumors with measurable disease. Primary objectives are to determine the RP2D and overall response rate (ORR) in phase I and II respectively. Secondary objectives include safety, overall benefit rate (OBR), median PFS, OS, and ORR in HRD positive and negative cohorts. Enrollment to the RiME trial is currently ongoing. The study is funded by research grants from Bristol Myers Squibb and Clovis. Clinical trial information: NCT03995017.

RECIST/CA-125 progression-free survival and the role of CA-125 surveillance in the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian carcinoma

<h3>Objectives:</h3> In the PAOLA-1/ENGOT-ov25 primary analysis (NCT02477644), adding the PARP inhibitor olaparib to maintenance bevacizumab (bev) after first-line platinum-based chemotherapy with bev led to a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with advanced high-grade ovarian cancer (HGOC), using modified RECIST v1.1 criteria (HR 0.59; 95% CI 0.49-0.72; <i>P</i><0.001; median PFS 22.1 vs 16.6 months) (Ray-Coquard <i>et al. NEJM</i> 2019). Limited evidence supports use of serum CA-125, a surrogate biomarker for progression, to detect relapse in pts receiving PARP inhibitor maintenance therapy. We evaluated RECIST/CA-125 progression and CA-125 surveillance in PAOLA-1. <h3>Methods:</h3> Pts with newly diagnosed, FIGO stage III-IV HGOC in response after platinum-based chemotherapy plus bev received bev (15 mg/kg q3w for 15 months) + olaparib (300 mg bid for 24 months) or pbo. Scans were performed every 24 weeks, or every 12 weeks if there was evidence of clinical or CA-125 progression. CA-125 levels were assessed every 12 weeks. Time to RECIST or CA-125 progression or death was a secondary endpoint; RECIST/CA-125 progression by biomarker status, response to initial therapy and CA-125 level at baseline were explored. <h3>Results:</h3> 537 pts were randomized to olaparib + bev and 269 to pbo + bev with median follow-up for PFS by RECIST/CA-125 of 24.2 vs 24.7 months (DCO 22 March 2019). In the ITT population, the benefit provided by olaparib + bev vs pbo + bev for PFS by RECIST/CA-125 (HR 0.58; 95% CI 0.48-0.70; <i>P</i><0.0001; median PFS 22.1 vs 15.4 months) was consistent with the primary analysis of PFS by RECIST. Of 462 pts with RECIST progression (ITT), 39% had RECIST progression alone and 45% had CA-125 progression more than 7 days before RECIST progression, with a median 2.4 months between CA-125 and RECIST progression (Table). In subgroup analyses, 49% of t<i>BRCA</i>m pts and 45% of HRD-positive pts had RECIST progression alone compared with only 37% of HRD-negative pts. 42% of pts with NED or CR had RECIST progression alone compared with 33% of pts with PR. 44% of pts with normal baseline CA-125 levels had RECIST progression alone compared with only 17% of pts with abnormal baseline CA-125 levels (<i>P</i><0.001). The rate of PFS events by RECIST/CA-125 was higher for pbo + bev vs olaparib + bev (74% vs 53%) (ITT). Of pts with RECIST progression, a similar proportion in each treatment arm had RECIST progression alone, including in subgroup analyses by biomarker status and response to initial therapy. <h3>Conclusions:</h3> Median PFS and HRs were consistent when progression was assessed by either RECIST or RECIST/CA-125 in PAOLA-1. Scans appear particularly important for detecting progression in HRD-positive pts, t<i>BRCA</i>m pts or pts with normal CA-125 levels at baseline as CA-125 levels did not seem to predict relapse in these pts. Results suggest that CA-125 surveillance alone may be sufficient to detect progression in most pts with abnormal baseline CA-125 levels when starting maintenance therapy.

Maintenance olaparib for patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1

<h3>Objectives:</h3> Newly diagnosed advanced ovarian cancer patients (pts) are at high risk of relapse and 5-year survival is 30–50%. Delay of recurrence, prolonged survival and, for some pts, increased chance of cure are goals of treatment in this setting. In SOLO1 (NCT01844986; GOG-3004) pts with advanced ovarian cancer and a <i>BRCA1</i> and/or <i>BRCA2</i> mutation (BRCAm) who were in response after first-line platinum-based chemotherapy derived significant progression-free survival (PFS) benefit from maintenance olaparib vs placebo (median 41 months follow-up; median not reached vs 13.8 months; hazard ratio 0.30; <i>P</i><.001; Moore <i>et al. NEJM</i> 2018). We report analyses after 5-years of follow-up (data cut-off [DCO]: March 5, 2020), performed to assess the long-term efficacy and tolerability of maintenance olaparib for newly diagnosed advanced ovarian cancer. <h3>Methods:</h3> Pts received maintenance olaparib (tablets; 300 mg bid) or placebo for up to 2 years or until progression. PFS and recurrence-free survival (RFS) were investigator-assessed by modified RECIST v1.1. An exploratory subgroup analysis of PFS in higher-risk (stage IV disease, stage III disease with residual disease following primary debulking surgery, inoperable stage III disease, or stage III disease and had undergone interval surgery) and lower-risk (stage III disease without residual disease following primary debulking surgery) pts was carried out. For pts in complete response at baseline, RFS was defined <i>post hoc</i> as time from randomization to disease recurrence (new lesions by imaging) or death. <h3>Results:</h3> A total of 260 pts were randomized to olaparib; 131 to placebo (median treatment duration 24.6 vs 13.9 months, respectively). After a median of 4.8 and 5.0 years of follow-up, median PFS was 56 vs 14 months in the olaparib and placebo arms, respectively (Table). In the higher-risk subgroup 42% of olaparib-arm vs 17% of placebo-arm pts were free from progression at 5 years; in the lower-risk subgroup 56% vs 25% of pts, respectively, were progression free at this time point. Among pts in complete response at baseline, risk of disease recurrence or death was reduced by 63%. The safety profile of olaparib was consistent with previous observations. No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported (previous DCO: olaparib, 3/260 [1%]; placebo, 0/130), and incidence of new primary malignancies remained balanced between arms (olaparib, 7/260 [3%]; placebo, 5/130 [4%]). <h3>Conclusions:</h3> For pts with a <i>BRCA</i>m and newly diagnosed advanced ovarian cancer, the benefit derived from 2 years of maintenance olaparib was sustained beyond the end of treatment, and after 5 years, almost half of pts were progression free vs 20% with placebo. This benefit was consistent across higher- and lower-risk pts. Over 50% of pts in complete response after first-line platinum-based chemotherapy remained free from relapse 5 years after randomization. A total of 5 years of follow-up is the longest for any PARP inhibitor in this setting and no new safety signals were observed.

Randomized phase II trial of durvalumab (anti-PDL1) and tremelimumab (anti-CTLA4) administered in combination versus sequentially for the treatment of recurrent platinum-resistant non-clear cell ovarian cancer (NCT03026062)

<h3>Objectives:</h3> Single agent immune checkpoint blockade (ICB) has demonstrated response rates of 5-15% in patients with recurrent high-grade ovarian cancer (HGOC), with another 15-40% of patients achieving stable disease. Combination ICB using ipilimumab and nivolumab resulted in improved response rates in a mixed population with platinum resistant and sensitive disease. The objective of the current trial was to evaluate sequential versus combination CTLA4 and PDL1 blockade strategies for extending progression free survival (PFS) in patients with platinum resistant/refractory HGOC. <h3>Methods:</h3> Patients were required to have pathologically confirmed platinum resistant or refractory epithelial ovarian cancer, no prior immunotherapy, and PS=0-1 for enrollment. The current abstract includes data only on subjects with high grade serous ovarian cancer (HGSOC), as enrollment of patients with clear cell histology is still ongoing. The primary endpoint was PFS and response was assessed using modified RECIST v1.1. Unlimited numbers of prior regimens were allowed. Patients were adaptively randomized to sequential arm: tremelimumab (3mg/kg q4 weeks x 4 doses) followed by durvalumab (1.5g IV q4 weeks for up to 9 doses) upon progression, or the combination arm: tremelimumab (1mg/kg IV plus durvalumab 1.5g IV q4wk for up to 4 doses followed by durvalumab monotherapy for up to 9 doses). For the Bayesian adaptive randomization, the probability of being assigned to an arm was proportional to the likelihood the arm had better PFS, such that patients were more likely to be randomized to the more effective arm. <h3>Results:</h3> A total of 61 subjects were adaptively randomized to sequential treatment (n=38) or combination therapy (n=23). 46 (79%) patients had wild-type breast cancer gene (<i>BRCA</i>). Median prior lines of therapy was 4 (range: 1-10). There was no difference in median PFS in the sequential arm (1.84 months; 95% CI: 1.77 – 2.17)) compared with the combination arm (1.87 months; 95% CI: 1.77 – 2.43), p=0.402. Similarly, median OS in the sequential and combination arms were 10.61 months (5.95 – 15.34) and 7.26 (4.24 – 15.57), respectively (p=0.810). In the sequential arm no objective responses were observed, although 12 patients (31.6%) exhibited stable disease. In the combination arm, 2 patients had partial response (8.7%) while one additional patient (4.4%) had stable disease. The adverse event profile was consistent with that previously reported for immune checkpoint therapy. <h3>Conclusions:</h3> There was no difference in the median PFS between the combination and sequential durvalumab plus tremelimumab treatment strategy arms in a heavily pretreated population of patients with platinum resistant/refractory HGOC. Response rates were comparable to prior reports, though the combination regimen did not add significant benefit as has been previously described with combination of ipilimumab/nivolumab. Further exploration into subpopulations that may have increased benefit from ICB is warranted.

A phase I, single-center, open-label study of RM-1929 photoimmunotherapy in Japanese patients with recurrent head and neck squamous cell carcinoma

BackgroundTo determine the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of a single cycle of RM-1929 photoimmunotherapy, an anti-EGFR antibody cetuximab conjugated with a light-activatable dye (IRDye®700DX), in Japanese patients with recurrent head and neck squamous cell carcinoma (rHNSCC).MethodsPatients received a single fixed dose (640 mg/m2) of RM-1929 and a fixed light treatment dose (50 J/cm2 for superficial illumination; 100 J/cm fiber diffuser length for interstitial illumination). Safety, tumor response (modified RECIST v1.1 by central radiology review), pharmacokinetics, and immunogenicity were evaluated.ResultsThree Japanese patients were enrolled who had failed ≥ 3 prior lines of therapy including radiation, chemotherapy, cetuximab, and immunotherapy. Target lesions were: submental lesion; right superficial cervical node lesion and oropharynx lesion; and external auditory canal lesion. All patients experienced ≥ 1 treatment-emergent adverse event (TEAE), but none were considered dose-limiting. TEAEs were mild to moderate in severity except for one grade 3 application-site pain, which was transient, resolved without sequelae within 24 h, and did not affect study treatment administration. Thirteen of 17 TEAEs reported were possibly or probably related to study treatment. Three patient reports of application-site pain and localized edema were deemed probably related to study treatment. Objective response was observed in two patients (both partial responses). The third patient had disease progression. RM-1929 concentrations and pharmacokinetic parameters were similar in all patients. No patients tested positive for anti-drug antibodies.ConclusionsRM-1929 photoimmunotherapy showed a manageable safety profile in rHNSCC. Tumor response in these heavily pre-treated patients was clinically meaningful and warrants further investigation.Clinical trial registrationThe trial was registered with the Japanese registry of clinical trials as jRCT2031200133.

AcelERA Breast Cancer (BC): Phase II study evaluating efficacy and safety of giredestrant (GDC-9545) versus physician’s choice of endocrine monotherapy in patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2-) locally advanced or metastatic breast cancer (LA/mBC).

TPS1100 Background: The standard-of-care therapy for ER+ BC typically involves modulation of estrogen synthesis and/or ER activity. Despite disease progression with standard treatments, growth and survival of the majority of tumors are thought to remain dependent on ER signaling; therefore, pts with ER+ BC can still respond to second- or third-line endocrine treatment (ET) after progression on prior therapy (Di Leo 2010; Baselga 2012). ESR1 mutations may drive estrogen-independent transcription and proliferation leading to resistance. The highly potent, nonsteroidal oral selective ER degrader, giredestrant, achieves robust ER occupancy and is active regardless of ESR1 mutation status. Phase I data have shown that giredestrant is well tolerated and active both as a single agent and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), palbociclib (Lim 2020). Single-agent giredestrant has also shown encouraging antitumor activity in pts previously treated with fulvestrant and/or a CDK4/6i. Methods: acelERA BC (NCT04576455) is a randomized, open-label, multicenter phase II study evaluating the efficacy and safety of giredestrant vs. physician’s choice of ET (fulvestrant or aromatase inhibitor) in males, or postmenopausal or pre/perimenopausal females with ER+/HER2– LA/mBC who have received 1–2 prior lines of systemic therapy in the LA or mBC settings, at least one of which must be ET. Randomization: 1:1 to receive giredestrant (30 mg PO QD on Days 1–28 of each 28-day cycle) or physician’s choice of ET per local guidelines. Men and pre-/perimenopausal women will receive a luteinizing hormone-releasing hormone agonist. Eligibility: ≥18 years, ECOG PS 0–1, histologically or cytologically confirmed diagnosis of LA (recurrent or progressed) or metastatic adenocarcinoma of the breast, measurable disease (per modified RECIST v1.1) or evaluable bone lesions, and ER+/HER2– tumors (locally assessed). Primary endpoint: progression-free survival (PFS; investigator-assessed per RECIST v1.1). Secondary endpoints: overall survival, objective response rate, duration of response, clinical benefit rate, PFS in pts with baseline ESR1 mutations, and quality of life. Safety, pharmacokinetics, biomarkers, and health status utility will also be assessed. Stratification: site of disease (visceral vs. nonvisceral), prior treatment with CDK4/6i (yes vs. no), and prior treatment with fulvestrant (yes vs. no). PFS will be compared using a stratified log-rank test; median PFS, using Kaplan–Meier analyses. Recruitment for the global enrollment phase is ongoing, the first patient was enrolled November 27, 2020. Clinical trial information: NCT04576455 .