Prior Platinum-based Therapy Research Articles

Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial.

5600 Background: Lenvatinib plus pembrolizumab is the standard treatment for patients with advanced endometrial cancer with mismatch repair-proficient (pMMR) disease who had disease progression after the receipt of prior systemic platinum-based therapy. Cadonilimab is a PD-1/CTLA-4 bi-specific antibody. We aimed to assess the combination of cadonilimab and lenvatinib in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy. Methods: In this phase II study with a safety-run in, eligible patients were aged 18 years or older with advanced endometrial cancer of any histologic subtype, except sarcoma, progressed after at least one prior platinum-based chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1. In the safety run-in period, a 3+3 dose de-escalation design was used to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of lenvatinib (16 mg or 12 mg once daily) combined with cadonilimab 10 mg/kg every 3 weeks. After the completion of safety run-in period, the phase II cohort at the RP2D will open. Approximately 29 patients are planned to receive treatment at the RP2D. The primary endpoint was objective response rate (ORR) at the RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between 8 May 2023 and 18 December 2023, 24 patients were enrolled. As of 31 December 2023, enrollment was ongoing. No DLTs were observed during the safety run-in period. The RP2D of lenvatinib is 16 mg once daily. Among 21 efficacy-evaluable patients, the ORR was 52.4% (95% CI: 29.1–75.7), and the DCR was 90.5% (95% CI: 69.6–98.8). The Medians for DOR, PFS, and OS were not reached. Grade 3–4 treatment-related adverse events included increased ALT (2 [8.3%]), increased AST (1 [4.2%]), increased creatine phosphokinase (1 [4.2%]), hypertension (1 [4.2%]), and intestinal perforation (1 [4.2%]). Conclusions: Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy. The combination therapy had a favorable and manageable safety profile. Clinical trial information: NCT05824481 . [Table: see text]

Tisotumab vedotin in head and neck squamous cell carcinoma: Updated analysis from innovaTV 207 Part C.

6012 Background: Recurrent or metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) is treated in the first-line with an immunotherapy-based approach, including in combination with platinum-based chemotherapy or as monotherapy, or platinum-based combination plus targeted therapy. Still, most pts experience disease progression, and the efficacy of subsequent line treatment options is limited. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate directed to tissue factor. TV at 1.7 mg/kg IV Q2W has demonstrated encouraging antitumor activity in 2L-4L r/m HNSCC from the innovaTV 207 (NCT03485209) study. Here, we present data from the full cohort, Part C. Methods: innovaTV 207 is an open-label, global, phase 2, multicohort, multicenter study evaluating TV monotherapy or in combination for advanced solid tumors. In Part C, pts with r/m HNSCC received TV monotherapy (1.7 mg/kg IV Q2W). All pts were required to have received a platinum-based regimen, either in the r/m setting, or have persistent disease following platinum-based chemoradiation and a checkpoint inhibitor (CPI), if eligible. Primary endpoint was confirmed objective response rate (cORR) per investigator. Secondary endpoints included duration of response (DOR), time-to-response (TTR), and safety. Results: As of 6 Sept 2023, 40 pts with HNSCC were treated. 39 (97.5%) pts received prior platinum-based therapy. In the r/m setting, 25 (62.5%) pts received ≤2 prior lines of systemic therapy (median: 2; range: 1-3), 40 (100%) pts received prior CPI, 23 (57.5%) pts received prior taxane, and 27 (67.5%) pts received prior cetuximab. The most common subsites at diagnosis were oropharynx (n=16, of which 12 were p16 positive), larynx (n=10), and oral cavity (n=9). In the full cohort, cORR was 32.5% (95% CI, 18.6-49.1), with 1 complete response and 12 partial responses. Median DOR was 5.6 mo (95% CI, 3.0-NR) and median TTR was 1.4 mo. Among pts with ≤2 prior lines (n=25), cORR was 40.0% (95% CI, 21.1-61.3). In this subgroup, DOR is not yet mature (range: 1.2+ to 7.9+ mo), and among the 10 responders, 6 pts remain in response; median TTR was 1.5 mo. In the full cohort, 85.0% of pts had at least 1 treatment-related adverse event (TRAE). Grade ≥3 TRAEs occurred in 25.0% of pts, of which the most common were peripheral neuropathy events (12.5%). Adverse events of special interest were prespecified for ocular, peripheral neuropathy, and bleeding events, and occurred in 21 (52.5%), 19 (47.5%), and 15 (37.5%) pts, respectively. Updated efficacy and safety data are planned. Conclusions: TV demonstrated encouraging antitumor activity in a heavily pretreated r/m HNSCC population with a manageable safety profile consistent with previous TV monotherapy data. The study is ongoing; TV represents a promising treatment option for pts with r/m HNSCC who have progressed after prior platinum-based therapy and immunotherapy. Clinical trial information: NCT03485209 .

A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation.

468214 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancers (NSCLC) in China. Glecirasib (Jacobio, Beijing, PRC) is a potent and highly selective covalent oral inhibitor of KRAS G12C. Methods: This phase 2 single-arm study (NCT05009329) of glecirasib was conducted in China at 43 sites, enrolling participants with locally advanced or metastatic KRAS G12C mutated NSCLC. Subjects must have received prior platinum-based therapy and an immune checkpoint inhibitor (ICI) as well as appropriate targeted agents for any actionable mutations per local standards. Primary study objective is overall response rate (ORR) assessed by independent review committee (IRC). The secondary study objectives include duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Here we report topline results from this pivotal study. Results: A total of 119 patients with NSCLC harboring KRAS G12C mutation were enrolled and treated with single agent glecirasib at 800mg daily (median follow up 10.4 months). The median age was 62 years, 79% was male and 21% was female, and 80.7% had ECOG PS 1. The prior lines of therapy include 1-3, with 94.1% (112/119) patients having received prior platinum-based therapy and ICI. Confirmed ORR was 47.9% (56/117; 95% CI, 38.5%-57.3%) and confirmed DCR was 86.3% (101/117; 95% CI, 78.7%-92%) assessed by IRC. Median PFS per IRC was 8.2 months (95% CI, 5.5 – 13.1), and median OS was 13.6 months (95% CI, 10.9 – NE). Median DOR has not been reached (95% CI, 7.2 – NE ). Overall, treatment-related adverse events (TRAEs) of any grade were observed in 97.5% of subjects. Most common TRAEs [≥15%] were anemia (56.3%), blood bilirubin increased (48.7%), alanine aminotransferase increased (35.3%), aspartate aminotransferase increased (35.3%), hypertriglyceridemia (28.6%) and γ-Glutamyl transferase increased (15.1%). Grade 3 and 4 TRAEs were observed in 39.5%. No grade 5 TRAEs occurred. Most of patients can stay on the treatment and 5.0% patients discontinued the treatment due to TRAE. In contrast to other FDA approved KRAS G12C inhibitor, Gleciasib has 6.7% of nausea, 7.6% vomiting, 3.4% diarrhea in which only one grade 3 nausea is reported. Conclusion: The pivotal phase 2 study of Glecirasib has met the primary endpoints and demonstrates impressive ORR and PFS with promising clinical activity for patients with KRAS G12C mutated advanced NSCLC. Glecirasib is well tolerated, with an extremely low gastrointestinal toxicity profile, which may improve patient compliance with oral therapy. Clinical trial information: NCT05009329 .

Bevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group

Most patients with advanced ovarian cancer (AOC) ultimately relapse after platinum-based chemotherapy. Combining bevacizumab, olaparib, and durvalumab likely drives synergistic activity. This open-label phase 2 study (NCT04015739) aimed to assess activity and safety of this triple combination in female patients with relapsed high-grade AOC following prior platinum-based therapy. Patients were treated with olaparib (300 mg orally, twice daily), the bevacizumab biosimilar FKB238 (15 mg/kg intravenously, once-every-3-weeks), and durvalumab (1.12 g intravenously, once-every-3-weeks) in nine French centers. The primary endpoint was the non-progression rate at 3 months for platinum-resistant relapse or 6 months for platinum-sensitive relapse per RECIST 1.1 and irRECIST. Secondary endpoints were CA-125 decline with CA-125 ELIMination rate constant K (KELIM-B) per CA-125 longitudinal kinetics over 100 days, progression free survival and overall survival, tumor response, and safety. Non-progression rates were 69.8% (90%CI 55.9%-80.0%) at 3 months for platinum-resistant relapse patients (N = 41), meeting the prespecified endpoint, and 43.8% (90%CI 29.0%-57.4%) at 6 months for platinum-sensitive relapse (N = 33), not meeting the prespecified endpoint. Median progression-free survival was 4.1 months (95%CI 3.5–5.9) and 4.9 months (95%CI 2.9–7.0) respectively. Favorable KELIM-B was associated with better survival. No toxic deaths or major safety signals were observed. Here we show that further investigation of this triple combination may be considered in AOC patients with platinum-resistant relapse.

Характеристика и управление нежелательными реакциями у пациентов с распространенным раком эндометрия, которые получают комбинацию ленватиниб плюс пембролизумаб

Background. Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation. Materials and methods. In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome. Results. As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed. Conclusion. Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications.

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab.

Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation. In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome. As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed. Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications. NCT03517449.

A randomised phase II trial of niraparib versus active symptom control in patients with previously treated mesothelioma: NERO.

TPS8600 Background: Malignant mesothelioma is a universally lethal cancer that has been increasing over the last three decades. No treatment has been licenced for patients with relapsed mesothelioma after receipt of licenced systemic anti-cancer therapy in the UK. A previous single-arm phase IIa trial (MiST1) evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma, which met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in a randomised trial in relapsed mesothelioma patients. NERO is currently in progress in this setting. Methods: Co-ordinated by the CRUK Southampton Clinical Trials Unit, NERO is a multicentre, two arm, open-label UK randomised phase II trial comparing niraparib + Active Symptom Control (ASC) versus ASC alone in mesothelioma patients who have relapsed after previously receiving platinum-based systemic therapy. NERO is not restricted by line of therapy and treatment allocation ratio is 2:1 (niraparib + ASC:ASC), stratified by histology and response to prior platinum-based therapy. Participants will receive either niraparib + ASC or ASC alone for a period of 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200/300 mg every day in a 21-day cycle. The primary endpoint is progression-free survival, where progression is determined by modified RECIST or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Time to event data will be analysed and presented using Kaplan-Meier curves according to the intention to treat principle, with treatment-related intercurrent events handled using the treatment strategy policy, and study withdrawal following the “while on study” strategy. A Cox proportional hazards model will be used to calculate the Hazard Ratio, 95% CIs and p-value adjusted for stratification factors. Median PFS and 6 and 12 month PFS will also be reported. Secondary endpoints include overall survival, best overall response, 12 and 24 week disease control, duration of response, treatment compliance and safety/tolerability. Patients consent to provide mandatory diagnostic tissue blocks, blood samples and an optional stool sample for translational research. These will be used to interrogate homologous recombination deficiency and its association with response in NERO, translational research comprising multi-omic analysis with multiplex immune landscape phenotyping will be analysed and correlated with clinical outcome using machine learning. NERO opened in July 2022 and will be run in approximately 10 UK secondary care hospitals with the aim of recruiting 84 evaluable patients (recruitment is currently 24 on 11-Jan-2023). Clinical trial information: NCT05455424 .

Pembrolizumab in Combination With Lenvatinib (Keytruda and Lenvima)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses pembrolizumab in combination with lenvatinib (Pembrolizumab: powder for solution for infusion 50 mg, or solution for infusion 100 mg/4 mL vial IV infusion over 30 minutes; lenvatinib: 4 mg and 10 mg capsules [as lenvatinib mesylate], oral).
 Indication: Adult patients with advanced endometrial carcinoma that is not MSI-H or dMMR who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation.

Real-World Time on Treatment Analysis of Pembrolizumab Treated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) Patients Stratified by ECOG PS in the United States

<h3>Purpose/Objective(s)</h3> There is limited evidence on the real-world use of pembrolizumab therapy post-approval in 1L R/M HNSCC. The study estimated real-world time on treatment (rwToT) of pembrolizumab monotherapy and pembrolizumab + platinum + 5-fluorouracil for 1L R/M HNSCC patients, stratified by ECOG PS. <h3>Materials/Methods</h3> This retrospective study of the nationwide de-identified electronic health record (EHR)-derived Flatiron Health Advanced H&N database selected patients initiating pembrolizumab monotherapy or pembrolizumab + platinum + 5-fluorouracil between 07/01/19 - 12/31/20 with follow-up until 07/31/21. Patients with prior platinum-based therapy ≤6 months, prior primary cancers, or treatment with a clinical study drug were excluded. rwToT was defined as length of time between first and last documented administration date pembrolizumab. Patients with a record of next line of therapy, death, or treatment gap ≥120 days from the last administration date were considered discontinued. Patients without a discontinuation event were censored at the end of follow up. Kaplan-Meier analysis was conducted to assess median rwToT and landmark on-treatment rates. All results were stratified by ECOG PS 0-1 (similar to KEYNOTE-048, the registrational clinical trial) and ECOG PS 2-3. <h3>Results</h3> A total of 402 patients initiated 1L treatment with pembrolizumab therapy. Of those patients, 297 (73.9%) had a recorded ECOG PS score, majority with an ECOG PS score of 0/1 (Overall: 77.8%, pembrolizumab monotherapy: 70.5%, pembrolizumab + platinum + 5-fluorouracil: 84.1%). The median rwToT was higher among the ECOG 0/1 patients compared to ECOG 2/3 patients for both regimens (pembrolizumab monotherapy: 4.4 vs 2.2 months, pembrolizumab + platinum + 5-fluorouracil: 5.0 vs 3.5 months). <h3>Conclusion</h3> In the real-world, treatment duration with pembrolizumab monotherapy or pembrolizumab+platinum+5-fluorouracil in 1L R/M HNSCC was similar to KEYNOTE-048, when restricted to a trial-matched population of ECOG PS 0-1 patients. Treatment duration tended to be shorter in the real-world ECOG PS 2/3 population, who are commonly excluded from clinical trials.

Pembrolizumab (Keytruda) in Combination With Lenvatinib (Lenvima)

&#x0D; CADTH recommends that Keytruda in combination with Lenvima (Keytruda-Lenvima) should be reimbursed by public drug plans for the treatment of adult patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior platinum-based systemic therapy, and are not candidates for curative surgery or radiation if certain conditions are met.&#x0D; Keytruda-Lenvima should only be covered in patients with endometrial cancer that has spread to the pelvis or other body parts, that is classified as proficient mismatch repair (pMMR), and has further spread after 1 prior systemic, platinum-based chemotherapy.&#x0D; Keytruda-Lenvima should only be reimbursed if prescribed in an outpatient oncology clinic or institution with expertise in delivering systemic therapy, when administered in combination, and if the cost is reduced.&#x0D;

Real-world time on treatment analysis of pembrolizumab treated recurrent/metastatic head &amp; neck squamous cell carcinoma (R/M HNSCC) patients stratified by ECOG PS in the United States.

e18007 Background: There is limited evidence on the real-world use of pembrolizumab therapy post-approval in 1L R/M HNSCC. The study estimated real-world time on treatment (rwToT) of pembrolizumab monotherapy and pembrolizumab + platinum + 5FU for 1L R/M HNSCC patients, stratified by ECOG PS. Methods: This retrospective study of the nationwide de-identified electronic health record (EHR)-derived Flatiron Health Advanced H&amp;N database selected patients initiating pembrolizumab monotherapy or pembrolizumab + platinum + 5FU between 07/01/19 - 12/31/20 with follow-up until 07/31/21. Patients with prior platinum-based therapy ≤6 months, prior primary cancers, or treatment with a clinical study drug were excluded. rwToT was defined as length of time between first and last documented administration date pembrolizumab. Patients with a record of next line of therapy, death, or treatment gap ≥120 days from the last administration date were considered discontinued. Patients without a discontinuation event were censored at the end of follow up. Kaplan-Meier analysis was conducted to assess median rwToT and landmark on-treatment rates. All results were stratified by ECOG PS 0-1 (similar to KEYNOTE-048, the registrational clinical trial) and ECOG PS 2-3. Results: A total of 402 patients initiated 1L treatment with pembrolizumab therapy. Of those patients, 297 (73.9%) had a recorded ECOG PS score, majority with an ECOG PS score of 0/1 (Overall: 77.8%, pembrolizumab monotherapy: 70.5%, pembrolizumab + platinum + 5-FU: 84.1%). The median rwToT was higher among the ECOG 0/1 patients compared to ECOG 2/3 patients for both regimens (pembrolizumab monotherapy: 4.4 vs 2.2 months, pembrolizumab + platinum + 5-FU: 5.0 vs 3.5 months). Conclusions: In the real-world, treatment duration with pembrolizumab monotherapy or pembrolizumab+platinum+5-FU in 1L R/M HNSCC was similar to KEYNOTE-048, when restricted to a trial-matched population of ECOG PS 0-1 patients. Treatment duration tended to be shorter in the real-world ECOG PS 2/3 population, who are commonly excluded from clinical trials.[Table: see text]

20MO Time to deterioration in quality of life in patients (pts) with advanced endometrial cancer (aEC) treated with lenvatinib plus pembrolizumab (L+P) or treatment of physician’s choice (TPC)

In study 309/KEYNOTE-775, L+P showed significant OS and PFS benefits and improved ORR vs TPC in pts with aEC following prior platinum-based therapy. There were no substantial differences in health-related quality of life (HRQoL) scores between the 2 arms at 12 weeks. We describe a post-hoc analysis of time to first (TTfD) and time to definitive (TTdD) deterioration (by 10 points) of patient-reported outcomes (PROs).

ENGOT-ov65/KEYNOTE-B96: Phase 3, randomized, double-blind study of pembrolizumab versus placebo plus paclitaxel with optional bevacizumab for platinum-resistant recurrent ovarian cancer.

TPS5617 Background: Despite therapeutic advances in ovarian cancer, platinum-resistant recurrent ovarian cancer (PROC) remains an area of high unmet clinical need and there is an urgent need for new treatments to further improve clinical outcomes. Addition of bevacizumab to non-platinum-based chemotherapy significantly improved PFS in patients with PROC but did not show a clear OS benefit. Thus far, the combination of paclitaxel and bevacizumab has shown the most promise in treatment of PROC, although the proportion of patients eligible for bevacizumab is limited by treatment-associated toxicities. Combination of the anti-PD-1 antibody pembrolizumab with weekly paclitaxel showed antitumor activity and manageable toxicity in patients with PROC in a single-arm, phase 2 study (Wenham Int J Gynecol Cancer 2018). The current study ENGOT-ov65/KEYNOTE-B96 (NCT05116189) compares the efficacy and safety of the addition of pembrolizumab to standard of care chemotherapy (weekly paclitaxel) with/without bevacizumab vs placebo plus weekly paclitaxel with/without bevacizumab in patients with PROC. Methods: In this randomized, placebo-controlled, double-blind, phase 3 study, eligible patients are aged ≥18 y with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1-2 prior lines of systemic therapy, including at least 1 prior platinum-based therapy with ≥4 cycles in first line. Patients must have platinum-resistant disease (radiographic evidence of PD ≤6 mo after last platinum-based therapy dose), be eligible for paclitaxel (with/without bevacizumab per investigator discretion), have ECOG PS ≤1, radiographically evaluable disease per RECIST v1.1, and have a tumor sample for central evaluation of PD-L1 status. Approximately 616 patients will be randomized 1:1 to receive pembrolizumab 400 mg IV or placebo Q6W for up to 18 cycles (̃2 y) plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of each Q3W cycle (with/without bevacizumab 10 mg/kg Q2W per investigator discretion) until PD or unacceptable toxicity. Randomization is stratified by planned bevacizumab use (yes vs no), region (US vs Europe vs rest of world), and PD-L1 status (combined positive score [CPS] &lt; 1 vs CPS 1- &lt; 10 vs CPS ≥10). Tumor PD-L1 status is determined using the PD-L1 IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. Tumor imaging is performed Q9W from randomization to week 54 and Q12W thereafter. The primary endpoint is PFS per RECIST version 1.1 by investigator review in patients with tumor PD-L1 CPS ≥1 and in all patients. Secondary endpoints are OS in patients with tumor PD-L1 CPS ≥1 and in all patients, PFS per RECIST version 1.1 by blinded independent central review in patients with tumor PD-L1 CPS ≥1 and in all patients, safety, and patient-reported outcomes. Enrollment is ongoing. Clinical trial information: NCT05116189.

Overall survival from a phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non–small cell lung cancer previously treated with immunotherapy: Lung-MAP nonmatched substudy S1800A.

9004 Background: Resistance to immune checkpoint inhibitor (ICI) therapy develops in most patients (pts) with advanced non-small cell lung cancer (NSCLC). Tumors that develop resistance to ICI constitute a major unmet need. Combined ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types through immune modulation. We evaluated pembrolizumab and ramucirumab (P+R) in advanced, ICI-exposed NSCLC, under the aegis of Lung-MAP, a master protocol for pts with stage IV, previously treated NSCLC. Pt characteristics and treatment toxicities were presented at ASCO 2021. Methods: S1800A was a randomized phase II trial for pts ineligible for a biomarker-matched substudy with acquired resistance to ICI defined as previous ICI therapy for at least 84 days with progressive disease (PD) on or after therapy. Eligibility stipulated PD on prior platinum-based doublet therapy (sequential or in combination with ICI) and ECOG PS of 0-1. Pts were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the standard of care (SOC) arm and were randomized to P+R or SOC (investigator’s choice of docetaxel+R; docetaxel, pemetrexed, gemcitabine). With a goal of 144 total/130 eligible pts, the primary objective was to compare overall survival (OS) between the arms using a 1-sided 10% level log-rank test upon 90 deaths. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts were enrolled with 137 eligible (69 P+R; 68 SOC [45 +R, 23 w/o R]). Main causes for ineligibility were lack of PD on ICI or chemotherapy (6 SOC, 6 P+R), &gt; 1 line of ICI (2 P+R), ICI discontinued due to toxicity (2 SOC), or lack of measurable disease (2 SOC, 1 P+R). OS was significantly improved with P+R (HR: 0.61 [0.38-0.97], 1-sided p-value = 0.019; median [95% CI] OS of 15.0 (13.2-17) months (mo) for P+R and 11.6 (8.5-13.8) mo in SOC arm). Progression-free survival (PFS) was not different between the arms (HR: 0.86 [0.57-1.31], 1-sided p-value=0.25; median PFS (95% CI) of 4.5 (4.0-6.9) mo for P+R and 5.2 (4.0-6.6) mo in SOC arm). ORR was not different between the arms (p=0.28). OS benefit for P+R was seen in most subgroups. Analysis of survival based on genomic alterations, tumor mutational burden and PD-L1 will be presented. Conclusions: Pembrolizumab + ramucirumab in pts with advanced NSCLC previously treated with chemotherapy and immunotherapy led to improved OS compared to SOC. Discordance of ORR and PFS from OS has been reported in prior ICI trials (Rittmeyer et al. Lancet 2017). This is the first trial in the 2nd line setting without a chemotherapy backbone to demonstrate a potential survival benefit compared to SOC regimens including docetaxel and ramucirumab using the Lung-MAP platform. Clinical trial information: NCT03971474.

Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC).

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

Pooled analysis of nivolumab treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck in the United States and Germany.

In the Phase-III clinical trial, CheckMate 141, nivolumab significantly improved survival versus standard of care in patients with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This pooled analysis investigated the real-world effectiveness of nivolumab, following prior platinum-based therapy, in patients with R/M SCCHN from the United States (US) Flatiron Health database and German HANNA prospective observational study. Overall, 782 patients (56% US; 44% Germany) were included. Median overall survival (OS) was 8.71 months, and progression-free survival was 4.11 months. Eastern Cooperative Oncology Group Performance Status 0 or 1, platinum sensitivity, and older age were associated with longer OS, in which number of prior lines of therapy had no significant effect. These findings demonstrate survival benefits of nivolumab in patients with R/M SCCHN in the real-world setting. The observed real-world effectiveness of nivolumab aligns with the efficacy of nivolumab in CheckMate 141.

Abstract CT234: VASTUS - a phase 1b/2a basket trial of a new PARP inhibitor, IDX-1197, including PARP inhibitor resistant cohort

Abstract [BACKGROUND]Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or germline or somatic homologous recombinant repair mutation (g/sHRRmt), and advanced serous ovarian cancer that are homologous recombination deficiency (HRD)-positive, g/sBRCAmt or sensitive to prior platinum treatment. However, there is limited knowledge about the efficacy of PARP inhibitors in other cancers with HRD with or without gBRCAmt, in platinum-resistant settings, and about efficacy after prior PARP inhibitor treatment. IDX-1197 is a new PARP inhibitor which is active against cell lines with acquired resistance to platinum and PARP inhibitors. VASTUS study is a basket trial composed of 9 different cohorts investigating use of IDX-1197 in various tumors known to be responsive to PARP inhibitors, as well as in tumors and settings that have not been well-investigated so far. [METHOD]VASTUS is a multi-center, basket trial (NCT04174716) to evaluate safety and efficacy of IDX-1197 as a monotherapy in 1) cancers that are known to be responsive to PARP inhibitors (breast cancer, ovarian cancer, and pancreatic cancer), 2) cancers where PARP inhibitors' safety and efficacy have not been confirmed (small cell lung cancer, biliary tract cancer, uroepithelial cancer, and gastric cancer), 3) any solid tumors resistant to prior platinum-based therapy, excluding refractory to prior platinum based therapy, and 4) any solid tumors that have been exposed to prior PARP inhibitors. In VASTUS trial, patients are selected by pathogenic mutations in HRD-related genes. In the cohort for tumors with prior exposure to PARP inhibitors, patients are eligible regardless of gene mutations as long as they have received prior PARP inhibitor. Study is composed of two parts – phase 1b to assess safety and tolerability of IDX-1197 and to determine recommended phase 2 dose; after review by data safety monitoring committee and go/no-go decision, phase 2a will be commenced to assess the efficacy of IDX-1197 based on objective response rate (ORR). Retrospective translational researches with tumor tissue and peripheral blood are planned (circulating tumor DNA), specifically for prior PARP inhibitor exposure cohort. As of 05 Jan 2021, 32 patients have been enrolled. Citation Format: Kyung-Hun Lee, Ahrum Min, Hee Kyung Ahn, Keun Seok Lee, Yong Wha Moon, Seung Tae Kim, Jeong Eun Kim, Joo Hyuk Sohn, Il Hwan Kim, Woo Kyun Bae, Myong Jae Lee, Eun-Jihn Roh, Chan-Young Ock, Won Sik Lee, Seock-Ah Im. VASTUS - a phase 1b/2a basket trial of a new PARP inhibitor, IDX-1197, including PARP inhibitor resistant cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT234.

Health-related quality of life (HRQoL) in advanced endometrial cancer (aEC) patients (pts) treated with lenvatinib plus pembrolizumab or treatment of physician’s choice (TPC).

5570 Background: In Study 309/KEYNOTE-775, lenvatinib + pembrolizumab (L+P) demonstrated significant and clinically meaningful improvement in OS, PFS, and ORR compared with TPC in aEC pts following prior platinum-based systemic therapy. Given the medical complexity/age of EC pts, QoL analyses are critical, but often under-reported. We present results of pt-reported HRQoL for Study 309/KEYNOTE-775. Methods: Pts were randomized 1:1 to receive lenvatinib 20 mg QD PO + pembrolizumab 200 mg IV Q3W (n=411) or TPC (n=416; doxorubicin 60 mg/m2 IV Q3W or paclitaxel 80 mg/m2 IV QW, 3 wks on/1 wk off). Pt-reported HRQoL was assessed at cycle 1 day 1, day 1 of each subsequent cycle and at time of discontinuation using EORTC QLQ-C30, its EC module QLQ-EN24, and EQ-5D-5L in treated pts who had ≥1 HRQoL assessment available. Higher scores indicate better functioning/QoL (EORTC QLQ-C30, EQ-5D-5L) or worse symptom severity (QLQ-EN24). Changes in EORTC QLQ-C30 global health status (GHS)/QoL was a secondary endpoint. This was analyzed from baseline to the latest timepoint at which overall completion was ≥60% and overall compliance was ≥80%, using constrained longitudinal data analysis; other HRQoL analyses were exploratory. Results: Completion and compliance rates of EORTC QLQ-C30 were &gt;95% in both groups at baseline. Primary analysis was conducted at wk 12 as completion rate was 80% for L+P and 62% for TPC; compliance rate was 93% for L+P and 87% for TPC. Baseline GHS/QoL scores were similar between the L+P group and TPC group: mean (SD) of 65.74 (21.87) vs 65.69 (22.71), respectively. Over 12 wks of follow-up, pts in both groups had slight decreases in GHS/QoL. Similar decreases were observed for pts receiving L+P vs TPC: -5.97 (95% CI: -8.36, -3.58) vs -6.98 (95% CI: -9.63, -4.33). The between-group difference in least-squares (LS) mean score change from baseline to wk 12 for L+P vs TPC was 1.01 points (95% CI: -2.28, 4.31). Over time, QoL scores were generally similar across treatments. Results were similar for other HRQoL endpoints (Table). Conclusions: No significant differences were observed in HRQoL scores between treatment groups. With no standard treatment approach following failure of platinum-based therapy, these data along with previously reported efficacy and safety findings from Study 309/KEYNOTE-775 further support that L+P has an overall favorable benefit/risk profile compared to chemotherapy. Clinical trial information: NCT03517449. [Table: see text]

OA04.03 Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results From EXCLAIM and Pooled Platinum-Pretreated Patient Populations

Mobocertinib is a potent first-in-class tyrosine kinase inhibitor (TKI) designed to target EGFR exon 20 insertion (EGFRex20ins) mutations. We report first results from the EXCLAIM extension cohort of a phase 1/2 study (NCT02716116) and results in patients with EGFRex20ins-mutant NSCLC who received prior platinum-based therapy from the dose-escalation/expansion parts of the study and the EXCLAIM extension cohort. This 3-part, open-label, multicenter study included dose-escalation/expansion cohorts and the EXCLAIM extension cohort. Data are presented for all patients treated in EXCLAIM (N=96) and for platinum-pretreated patients from the dose-escalation/expansion cohorts (n=28) and from EXCLAIM (n=86); all received mobocertinib 160 mg orally QD. Enrolled patients had locally advanced/metastatic EGFRex20ins NSCLC, ECOG performance status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease. The primary endpoint is confirmed ORR assessed by IRC per RECIST v1.1. In EXCLAIM, 96 patients were enrolled and treated; median age, 59 years [range: 27–80]; female, 65%; Asian, 69%; ≥2 prior systemic anticancer lines, 49% (range: 1–4). Median time on treatment was 6.5 months (range: 0–14). Confirmed ORR was 23% (22/96; 95% CI: 15%–33%) per IRC and 32% (95% CI: 23%–43%) per investigator; median DoR (Kaplan-Meier estimates) was not mature; median PFS was 7.3 months. See Table. In the analysis of platinum-pretreated patients (n=114), median age, 60 years [range: 27–84]; female, 66%; Asian, 60%; ≥2 prior systemic anticancer lines, 59% (range: 1–7). Median time on treatment was 7 months (range: 0–31); 38 patients (33%) remained on treatment as of 29-May-2020. Confirmed ORR was 26% (30/114; 95% CI: 19%–35%) per IRC and 35% (40/114; 26%–45%) per investigator. Median PFS was 7.3 months: 12-month PFS rate was 33% (95% CI: 21%–47%). Responses were observed among all prespecified subgroups, including Asian/non-Asian patients and those with/without baseline stable brain metastases. The most common treatment-related adverse events (TRAEs; ≥30%): diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%), and vomiting (30%); grade ≥3 TRAEs (≥5%): diarrhea (22%), anemia (5%), and dyspnea (5%). Nineteen patients (17%) discontinued due to AEs, most commonly diarrhea (4%) and nausea (4%). The safety profile observed in EXCLAIM was largely consistent with that observed in the platinum-pretreated population. Mobocertinib demonstrated clinically meaningful benefit in previously treated patients with NSCLC and EGFRex20ins mutations, with a manageable safety profile.

TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy.

TPS498 Background: Treatment options are limited for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who progress following prior platinum-based and checkpoint inhibitor (CPI) therapy. Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase-I inhibitor) via a unique hydrolyzable linker. A phase II registrational study, TROPHY-U-01 study, confirmed the initial positive efficacy signal in mUC. SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in patients with mUC (median 3 prior lines of therapy and 87% with ≥1 Bellmunt risk factors) who progressed after prior platinum-based and CPI therapies (n=113; Loriot ESMO 2020). The results compared favorably with historic single-agent chemotherapy (ORR ~10%; OS ≤7 months). A phase III trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in patients with locally advanced unresectable or mUC who progressed after prior platinum-based and CPI therapies (with Eastern Cooperative Oncology Group performance status 0–1 and adequate hematologic, hepatic, and renal function). Patients will be randomized 1:1 to receive SG 10 mg/kg intravenously (IV) on day 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in patients deemed to be receiving clinical benefit per investigator assessment. Approximately 482 patients will be enrolled to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors v1.1), safety, and quality of life. Study initiation is ongoing and enrollment begins in Q4 2020 across ~90 sites. Clinical trial information: NCT04527991.