Investigator-assessed Objective Response Rate Research Articles

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis

ObjectiveOlaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non‑platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. MethodsIn this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. ResultsOf 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. ConclusionsOlaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142

In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, etal. Nivolumabplus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. Patients received nivolumab (3 mg/kg)plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals.

S256: TABELECLEUCEL FOR EBV-DRIVEN POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE FOLLOWING ALLOGENEIC HEMATOPOIETIC CELL OR SOLID ORGAN TRANSPLANT AFTER FAILURE OF RITUXIMAB ± CHEMOTHERAPY (ALLELE)

Background: Tabelecleucel is an investigational, off-the-shelf, allogeneic Epstein–Barr Virus (EBV)-specific T-cell immunotherapy being explored in patients (pts) with EBV-driven post-transplant lymphoproliferative disease (EBV+ PTLD). Median overall survival (OS) after rituximab (R) ± chemotherapy (C) failure is 0.7 months in EBV+ PTLD post allogeneic hematopoietic cell transplant (HCT) (Sanz ASH 2021) and 4.1 months post solid organ transplant (SOT) after R+C failure (Dharnidharka ASH 2021), demonstrating an urgent need for therapies in this ultra-rare disease. Tabelecleucel has shown promising outcomes (Prockop JCI 2020). Additionally, an investigator-assessed objective response rate (ORR) of >60% with >80% 2-year OS (Prockop EBMT 2021, Prockop ATC 2021, Prockop ASH 2021) was seen in pts with relapsed/refractory (R/R) EBV+ PTLD, with either complete or partial response to tabelecleucel. Safety data in >180 pts with tabelecleucel treated EBV+ PTLD demonstrate tumor flare reaction (TFR) as the only identified risk (Atara Biotherapeutics, Data on file). Aims: Report data from the ongoing Phase 3 ALLELE study (NCT03394365). Methods: ALLELE is a multicenter, open-label study investigating tabelecleucel in pts with EBV+ PTLD post HCT after R failure (n=33) and post SOT after R±C failure (n=33). Pts receive tabelecleucel at 2 x 106 cells/kg on Days 1, 8 and 15 in 35-day cycles. Response is evaluated by investigator and by independent oncologic response adjudication (IORA; primary assessment) using Lugano Classification with LYRIC modification. Efficacy endpoints include ORR, duration of response (DOR), time to response (TTR), and OS. Pts are assessed post treatment for up to 5 years for survival. Results: As of May 2021, 38 pts (14 HCT, 24 SOT) were evaluable by IORA and had the opportunity for 6 months follow-up. Median age was 52.9 (range, 3.2–81.5) years, 44.4%/47.2% of pts were high/intermediate risk per PTLD-adapted prognostic index, and median number of lines of prior systemic treatment was 1 (range, 1–5). R/R HCT and SOT pts received a median (range) of 3 (1–5) and 2 (1–6) cycles of tabelecleucel, respectively. ORR was 50.0% (19/38, 95% CI: 33.4, 66.6) overall, 50.0% (7/14, 95% CI: 23.0, 77.0) in HCT, and 50.0% (12/24, 95% CI: 29.1, 70.9) in SOT (Table). Overall, median TTR was 1.1 (0.7–4.7) months, 11 of 19 responders had DOR > 6 months, and median DOR was not reached (Table). Median OS was 18.4 (95% CI: 6.9, NR) months overall, not yet reached for HCT, and 16.4 (95% CI: 3.5, NR) months for SOT. 1-year survival rates were 61.1% (95% CI: 42.9, 75.0) overall, 66.8% (95% CI: 32.4, 86.6) for HCT, and 57.4% (95% CI: 35.2, 74.5) for SOT. Median OS was NR (95% CI: 16.4, NR) for responders and 5.7 (95% CI: 1.8, 12.1) months for non-responders. Responders had a higher 1-year survival rate vs non-responders: 89.2% (95% CI: 63.1, 97.2) vs 32.4% (95% CI: 12.1, 54.9) (Table). Serious treatment emergent AEs (TEAEs) and fatal TEAEs were reported in 57.1% and 7.1% of HCT and 62.5% and 16.7% of SOT pts respectively. No fatal TEAE was treatment related. There were no reports of TFR, infusion reactions, cytokine release syndrome, marrow rejection, or transmission of infectious diseases, and no events of graft vs host disease or organ rejection reported as related to tabelecleucel. Image:Summary/Conclusion: Tabelecleucel Phase 3 data show clinically meaningful outcomes and promising ORR and OS in a pt population with poor survival and no approved therapies. Tabelecleucel was well tolerated without evidence of safety concerns typically observed with other adoptive T-cell therapies.

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

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

Abstract 5180: A randomized, double-blind, placebo-controlled phase III study to evaluate AK104 plus platinum-containing chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer

Abstract Background: The current first-line standard of care for recurrent or metastatic cervical cancer is platinum-based doublet chemotherapy ± bevacizumab, but its efficacy is limited. Immunotherapies with programmed cell death receptor-1 (PD-1) inhibitor or combination of PD-1 and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors have been demonstrated to improve the clinical benefit for patients with recurrent or metastatic cervical cancer as second- or late-line treatment[1,2]. Their role in first-line treatment is under assessment. AK104 is a bispecific antibody (BsAb) that binds to both PD-1 and CTLA-4. This phase III trial aims to evaluate the efficacy and safety of AK104 plus standard chemotherapy with or without bevacizumab as first-line treatment for recurrent/metastatic cervical cancer. Trial Design: This phase III trial is a randomized, double-blind, placebo-controlled, multi-center study. Eligible patients are aged ≥ 18 and≤75 years, diagnosed with squamous cell carcinoma, adenocarcinoma or adenosquamous cell carcinoma of the cervix, not amenable to curative surgery or concurrent chemoradiotherapy, ECOG PS 0-1, and life expectancy ≥3 months. Patients will be excluded if they have prior systemic therapy for persistent, recurrent or metastatic disease, or have previously used anti-angiogenic therapy or immune therapy. Approximately 440 patients will be randomized (1:1) to AK104 + cisplatin/carboplatin+ paclitaxel± bevacizumab or placebo + cisplatin/carboplatin + paclitaxel ± bevacizumab. The treatment will be given every 3 weeks for up to 6 cycles, followed by maintenance therapy of AK104/placebo± bevacizumab until disease progression, intolerable toxicity, loss of clinical benefit as judged by the Investigator, withdrawal of consent, or completion of 2 years treatment of AK104/placebo. The primary endpoints are blinded independent central review (BICR)-assessed progression-free survival (PFS) and overall survival (OS). Second endpoints include Investigator-assessed PFS, BICR and Investigator-assessed Objective response rate (ORR), Disease control rate (DCR), Duration of response (DoR) and Time to response (TTR), and safety and tolerability for the treatment regime. The trial is currently enrolling patients. Clinical trial information: NCT04982237. Research Sponsor: Akeso Biopharma Co,. Ltd. Citation Format: Xiaohua Wu, Jing Wang, Yi Huang, Yuzhi Li, Yang Sun, Ke Wang, Michelle Xia, Baiyong Li, Wei Liu. A randomized, double-blind, placebo-controlled phase III study to evaluate AK104 plus platinum-containing chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5180.

Abstract CT032: Activity and safety of alectinib for ALK-altered solid tumors from MyPathway

Abstract Purpose: Alectinib is FDA-approved for ALK-positive, metastatic non-small cell lung cancer (NSCLC). We analyzed alectinib treatment in a pan-tumor population with ALK alterations from MyPathway (NCT02091141), a multi-basket study assessing approved therapies in non-indicated advanced solid tumors with relevant alterations. Methods: Enrolled patients (pts) were ≥18 yrs old and had metastatic tumors with ALK gene rearrangements, putative activating non-synonymous ALK mutations, and/or ALK gene amplification. Pts received alectinib 600 mg PO BID. The primary endpoint was investigator-assessed objective response rate (ORR; complete response [CR] + partial response [PR]). Other endpoints included duration of response (DOR), disease control rate (DCR; CR + PR + stable disease [SD] >4 mos), progression-free survival (PFS), and safety. Results: By the 11-18-2021 data cutoff, 21 pts with various tumor types had been enrolled and treated (ALK mutations or amplification, n=11 [52.4%]; ALK rearrangements +/- other ALK alterations, n=10 [47.6%]). Pts had a median of 2 (range, 1-5) prior lines of therapy. In the 10 pts with ALK rearrangements, there were 3 PRs (30.0%) with a median DOR of 6.8 mos (Table). An additional 3 pts in this group had SD >4 mos; DCR was 60.0% (6/10). In contrast, there were no responses among the 11 pts with ALK mutations or amplification. Confirmed ORR for the entire group was 14.3% (3/21), and DCR was 42.9% (9/21). Median PFS was 8.2 mos in pts with ALK rearrangements vs 1.8 mos for those with other ALK alterations. Alectinib-related adverse events (AEs) were observed in 85.7% of pts, with 3 (14.3%) experiencing grade 3 AEs (anemia; hypokalemia; and changes in AST, ALT, and/or blood creatinine levels). AEs were consistent with the known alectinib safety profile. Conclusions: Although the number of pts is small, alectinib appears active in those with non-NSCLC advanced solid tumors with ALK rearrangements. As in NSCLC, cancers with ALK mutations or amplification were not responsive to ALK inhibition. Table. Clinical outcomes Clinical Response Rearrangement (n=10) Mutation (n=7) Amplification (n=4) Median PFS, mos (all alterations) n Indications n Indications n Indications PR 3a Melanoma, Papillary urothelial carcinoma, Colon adenocarcinoma 0 NA 0 NA 9.3 SD >4 mos 3b,c Colon adenocarcinoma, Uterine leiomyosarcoma, Pancreatic adenocarcinoma 2 Squamous cell carcinoma, Soft tissue sarcoma 1 Uterine body clear cell carcinoma 5.7 SD ≤4 mos 0 NA 1 Fallopian tube serous carcinoma 0 NA PD 3d,e Colon adenocarcinoma, Esophageal adenocarcinoma, Uterine serous carcinoma 4 Anaplastic thyroid carcinoma, Esophageal adenocarcinoma, Colon adenocarcinoma (2) 3 Ovarian serous carcinoma, Gastric squamous cell carcinoma, Peritoneal non-small cell carcinoma 1.7 Non-evaluable 1f Uterine inflammatory myofibroblastic tumor 0 NA 0 NA NA aFusion gene partners: EMILIN1, DCTN1, and DIAPH2. bOne pt with ALK rearrangement and SD >4 mos also had ALK amplification. cFusion gene partners: STRN, IGFBP5, and EML4. dPts with ALK rearrangement and PD also had an ALK mutation (n=1) or ALK amplification (n=1). eFusion gene partner: STRN; fusion genes unknown for 2 pts. fPt withdrew prior to clinical assessment and was censored for PFS at 0.03 mos. NA, not applicable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. Citation Format: Charles Swanton, Claire F. Friedman, Christopher J. Sweeney, Funda Meric-Bernstam, David Spigel, Ron Bose, Howard Burris, Walter C. Darbonne, Julia Malato, Jonathan Levy, Yong Wang, Tania Szado, Katja Schulze, John Hainsworth, Razelle Kurzrock. Activity and safety of alectinib for ALK-altered solid tumors from MyPathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT032.

Abstract CT124: NeoCOAST-2: a randomized, open-label, phase 2 study of neoadjuvant durvalumab plus novel immunotherapies and chemotherapy (CT) followed by adjuvant durvalumab plus novel agents, in patients with resectable non-small-cell lung cancer (NSCLC)

Abstract Background: Neoadjuvant and adjuvant platinum-based CT improve survival rates in patients with resectable, early-stage NSCLC vs surgery alone. PD-1/PD-L1 inhibitors have shown clinical efficacy in patients with resectable, early-stage NSCLC, in both the neoadjuvant and adjuvant settings. The anti-PD-L1 monoclonal antibody (mAb) durvalumab, in combination with either the anti-CD73 mAb oleclumab or the anti-NKG2A mAb monalizumab, improved response rates and progression-free survival in patients with unresectable, Stage III NSCLC in the phase 2 COAST trial (NCT03822351). The NeoCOAST trial (NCT03794544) is currently evaluating the combination of durvalumab with oleclumab or monalizumab as neoadjuvant treatment in patients with resectable, early-stage NSCLC. NeoCOAST-2 (NCT05061550) is a multicenter study of neoadjuvant durvalumab combined with CT and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab, in patients with resectable, Stage IIA-IIIA NSCLC. Methods: Eligible patients must have previously untreated, histologically/cytologically confirmed NSCLC, a WHO/ECOG performance status of 0 or 1, and life expectancy of ≥12 weeks. Patients must have tumor samples available for biomarker analyses, have planned surgery consisting of lobectomy, sleeve resection, or bilobectomy, and have a pre- or post-bronchodilator FEV1 of 1.0 L and DLCO >40% postoperative predictive value. Patients with sensitizing EGFR mutations or ALK translocations, history of allogeneic organ transplantation, active or prior documented autoimmune or inflammatory disorders, or uncontrolled intercurrent illness, are excluded. Approximately 140 patients will be randomized 1:1, stratified by PD-L1 expression (<1% vs ≥1%), to receive IV durvalumab + oleclumab or monalizumab + CT Q3W for 4 cycles prior to surgery, followed by durvalumab + oleclumab or monalizumab Q4W post surgery. Surgery must occur within 40 days of the last dose of neoadjuvant therapy. Patients will receive adjuvant therapy starting within 10 weeks after surgery, for 12 cycles or until disease progression (per RECIST v1.1). The primary endpoints are pathological complete response rate per blinded independent pathologist review, and safety and tolerability. Secondary endpoints include investigator-assessed event-free survival and disease-free survival, feasibility of planned surgery, major pathological response rate, changes in circulating tumor DNA, investigator-assessed objective response rate following neoadjuvant therapy, overall survival, pharmacokinetics and immunogenicity. Citation Format: Tina Cascone, Alexander Spira, Rosario G. Campelo, Dong-Wan Kim, Oday Hamid, Yee Soo-Hoo, Rakesh Kumar, Italia Grenga, Patrick Forde. NeoCOAST-2: a randomized, open-label, phase 2 study of neoadjuvant durvalumab plus novel immunotherapies and chemotherapy (CT) followed by adjuvant durvalumab plus novel agents, in patients with resectable non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT124.

Updated efficacy and safety results from the phase 2 study of serplulimab, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors.

2592 Background: Serplulimab is a novel humanized monoclonal antibody against PD-1. At ASCO 2021, we have presented the results from the phase 2 serplulimab study (NCT03941574) in patients with unresectable/metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors who have progressed on or been intolerant to standard therapies with a median follow-up of 7.7 months. Here, we report the updated efficacy and safety results together with the results from sensitivity analysis after another 6-month follow-up. Methods: In this single-arm, open-label, multicenter, phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were enrolled to receive 3 mg/kg of intravenous serplulimab every two weeks for up to two years. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per RECIST v1.1. Secondary endpoints included ORR assessed by the investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 10, 2021, 108 patients had received at least one dose of study treatment and were included in the safety set (SS). Among them, 68 patients with confirmed MSI-H (by local sites or central lab) were included in the main efficacy analysis population (MEAP); 58 patients with confirmed MSI-H (by central lab) and had no major protocol deviations were included in the sensitivity analysis population (SAP). The median follow-up duration was 13.5 months in the MEAP and 14.0 months in the SAP. IRRC-assessed ORR per RECIST v1.1 was 39.7% (95% CI 28.0–52.3; 3 complete response [CR]) in the MEAP and 43.1% (95% CI 30.2–56.8; 2 CR) in the SAP. Investigator-assessed ORRs were 38.2% (95% CI 26.7–50.8; 1 CR) and 41.4% (95% CI 28.6–55.1; 1 CR) in the MEAP and the SAP, respectively. Median DoR, PFS, and OS were not reached; 12-month OS rate was 74.5% (95% CI 62.2–83.3) in the MEAP and 82.4% (95% CI 69.7–90.1) in the SAP. In the SS, 57 (52.8%) patients had grade ≥3 treatment-emergent adverse events, most commonly anemia (9.3%). Thirteen (12.0%) patients had grade ≥3 immune-related adverse events. Three (2.8%) deaths (2 progressive disease and 1 intestinal obstruction) that might be related to serplulimab were reported. Conclusions: The encouraging antitumor activity and the manageable safety profile sustained after a longer duration of follow-up, supporting the further development of serplulimab as a potential tissue-agnostic antitumor treatment. Clinical trial information: NCT03941574.

A phase II study of alectinib in combination with bevacizumab as first-line treatment in advanced NSCLC with confirmed ALK fusion: ALEK-B trial.

9074 Background: Alectinib is one of the standard treatment options as an upfront therapy in advanced ALK-rearranged non-small-cell lung cancer. However, all patients will eventually progress to target therapy, developing resistance mechanisms. Preclinical data have demonstrated an enhanced activity combining an anti-vascular endothelial growth factor blockade to ALK tyrosine inhibitors. Hence, this study assesses the safety and efficacy of adding bevacizumab to alectinib. Methods: ALEK-B is an open-label phase II trial investigating the efficacy and safety of combined alectinib 600mg daily and bevacizumab 15mg/kg every three weeks in untreated patients with advanced ALK fusion-positive NSCLC. Every patient had confirmed molecular diagnosis by next-generation sequencing (Foundation One CDx) at baseline and progression. The primary endpoint was investigator progression-free survival (PFS). Secondary endpoints were investigator-assessed objective response rate (ORR), intracranial response (ICR), time to central nervous system (CNS) progression, and overall survival. Hence, we present the first interim analysis. Results: Between April 2020 and October 2021, 37 patients were recruited. At the data cut-off of January 31st, 2022, the median follow-up was 15.6 months (IQR 12.5), and an event of disease progression or death occurred in 1 of 36 patients (2.7%). The 12-month event-free survival rate was 97.1% (95% CI 91 to 99), and median PFS was not reached (95% IC 8.9 to NR). Of 36 evaluable patients, 35 had an objective response [ORR 97.2% (95% CI 91 to 99)], and 3 (8.3%) experienced a complete response. Five patients had brain metastases at baseline; among those with measurable disease (n = 4), the ICR was 100%, one complete response, and median duration of response of 11.4 months (IQR 13.1). The 12-month CNS event-free rate was 100%. Any grade adverse events occurred in 86.4% of patients; most common were AST/ALT increase (40.5%), diarrhea (32.4%), blood bilirubin increase (21.6%), anemia (18.9%), and peripheral edema (18.9%). Grade 1-2 hypertension and proteinuria occurred in five (13.5%) patients, and no > G3 occurred. Grade ≥3 treatment-related AEs (TRAEs) occurred in 32.4%; most frequent were AST/ALT increase (27%) and creatinine increase (5.4%). Conclusions: The combination of Alectinib and bevacizumab demonstrated to be a safe and highly effective treatment in terms of response in the first-line setting. Moreover, it seems promising for patients with brain metastases. These results warrant the design of larger confirmatory trials, ideally a randomized phase III study. Clinical trial information: NCT03779191.

Phase II study of trastuzumab-pkrb and docetaxel anhydrous combination therapy in recurrent or metastatic salivary ductal carcinomas (KCSG HN18-08/KM11).

6018 Background: Salivary gland cancers (SGCs) are relatively rare, accounting for 1-6% of all neoplasms of the head and neck, have diverse disease course with respect to origin and pathology. Salivary duct carcinoma (SDC) is the most aggressive tumor subtype of primary SGC, showing high rates of local recurrence and distant metastases. In regard to previous studies which reported a high prevalence of HER2 positivity in SDCs, we conducted a single-arm, phase II study to evaluate the antitumor activity and safety of Herzuma (a trastuzumab biosimilar which demonstrated an equivalent efficacy to reference trastuzumab) in combination with docetaxel anhydrous (Nanoxel) in patients with HER2-positive advanced SDCs. Methods: Eligible patients had histologically confirmed HER2-positive (defined as IHC≥2+ and/or FISH HER2/CEN17 ratio ≥2.0) recurrent/metastatic SDC, or subtypes of SGC that were pathologically similar to SDC (excluding ACCs). They received Herzuma (8mg/kg i.v. loading dose, followed by 6mg/kg i.v.) and Nanoxel (75mg/m2 i.v.) every 3 weeks. The primary endpoint was the investigator-assessed objective response rate (ORR) according to RECIST v1.1. Secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. The calculated sample size was 43 patients for H1 of ORR ≥40%. Safety was evaluated by CTCAE v4.0. Results: A total of 43 patients were enrolled. Patient characteristics included: median age 60 (range 35–81); 86% male; 84% ECOG1; 84% SDC, 9% adenocarcinoma, 2% high grade mucoepidermoid carcinoma, and 5% other subtypes. Confirmed ORR was seen in 67% (95% CI, 52–81). No patient had a complete response as their BOR, 29 (67%) had a partial response, 11 (26%) had stable disease, 1 (2%) had progressive disease, and 2 (5%) were unevaluable. The DCR was 93% (95% CI, 81–99). The median PFS and OS were 8.2 months (95% CI, 6.7–9.7) and 23.3 months (95% CI, 19.9–26.7), respectively. Thirty-eight (88%) patients experienced a treatment-related AE (TRAE), with 15 (35%) patients experiencing ≥grade 3 TRAE including: neutropenia (10), febrile neutropenia (4), anemia (1), sepsis (1), anaphylaxis (1), decreased LVEF (1). There were no treatment-related deaths. Conclusions: The study met the primary endpoint of ORR. Herzuma and Nanoxel combination therapy demonstrated a promising treatment outcome in patients with HER2-positive recurrent/metastatic SDC. Clinical trial information: NCT03614364.

An investigator-initiated phase II trial of a PARP inhibitor niraparib monotherapy for patients with pre-treated, BRCA-mutated, unresectable/recurrent biliary tract, pancreatic, and other gastrointestinal cancers (NIR-B trial).

TPS4174 Background: Recent comprehensive genomic profiling tests have revealed therapeutic target molecules. However, because many targets are present in only a small fraction of patients, a large number of patients need to be screened for enrollment in a single study. In order to overcome this patient identification barrier, the SCRUM-Japan, nationwide large-scale genomic profiling platform, efficiently has been performed umbrella- and basket-type clinical trials. Among the platforms, we have reported that there are BRCA1/2-mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is an anticancer drug belonging to poly(ADP-ribose) polymerase (PARP) inhibitors. Niraparib has been shown to be selective for PARP1/2, to be more cytotoxic among other PARP inhibitor because of its PARP trapping activity. Methods: This is an investigator-initiated, multicenter, three-cohort phase 2 study. Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (cohort A), pancreatic cancers (cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Primary endpoint is the investigator-assessed objective response rate in each cohort with a threshold-response rate of 10% and an expected response rate of 35%. Key secondary endpoints are progression-free survival, overall survival, disease control rate, duration of response, and safety. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL receive 200 mg of niraparib, orally once daily. Furthermore, pre-treatment tumor tissue and serial ctDNA will be collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. The trial was initiated in January 2021 with enrollment being ongoing. Thirty-three out of planned 60 patients (cohort A/B/C; 25/25/10, respectively) have been enrolled as of December 2021. Funding: Takeda Pharmaceutical Co., Ltd. Clinical trial information: jRCT2011200023.

KITE-363: A phase 1 study of an autologous anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) B-cell lymphoma (BCL).

TPS7579 Background: One mechanism by which B-cell tumors can resist the effects of CD19-targeted CAR T-cell therapy is through CD19 antigen escape (Neelapu et al. ASH 2019). Recent analyses in large B-cell lymphoma (LBCL) demonstrated that approximately one-third to two-thirds of relapses after infusion of CAR T-cell therapy were CD19 negative (Plaks et al. Blood. 2021; Spiegel, Dahiya et al. Blood. 2021; Spiegel et al. Nat Med. 2021). KITE-363 is an autologous CAR T cell transduced with a bicistronic vector with resultant expression of a CD19 CAR with a CD28 costimulatory domain and a CD20 CAR with a 41BB costimulatory domain. In preclinical studies, KITE-363 recognized and eliminated tumor cells expressing CD19 and/or CD20. KITE-363 CAR T-cell therapy has the potential to rescue CD19-negative relapsing patients with BCL as well as prevent CD19 antigen escape by minimizing selective pressure through upfront therapeutic dual targeting. This Phase 1, first-in-human, open-label, multicenter study (NCT04989803) will evaluate the safety and preliminary efficacy of KITE-363 in patients with R/R BCL. Methods: The Phase 1 design includes a 3+3 dose-escalation portion (1A), with 5 planned CAR T-cell levels, and a dose expansion portion (1B). Patients may receive optional corticosteroid bridging therapy following leukapheresis. Patients will then receive conditioning chemotherapy (cyclophosphamide and fludarabine) on Day ‒5 to Day ‒3 followed by KITE-363 infusion on Day 0. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per Lugano criteria (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete response rate, time to next treatment, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells in blood and cytokines in serum. Eligible adult patients have histologically confirmed BCL, including LBCL, indolent non-Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma (HL), and BCL, unclassifiable (with features intermediate between diffuse LBCL and classical HL), that is R/R after ≥2 lines of therapy (patients with LBCL may have primary refractory disease). Other key inclusion criteria are adequate bone marrow and organ function and ECOG performance status 0‒1. Key exclusion criteria are central nervous system (CNS) involvement from lymphoma, active infection including hepatitis B and C, and clinically significant CNS disorder. This study is currently open and accruing patients. Clinical trial information: NCT04989803.

A phase II study of KN046 monotherapy as 2nd line and above treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).

e16305 Background: Pancreatic cancer is a malignancy with poor prognosis and high mortality ranking 7th worldwide and with a 5-year survival rate of 10.8%. More than 50% pts are diagnosed at the late stage. The monoclonal antibodies of immune checkpoint inhibitors are also being investigated but has very limit progression free survival (PFS) and overall survival (OS) benefit. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) in a phase 2 study arm 2 (NCT04324307) was reported before. Here, we report the efficacy and safety of KN046 as a monotherapy in the 2nd line and above setting (arm1). Methods: This ongoing phase 2 trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and failed to at least one systemic anti-tumor treatment in arm 1. Single agent of KN046 (5mpk, Q2W) were administered until disease progression or intolerable toxicity. Tumor response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed objective response rate (ORR). Secondary endpoints including disease control rate (DCR), PFS, OS and safety, etc. Results: As of Jan 10, 2022, 21pts were enrolled, median (range) age was 57 (51-64) years, 14 (66.7%) pts ECOG 1, 16 (76.2%) pts had distant metastases, and 11 (52,4%) pts had received ≥2 lines systemic treatment. Median KN046 exposure time was 4.1(2.1,6,4) wks. 9 pts were included in the efficacy analysis with 1 PR and 3 SD. 21 pts in the safety analysis. Confirmed ORR was 11.1% (95% CI: 0.28,48.25), and DCR was 44.4% (95% CI: 13.7,78.8). Median PFS was 2.1 months (95% CI:1.61̃7.29), PFS rate in 6 and 9 months were 31.4% and 21%, respectively. Median OS was 7.5months (95% CI:3.02-NR), OS rate in 6 and 9 months were 61.3% and 49.5%, respectively. The incidence of KN046 related treatment-emergent adverse events (TRAE) was 71.4% (15/21), with 14.3% (3/21) ≥grade 3 TRAEs. Two pts experienced TRAE leading to discontinuation. The most common TRAEs (≥10%) were rash (n=6, 28.6%), alanine aminotransferase increased, chills, γ-glutamyl transferase increased and platelet count decreased (n = 3, 14.3%, respectively). No TRAE leading to death occurred. Conclusions: KN046, a bispecific antibody as 2nd line and above monotherapy for unresectable locally advanced or metastatic PDAC patients demonstrated a good PFS and OS benefit as well as acceptable safety profile, supporting KN046 in combination of chemotherapy as first line treatment. Clinical trial information: NCT04324307.

P-26 HERIZON-GEA-01: A phase 3 study of zanidatamab in combination with chemotherapy with or without tislelizumab in first-line human epidermal growth factor receptor 2 positive (HER2+) advanced/metastatic gastroesophageal adenocarcinoma (GEA)

Gastroesophageal adenocarcinomas (GEAs), including gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinomas, are common cancers with high morbidity and mortality. In approximately 25% of GEA cases, HER2 is overexpressed/amplified. Patients with advanced/metastatic HER2+ GEA are typically treated with trastuzumab, a HER2-targeted therapy, plus chemotherapy in the first-line setting. Preliminary data suggests that the addition of an immune checkpoint inhibitor to the treatment regimen may further improve patient outcomes. Zanidatamab is a novel, bispecific HER2-targeting monoclonal antibody (mAb) that binds to two non-overlapping extracellular domains (ECD4 and ECD2) on HER2. This bispecific binding forms HER2 clusters and induces greater internalization and downregulation of cell surface HER2 compared to trastuzumab (as observed in preclinical studies). Zanidatamab also causes growth signal reduction and triggers immune-mediated antitumor activity through antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). Early studies have shown that zanidatamab has a manageable safety profile with encouraging antitumor activity in HER2+ GEA, when used both as a monotherapy and in combination with chemotherapy in later-line treatment. In the first-line setting in a phase 2 study, zanidatamab plus chemotherapy demonstrated a confirmed objective response rate (ORR) of 75%, median duration of response (DOR) of 16.4 months, and median progression-free survival (PFS) of 12.0 months. Separately, the anti-programmed cell death-1 (PD1) mAb tislelizumab has demonstrated a manageable safety profile and clinical activity in multiple cancers, including gastric and GEJ adenocarcinoma. The combination of zanidatamab with chemotherapy plus tislelizumab is being studied in an ongoing phase 1b/2 study and has recently completed accrual. HERIZON-GEA-01 (NCT05152147; EudraCT#: 2021-000296-36), is a global, randomized, open-label, active-comparator, phase 3 study that will further investigate the efficacy and safety of zanidatamab in combination with chemotherapy with or without tislelizumab as first-line treatment for patients with advanced/metastatic HER2+ GEA. Key eligibility criteria include: age ≥ 18 years, untreated, unresectable locally advanced/metastatic GEA that is HER2+ (IHC3+ or IHC2+/ISH+) per central testing, ECOG PS of 0 or 1, and adequate organ function, including LVEF > 50%. Enrolled patients will be assigned randomly (1:1:1) to either: trastuzumab (6 mg/kg IV Q3W) plus chemotherapy; zanidatamab (1800 mg IV [patient 2 IV Q3W and capecitabine 1000 mg/m2 oral BID on days 1–15) or FP (cisplatin 80 mg/m2 IV Q3W and 5-fluorouracil 800 mg/m2 continuous IV on days 1–5). The primary endpoints of the study are PFS per RECIST v1.1 assessed by blinded independent central review (BICR), and overall survival. Secondary endpoints include: BICR-assessed confirmed ORR and DOR; investigator-assessed PFS, ORR, and DOR; incidence and severity of AEs; and changes in health-related quality of life (HRQoL). 714 patients are planned to be enrolled from ∼300 sites in 30+ countries across North America (not including the US), South America, Europe, Africa, Asia, and Oceania. The study is currently recruiting patients. NCT05152147; EudraCT#: 2021-000296-36. Sponsor.

Long-term efficacy and safety of larotrectinib in a pooled analysis of patients with tropomyosin receptor kinase (TRK) fusion cancer.

3100 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in multiple tumors. Larotrectinib is a highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, approved to treat adult and pediatric patients (pts) with TRK fusion cancer. In an integrated analysis of 206 pts with non-primary CNS TRK fusion cancer, larotrectinib demonstrated an investigator-assessed objective response rate (ORR) of 75%; median progression-free survival (PFS) was 35.4 months (mo; Hong et al, ASCO 2021). We report updated efficacy and safety data based on central review assessments in an expanded dataset. Methods: Data were pooled from three clinical trials (NCT02576431, NCT02122913, and NCT02637687) of pts with non-primary CNS TRK fusion cancer treated with larotrectinib. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. ORR was assessed by independent review committee (IRC) per RECIST v1.1. Data cut-off was July 20, 2021. Results: As of data cut-off, 244 of 269 larotrectinib-treated pts were evaluable for efficacy by IRC. There were 25 different tumor types. The most common were soft tissue sarcoma (STS [43%], including infantile fibrosarcoma [18%] and other STS [25%]), thyroid (11%), lung (10%), salivary gland (9%), and colorectal (7% [colon, n = 18; rectal, n = 1]). Ninety-four (35%) pts were aged < 18 years; 175 (65%) were ≥18 years. Pts had gene fusions involving NTRK1 (46%), NTRK2 (3%), or NTRK3 (51%). A total of 27%, 28%, and 45% of pts had 0, 1, and ≥2 prior lines of systemic therapy, respectively. The ORR was 69% (95% confidence interval [CI] 63–75): 64 (26%) complete response (CR), including 13 (5%) pathological CR, 104 (43%) partial response,41 (17%) stable disease, 20 (8%) progressive disease, and 15 (6%) not determined. Median time to response was 1.8 mo (range 0.9–16.2). Median duration of response (DoR) was 32.9 mo (95% CI 27.3–41.7); median follow-up was 28.3 mo. Median PFS was 29.4 mo (95% CI 19.3–34.3); median follow-up was 29.3 mo. At a median follow-up of 32.2 mo, median overall survival (OS) was not reached; the 48-mo OS rate was 64% (95% CI 55–73). Treatment duration ranged from 0.1 to 67.9 months. Treatment-related adverse events (TRAEs) were mainly Grade 1–2; 50 (20%) pts had Grade 3–4 TRAEs. Five (2%) pts discontinued treatment due to TRAEs. To exclude the possible confounding effect of ongoing enrollment on median DoR, we conducted an exploratory analysis in the subset of 164 pts who were analyzed as of July 2019. The ORR was 74% (95% CI 67–81) and median DoR was 34.5 mo (95% CI 27.6–43.3); median follow-up was 34.1 mo. Conclusions: With longer follow-up, larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favorable safety profile. These results highlight the importance of testing for NTRK gene fusions in cancer pts. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.

A phase IB/II study of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer (KCSG BR18-16).

1098 Background: Combining immune checkpoint inhibitors with chemotherapy has become a promising therapeutic strategy in metastatic breast cancer. Eribulin is a potent microtubule inhibitor and modulates the immune microenvironment of tumor cells. Therefore, combining eribulin to nivolumab may synergize antitumor efficacy in metastatic breast cancer. Methods: Adult patients with histologically confirmed recurrent/metastatic HER2- breast cancer were enrolled prospectively from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). Key eligibility criteria included prior treatment with taxanes and/or anthracyclines, ≥1 measurable disease, and ≤2 prior cytotoxic chemotherapies in the metastatic setting. Patients received nivolumab 200 mg intravenously (IV) on day 1 plus eribulin 1.4 mg/m2 IV on day 1 and 8 of every 3 weeks until disease progression or intolerable toxicity. The dose level was determined from safety profile of three patients in run-in phase. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included investigator-assessed objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), overall survival (OS), and toxicity profile of the combination treatment. The association between PD-L1 expression by SP142 Ab and efficacy was analyzed. Results: From August 2019 to June 2021, 90 patients (HR+HER2- 45 pts/TNBC 45 pts), with a median age of 51 (range 31–71), were enrolled in the study. With a median study follow-up time of 16.3 months, 68 (75.6%) patients experienced progressive disease. PFS rate at 6-months was 49.6% and 24.1% in patients with HR+HER2- and TNBC group, respectively. Median PFS was 5.6 months (95% CI: 4.3-6.8) and 3.0 months (95% CI: 1.3-4.7) for HR+HER2- and TNBC group, respectively. ORRs were 53.3% (CR:0, PR: 24) for HR+HER2- and 21.8% (CR1, PR: 12) for TNBC. Patients with PD-L1+ tumors (PD-L1 expression ≥ 1% on TC or IC) had similar ORR compared to PD-L1- tumors (ORR 50% vs. 53.8% in HR+HER2-, 30.8% vs. 29.0% in TNBC). The most common grade 3/4 adverse event was neutropenia (15/90, 16.7%), and the most common immune-related adverse events were grade 1/2 hypothyroidism (19/90, 21.1%) and grade 1/2 pruritus (16/90, 17.8%). Five patients had discontinued study treatment due to immune-related adverse events (3 pneumonitis, 1 hepatitis, 1 skin rash). Conclusions: In this parallel phase II clinical trial, the addition of nivolumab to eribulin showed promising efficacy and tolerable safety profile in previously treated HER2- MBC. Further survival and exploratory analyses to find predictive markers will be followed. Clinical trial information: NCT04061863. [Table: see text]

Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial

Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST (NCT02848651), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB–IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.

Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma.

Objective Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).Methods We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.Results Twenty-nine patients (median age: 60; range: 6–80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51–87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64–97) for PTC/FTC and 29% (95% CI 4–71) for ATC. Median time to response was 1.87 months (range 1.64–3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1–2.Conclusion In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.Significance statementNTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.

A Phase 2 Study of Magrolimab Combination Therapy in Patients with Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Novel combination therapies are needed to extend the survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC). Magrolimab is a humanized monoclonal antibody that blocks the immune checkpoint CD47, a "do not eat me" signal, overexpressed on cancer cells. Magrolimab binding to CD47 leads to phagocytosis of cancer cells and enhances antitumor efficacy through stimulation of both innate and adaptive immune responses. The current study (NCT04854499) is investigating the safety, tolerability, recommended Phase 2 dose (RP2D), and efficacy of three experimental magrolimab-containing regimens: 1) magrolimab + pembrolizumab + 5-fluorouracil + platinum (cisplatin or carboplatin) [MPFP]; 2) magrolimab + pembrolizumab (MP); and 3) magrolimab + docetaxel (MD). <h3>Materials/Methods</h3> This Phase 2, open-label study includes two safety run-in cohorts and three Phase 2 cohorts. The primary endpoints of the two run-in cohorts are to evaluate the incidence of adverse events and laboratory abnormalities as dose-limiting toxicities with MPFP in patients with untreated RM-HNSCC, and with MD in patients with RM-HNSCC treated with 1 to 2 lines of prior systemic therapy. The primary endpoints of Phase 2 are to evaluate the progression-free survival with MPFP versus PFP in patients with untreated RM-HNSCC (cohort 1), and the investigator-assessed objective response rates with MP in patients with untreated RM-HNSCC with PD-L1 CPS ≥1 (cohort 2) and with MD in patients with RM-HNSCC treated with 1 to 2 lines of prior systemic therapy (cohort 3). Magrolimab is administered IV on days 1, 8 and 15 of cycles 1 and 2, and day 1 of cycle 3 onward. Pembrolizumab, 5-fluorouracil, cisplatin, carboplatin, and docetaxel will be administered according to manufacturer's prescribing information. Patients will continue treatment until unacceptable toxicity or disease progression. Planned enrollment is ∼233 participants. Recruitment is ongoing. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial

BackgroundLenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. ObjectiveTo assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. Design, setting, and participantsA randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor–targeted therapy (prior anti–programmed death-1/programmed death ligand-1 therapy permitted). InterventionPatients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. Outcome measurements and statistical analysisThe primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORRwk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. Results and limitationsThe ORRwk24 for the 14-mg arm (32% [95% confidence interval {CI} 25–39]) was not noninferior to the ORRwk24 in the 18-mg arm (35% [95% CI 27–42]; odds ratio: 0.88; 90% CI 0.59–1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. ConclusionsThe study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. Patient summaryIn this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used.