Independent Radiological Committee Research Articles

Randomized controlled, open-label, phase IIb/III study of lurbinectedin in combination with doxorubicin versus doxorubicin alone as first-line treatment in patients with metastatic leiomyosarcoma.

TPS11590 Background: Lurbinectedin (LUR) is a synthetic chemical entity structurally related to trabectedin that inhibits oncogenic transcription and is active in tumors addicted to transcription. Synergistic activity of the combination of LUR with Doxorubicin (DOX) was found in solid tumors. Preliminary results from two trials showed efficacy for LUR/DOX in anthracycline-naïve advanced Leiomyosarcoma (LMS) (1st or 2nd line) at different doses. In a phase 2 trial in soft tissue sarcoma (STS) patients (pts) (mostly with LMS: 12/20 pts), a combination of DOX 50 mg/m2 + LUR 2 mg/m2 Day (D)1 q3wk resulted in a response rate (RR) of 35% (4/7 LMS pts responding) and a disease control rate (DCR) at 24 wks of 40% (1). A phase 1b/2 trial in 10 advanced STS pts found a RR of 60% (5 were LMS, with 3 partial responses) treated at DOX 25 mg/m2 D1 or D1,D8 + LUR 3.2 mg/m2 D1 q3wk, (2). The promising results of these trials provide a rationale for further exploring this combination in a phase 2b/3 trial as first-line therapy for metastatic LMS (SaLuDo - NCT06088290). Methods: SaLuDo is a randomized, open-label study evaluating LUR in combination with DOX compared to DOX alone as first-line treatment of pts with metastatic LMS. The primary endpoint is progression-free survival (PFS) according to Independent Radiological committee (IRC). Secondary endpoints include overall survival, PFS according to Investigator assessment (IA), overall response rate, duration of response, and clinical benefit rate (according to IRC and IA), safety profile, patient-reported outcomes, pharmacokinetics, and exploratory pharmacogenomic analysis. Main inclusion criteria include age ≥ 18 years, confirmed diagnosis of metastatic LMS, and no prior systemic treatment for metastatic disease. Exclusion criteria include prior treatment with anthracyclines, lurbinectedin or trabectedin. The phase 2b part of the study will randomize approximately 120 pts into 3 arms (1:1:1): Control arm (DOX 75 mg/m2 D1 q3wk; experimental ARM A (DOX 50 mg/m2 D1 + LUR 2.2 mg/m2 D1 + 1ry GCSF prophylaxis q3wk), and experimental ARM B (DOX 25 mg/m2 D1 + LUR 3.2mg/m2 D1 + 1ry GCSF prophylaxis q3wk). Stratification will be done according to site of primary tumor (uterine vs. soft tissue), sites of metastatic disease (lung as unique site vs. other) and time from diagnosis to study entry (≤ 12 months vs. >12 months). One of the two experimental arms will be dropped out at the end of phase 2b. The study will then enter the phase 3 part and approximately 120 pts will be randomized 1:1 between the control arm and the selected experimental arm. An Independent Data Monitoring Committee will oversee the conduct of the study. The first patient was randomized in 09/2023. The phase 2b part of the study is ongoing and recruiting patients in Europe and the USA. 1. Cote EJC 2020; 126:21-32. 2. Cote. JCO 2023; 41: Abst 11507. Clinical trial information: NCT06088290 .

STELLAR-305: A randomized phase 2/3 study of zanzalintinib plus pembrolizumab versus pembrolizumab alone in patients with previously untreated PD-L1 positive recurrent/metastatic head and neck squamous cell carcinoma.

TPS6114 Background: VEGFR, MET, and the TAM kinase AXL are overexpressed in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC); their activation contributes to increased tumor aggressiveness and poor prognosis. The immune checkpoint inhibitor (ICI) pembrolizumab, as monotherapy or in combination with chemotherapy, is a standard of care in patients with PD-L1 expressing R/M HNSCC. However, the response rate and survival benefit with pembrolizumab monotherapy are unsatisfactory, and addition of chemotherapy results in unfavorable toxicity. Zanzalintinib is a novel, multi-targeted tyrosine kinase inhibitor (TKI) of VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). Preclinical data suggest zanzalintinib-mediated inhibition of these kinases may suppress tumor growth and angiogenesis, while simultaneously promoting an immune-permissive tumor microenvironment that may enhance response to ICIs. Zanzalintinib + ICI combination has shown promising antitumor activity and manageable safety in a phase 1 study in solid tumors. To further support the TKI-ICI combination, phase 2 clinical activity was observed in R/M HNSCC with the multi-targeted TKI cabozantinib (inhibits VEGFR, MET, and TAM kinases) in combination with pembrolizumab. The present study, STELLAR-305, will evaluate the efficacy and safety of zanzalintinib + pembrolizumab vs pembrolizumab alone in previously untreated, PD-L1-positive, R/M HNSCC. Methods: STELLAR-305 (NCT06082167) is a randomized, double-blind, phase 2/3 study. Eligible patients are adults (≥18 years) with histologically or cytologically confirmed R/M HNSCC that is incurable with local therapy. Patients may not have been treated with systemic therapy, unless given as part of multimodal treatment for locally advanced disease and completed >6 months before randomization. Patients must have a primary tumor location of the oropharynx (HPV testing required), oral cavity, hypopharynx, or larynx; those with nasopharynx, salivary gland, or occult primary sites are excluded. Other eligibility criteria include a PD-L1 CPS ≥1, measurable disease per RECIST v1.1, and an ECOG performance status of 0–1. Patients with prior treatment with ICIs or zanzalintinib are not eligible. Patients will be randomized 1:1 to zanzalintinib + pembrolizumab, or placebo + pembrolizumab. The dual primary endpoints are PFS per RECIST v1.1 by blinded independent radiology committee and overall survival. Secondary endpoints include safety, PFS per RECIST v1.1 by investigator, objective response rate, and duration of response. If minimum efficacy requirements are met in phase 2, the study will proceed to phase 3 with approximately 500 patients enrolled across both phases. STELLAR-305 is currently enrolling, with 200 sites estimated for global expansion. Clinical trial information: NCT06082167 .

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study

The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up. COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791. Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation). First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals. Exelixis and Ipsen.

CONTACT-02: Phase 3 study of cabozantinib (C) plus atezolizumab (A) vs second novel hormonal therapy (NHT) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

18 Background: Pts who have progressed on a prior NHT and have mCRPC with extrapelvic nodal or visceral metastasis have a poor prognosis with limited, broadly available treatment options beyond chemotherapy. C promotes an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors (ICIs). Methods: Pts randomized 1:1 to C+A (C [40 mg PO QD] + A [1200 mg IV Q3W]) or control (ctrl) (abiraterone [1000 mg PO QD] + prednisone [5 mg PO BID] or enzalutamide [160 mg PO QD]) were stratified by liver metastasis (yes/no), prior docetaxel for mCSPC (yes/no), and prior NHT for mCSPC/M0CRPC/mCRPC. Key eligibility criteria: mCRPC with disease progression on one prior NHT, measurable extrapelvic nodal or visceral disease, ECOG PS ≤1, ongoing androgen deprivation therapy. Docetaxel was allowed for mCSPC. Dual primary endpoints are radiographic PFS by blinded independent radiology committee (BIRC) per RECIST 1.1 in the first 400 randomized pts (PITT) and OS in all randomized pts (ITT). Secondary endpoint is ORR by RECIST 1.1 per BIRC. Results: At the data cutoff (Feb 28, 2023), 507 pts (ITT) were randomized to receive C+A (n=253) or ctrl (n=254). Baseline and clinical characteristics were balanced between C+A and ctrl arms: 25% and 26% had liver metastasis, 21% and 20% received docetaxel for mCSPC, and 72% and 74% received first NHT for mCRPC. Median follow-up was 12.0 mo for ITT and 14.3 mo for PITT populations. Median PFS was significantly longer with C+A vs ctrl (6.3 vs 4.2 mo; HR 0.65, 95% CI 0.50-0.84; P=0.0007) including in subgroups with liver metastasis (6.0 vs 2.1 mo; HR 0.47 [95% CI 0.30- 0.74]) or prior docetaxel treatment for mCSPC (8.8 vs 4.1 mo; HR 0.55 [0.32-0.96]). ORR was higher in C+A vs ctrl in pts with follow-up ≥6 mo in ITT (13.6% [23/169] vs 4.2% [7/165]). Median DOR was 9.7 mo for C+A vs not reached for ctrl, and time to response was 2.3 vs 4.6 mo. DCR was 72.8% (123/169) vs 54.5% (90/165). OS data are immature. Treatment-emergent adverse events (TEAE) occurred in 97% in C+A vs 87% in ctrl (grade 3/4 events, 48% vs 23%). Grade 5 TEAEs occurred in 9% vs 12% and no grade 5 treatment-related AEs occurred in either arm. TEAEs led to the discontinuation of all treatment components in 16% in C+A and 15% in ctrl. Conclusions: C+A significantly improved PFS vs second NHT in pts who had progressed on a prior NHT and have mCRPC with extrapelvic nodal or visceral disease, a population with high unmet medical need. These PFS benefits were particularly notable in pts with liver metastasis and those who previously received docetaxel for mCSPC. Toxicities reported with each treatment arm were manageable. CONTACT-02 is the only phase 3 study of an ICI-based regimen to show a significant and clinically meaningful improvement in PFS in prostate cancer with visceral metastasis. Follow-up for OS is ongoing. Clinical trial information: NCT04446117.

AFM13 in Combination with Allogeneic Natural Killer Cells (AB-101) in Relapsed or Refractory Hodgkin Lymphoma and CD30 + Peripheral T-Cell Lymphoma: A Phase 2 Study (LuminICE)

Background and Significance Limited treatment options are available for patients with relapsed or refractory (R/R) Hodgkin lymphoma (HL) and no standard-of-care therapy is established for R/R peripheral T-cell lymphoma (PTCL); novel therapies to improve outcomes in these patients are required. AFM13 is a tetravalent, bispecific innate cell engager that binds CD16A on natural killer (NK) cells and CD30 expressed (CD30 +) on HL and PTCL cells, enhancing NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). AFM13 monotherapy trials in patients with R/R HL and PTCL have shown promising clinical activity and a tolerable safety profile (Sasse et al. Blood 2020; Kim et al. Cancer Res 2023). Recently, a Phase 1/2 study of AFM13 in combination with cord blood (cb)-derived NK cells in patients with R/R CD30 + lymphomas treated at the recommended phase 2 dose (n=35) achieved an objective response rate (ORR) of 94% and a complete response (CR) rate of 71% (Nieto et al. Blood 2022, oral presentation). AB-101 is a non-genetically modified, allogeneic, cryopreserved, off-the-shelf, cb-derived NK cell product optimized for enhanced ADCC through selection for the KIR-B haplotype and the CD16 F158V polymorphism. AB-101 has demonstrated potent killing of tumor cell lines in vitro and in vivo and preliminary results of a Phase 1/2 trial of AB-101 alone and in combination with rituximab in patients with R/R B cell non-Hodgkin lymphoma demonstrated AB-101 is well tolerated (Khanal et al. J Clin Oncol 2023). Combining AFM13 with AB-101 has the potential to synergistically enhance and redirect antitumor immune responses to target HL and CD30 + PTCL cells. Study Design and Methods This Phase 2, open-label, multi-center, multi-cohort study (NCT05883449) aims to evaluate the efficacy and safety of AFM13 in combination with AB-101 in patients with R/R HL and certain R/R CD30 + PTCL subtypes. PTCL subtypes permitted are PTCL not-otherwise specified, angioimmunoblastic T-cell lymphoma, and ALK-positive and -negative anaplastic large cell lymphoma (ALCL). Patients aged ≥18 years are planned for enrolment and patients with R/R HL must have received at least two prior lines of therapy including prior combination chemotherapy, brentuximab vedotin (BV) and a checkpoint inhibitor. Patients with R/R PTCL must have confirmed CD30 expression of ≥1% by immunohistochemistry and have received at least one prior line of combination chemotherapy; patients with ALCL must have received or been intolerant to BV. Prior autologous or allogeneic hematopoietic stem cell transplant is permitted. Exclusion criteria include treatment with any anti-cancer agent ≤21 days prior to enrolment, continuing toxicity from a prior therapy, central nervous system involvement, or previous treatment with AFM13 or NK cells. The primary objective is to determine the ORR (complete and partial responses) by Independent Radiology Committee (IRC) based on PET-CT per Lugano classification. Secondary objectives include safety and immunogenicity, complete response rate, duration of response and progression free survival. Treatment will be given intravenously (IV) over 48-day cycles for up to 3 cycles. A run-in phase will assess two dose levels of AFM13 and AB-101 in 4 cohorts (Figure). A standard lymphodepletion regimen of fludarabine (30 mg/m 2/day) and cyclophosphamide (300 mg/m 2/day) will be administered IV from Day −5 to Day −3 at the start of each treatment cycle. Following this, AFM13 (200 mg or 300 mg once weekly) will be given, with AB-101 (dose level 1 or 2, see Figure) given 1 hour later per cycle. Patients will also receive 6 ×10 6 IU of IL-2 subcutaneously at least 1 hour after each AB-101 dose. Cohorts 1 and 2 will enrol in parallel; cohorts 3 and 4 will start only if cohorts 1 and 2 are cleared per protocol safety criteria. After cycle 1 has completed for each subject enrolled in all 4 cohorts, an analysis of the safety and clinical responses will be performed to determine the two dose levels to be evaluated in the main study. In addition, an exploratory cohort (cohort 5) will begin enrolment of patients with CD30 + PTCL. Disease and efficacy assessments will be conducted at screening and on Day 43 (± 3 days) of each cycle.

INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH RESIDUAL OR RECURRENT GRADE 2 GLIOMA WITH AN IDH1/2 MUTATION

Abstract AIMS Current treatments grade 2 gliomas are not curative and can be associated with short- and long-term toxicities. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes, has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. METHOD In the phase 3 INDIGO study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS &amp;gt;80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). RESULTS As of 06 Sep2022, 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Median PFS by BIRC was 27.7 mos with VOR and 11.1 with PBO (HR, 0.39; 95% CI, 0.27, 0.56; 1-sided P=0.000000067). Median TTNI was not reached with VOR and 17.8 mos with PBO (HR, 0.26; 95% CI, 0.15, 0.43; 1-sided P=0.000000019). All-grade adverse events (AEs) occurring in &amp;gt;20% pts receiving VOR vs PBO were alanine aminotransferase increased, COVID-19, fatigue, aspartate aminotransferase increase, headache, diarrhea, nausea. Common grade ≥3 AEs (&amp;gt;5%): ALT increased (9.6% vs 0%). CONCLUSIONS VOR significantly improved PFS by BIRC versus PBO with a manageable safety profile. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.

KS02.6.A INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE III STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH RESIDUAL OR RECURRENT GRADE 2 GLIOMA WITH AN IDH1/2 MUTATION

Abstract BACKGROUND Grade 2 gliomas are slowly progressive, malignant brain tumours with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease-defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) - an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes - has shown a tolerable safety profile and preliminary clinical activity in Phase I studies. MATERIAL AND METHODS In this randomized, double-blind, placebo (PBO)-controlled Phase III study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or PBO daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumour size. Key eligibility criteria included: age ≥12; Karnofsky performance scale (KPS) &amp;gt;80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). RESULTS As of 6 Sep 2022 (2nd planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16-71); KPS =100: 53.5%; histological subtype: oligodendroglioma (172) and astrocytoma (159); median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (VOR: 131; PBO: 95). PFS by BIRC was statistically significant in favour of the VOR arm (HR 0.39, 95% CI 0.27-0.56; P=0.000000067). Median PFS: VOR: 27.7 months (mo); PBO: 11.1 mo. TTNI was statistically significant in favour of the VOR arm (HR 0.26, 95% CI 0.15-0.43; P=0.000000019). Median TTNI: PBO: 17.8 mo; VOR: not reached. All reported P values are one sided. All-grade adverse events (AEs) occurring in &amp;gt;20% pts receiving VOR vs PBO were alanine aminotransferase (ALT) increased (38.9 vs 14.7%); COVID-19 (32.9 vs 28.8%); fatigue (32.3 vs 31.9%); aspartate aminotransferase increase (28.7 vs 8.0%); headache (26.9 vs 27.0%); diarrhoea (24.6 vs 16.6%); nausea (21.6 vs 22.7%). Common grade ≥3 AEs (&amp;gt;5%): ALT increased (9.6% vs 0%). CONCLUSION This is the first prospective, randomized Phase III study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC, compared with PBO, with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed.

INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation.

LBA1 Background: Grade 2 gliomas are slowly progressive, malignant brain tumors with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) – an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. Methods: In this randomized, double-blind, placebo-controlled phase 3 study (NCT04164901) patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS &gt;80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). Results: As of 6Sep2022 (2nd planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16 to 71); KPS =100: 53.5%; histological subtype: oligodendroglioma: 172 and astrocytoma: 159; median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (131VOR; 95PBO). PFS by BIRC was statistically significant in favor of the VOR arm (HR, 0.39; 95% CI, (0.27, 0.56); P=0.000000067). Median PFS: VOR: 27.7 mos; PBO: 11.1 mos. TTNI was statistically significant in favor of the VOR arm (HR, 0.26; 95% CI, (0.15, 0.43); P=0.000000019). Median TTNI: PBO: 17.8 mos; VOR: not reached. All reported P values are one-sided. All-grade adverse events (AEs) occurring in &gt;20% pts receiving VOR vs PBO were alanine aminotransferase increased (38.9% vs 14.7%), COVID-19 (32.9% vs 28.8%), fatigue (32.3% vs 31.9%), aspartate aminotransferase increase (28.7% vs 8.0%), headache (26.9% vs 27.0%), diarrhea (24.6% vs 16.6%), nausea (21.6% vs 22.7%). Common grade ≥3 AEs (&gt;5%): ALT increased (9.6% vs 0%). Conclusions: This is the first prospective, randomized phase 3 study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC compared with PBO with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed. Clinical trial information: NCT04164901 .

Abstract CT022: Five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the phase II L-MIND study

Abstract Background: Tafasitamab, an anti-CD19 immunotherapy that enhances antibody-dependent cellular cytotoxicity and phagocytosis, received accelerated approval in the USA and conditional authorization in Europe in combination with lenalidomide (LEN) for patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) based on the results of the open-label, multicenter, single-arm, Phase II L-MIND study (NCT02399085; Salles G, et al. Lancet Oncol 2020, Duell J, et al. Haematologica 2021). Here, we report the final, 5-year follow-up of L-MIND. Data cut-off was Nov 14, 2022. Methods: Pts were aged ≥18 years with ASCT-ineligible R/R DLBCL, 1-3 prior systemic therapies (including a CD20-targeting regimen), and ECOG PS 0-2. Tafasitamab (12 mg/kg) was given for up to 12 cycles in combination with LEN (25 mg), then as monotherapy until disease progression (PD) or unacceptable toxicity. The primary endpoint was best objective response rate (ORR; complete response [CR] or partial response [PR], by independent radiology committee). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). Exploratory analyses evaluated efficacy endpoints by prior lines of therapy (pLoT). Results: Of 81 pts enrolled, 80 were treated (full analysis set [FAS]). The ORR (FAS) of 57.5% [95% CI: 45.9-68.5], with CR of 41.2% [30.4-51.6] (n=33) and PR of 16.2% [8.9-26.2] (n=13), was generally consistent with the primary and 3-year analyses. Median DoR was not reached (NR) with median follow up (mFU) of 44.0 months [29.9-57.0]. Median PFS was 11.6 months [5.7-45.7] (mFU 45.6 [22.9-57.6]) and median OS was 33.5 months [18.3-NR] (mFU 65.6 [59.9-70.3]). At data cut-off, OS was &amp;gt;60 months in 21 pts (18 with best response of CR, 1 PR, 1 stable disease and 1 PD), including 14 with 1 pLoT and 7 with ≥2 pLoT. Pts with 1 pLoT (n=40) in the FAS had higher ORR (67.5%; 52.5% CR [n=21] and 15% PR [n=6]) compared to pts with ≥2 pLoT (n=40; 47.5%; 30% CR [n=12] and 17.5% PR [n=7]). However, median DoR was not reached for both subgroups, indicating similar long-term efficacy for responders. AEs were consistent with previous reports and manageable; incidence declined after transition from combination to tafasitamab monotherapy and again with monotherapy &amp;gt;2 years. Conclusion: The final, 5-year analysis of L-MIND showed prolonged durable responses with tafasitamab + LEN combination therapy, followed by long-term tafasitamab monotherapy, in pts with R/R DLBCL ineligible for ASCT, with median DoR not reached after 44 months mFU. No new safety signals were identified, confirming the tolerability profile observed with earlier data cuts. These long-term data suggest that this immunotherapy may have curative potential that is being explored in further studies. Citation Format: Johannes Duell, Pau Abrisqueta, Marc Andre, Marinela Augustin, Gianluca Gaidano, Eva González Barca, Wojciech Jurczak, Nagesh Kalakonda, Anna Marina Liberati, Kami J. Maddocks, Tobias Menne, Zsolt Nagy, Olivier Tournilhac, Abhishek Bakuli, Aasim Amin, Konstantin Gurbanov, Gilles Salles. Five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the phase II L-MIND study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT022.

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study.

Cabozantinib showed a favorable benefit-risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open-label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. Patients with previously treated, advanced HCC received cabozantinib 60mg/day. Progression-free survival (PFS) and tumor response rates in prior-sorafenib and sorafenib-naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin-bilirubin (ALBI) score. Median cabozantinib exposure was 5.6months. In the prior-sorafenib cohort (n=20), median PFS was 7.4months per IRC assessment and 5.6months per investigator assessment. In the sorafenib-naïve cohort (n=14), median PFS was 3.6 and 4.4months per IRC and investigator assessment, respectively. Six-month PFS rate per IRC and investigator assessment in the prior-sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib-naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior-sorafenib cohort and 64.3% in the sorafenib-naïve cohort. Median overall survival (Kaplan-Meier estimate) was 19.3 and 9.9months in the prior-sorafenib and sorafenib-naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar-plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC.

CTNI-30. LOGGIC/FIREFLY-2: A PHASE 3, RANDOMIZED TRIAL OF TOVORAFENIB VS. CHEMOTHERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED LOW-GRADE GLIOMA HARBORING AN ACTIVATING RAF ALTERATION

Abstract BACKGROUND Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing. METHODS LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients &amp;lt; 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.

A dose-escalation and expansion study of the safety and pharmacokinetics of XB002 in subjects with inoperable locally advanced or metastatic solid tumors (301)

<b>Objectives:</b> Cervical cancer and epithelial ovarian cancer (EOC) are two of the most prevalent gynecologic cancers associated with high mortality. Despite recent advancements in therapy, there is an unmet need for novel treatments to improve survival outcomes. XB002 is an antibody-drug conjugate (ADC) that targets tissue factor (TF). TF is a protein overexpressed in many solid tumors, including gynecologic cancers, and is associated with disease progression and poor prognosis. XB002 is a human mAb (25A3) directed against TF conjugated to a novel cytotoxic agent (payload) N-acyl sulfonamide auristatin, ZD02044. XB002 has been designed to improve the therapeutic potential of ADCs targeting TF as a new therapeutic strategy in cancers. XB002 has demonstrated activity in several solid tumor xenograft models. The objective of this ongoing first-in-human study is to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), and preliminary antitumor activity of XB002 in patients with advanced solid tumors with limited treatment options. Presented here are the trial design and details of the cervical and EOC cohorts. <b>Methods:</b> In this phase 1, non-randomized, open-label, multicenter, dose-escalation, and dose-expansion study (NCT04925284), patients with advanced solid tumors will receive XB002 IV every three weeks at a starting dose of 0.16 mg/kg. In the dose-escalation stage, an i3+3 study design will be used to identify the maximum tolerated dose (MTD)/recommended dose (RD) and/or the maximum allowed dose of XB002. Dose level decisions will be made by the Cohort Review Committee after review of all available safety and PK data. In the cohort-expansion phase, the MTD/RD will be further evaluated for safety and preliminary efficacy in multiple tumor-specific expansion cohorts that will be enrolled using a Simon's 2-stage design. Patients will be treated until radiographic progression per RECIST v1.1 or unacceptable toxicity. Patients in the cervical and EOC expansion cohorts must have received ≤2 (cervical) or ≤3 (EOC) lines of prior systemic anticancer therapy for locally advanced or metastatic disease. Patients must have received prior platinum-containing therapy in both cohorts, and patients must have platinum-resistant disease in the EOC cohort. The primary endpoint of the cohort-expansion stage will be objective response rate (ORR) per RECIST v1.1 assessed by the investigator. Other endpoints will include duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 assessed by the investigator, and overall survival; ORR, DOR, and PFS may also be assessed by a blinded independent radiology committee in select expansion cohorts. The effects of XB002 on tumor and blood biomarkers, including TF expression, will be assessed in exploratory analyses. For patients with EOC, blood samples for CA125 assessment will be collected at screening and throughout treatment in both stages of the study.

A phase 1 dose-escalation and expansion-cohort study of the oral CDK7 inhibitor XL102 as a single-agent and in combination therapy in patients (pts) with advanced solid tumors.

TPS3176 Background: XL102 is an orally bioavailable, selective, and covalent small-molecule inhibitor of cyclin-dependent kinase 7 (CDK7). CDK7 is a serine/threonine kinase that is overexpressed in multiple tumor types. CDK7 controls cell cycle progression via the phosphorylation of CDKs (1, 2, 4, and 6) and regulates transcription through phosphorylation of RNA polymerase II. XL102 induced cell death in various cancer cell lines and caused tumor regression in multiple human tumor cell line to mouse xenograft tumor models. Here, we present the study design of an ongoing phase 1 trial in pts with advanced solid tumors, including hormone receptor-positive breast cancer (HR+BC), triple-negative breast cancer (TNBC), epithelial ovarian cancer (EOC), and metastatic castration-resistant prostate cancer (mCRPC). Methods: This first-in-human, open-label, phase 1 trial (NCT04726332) consists of a dose-escalation stage and a disease-specific cohort expansion stage. In the dose-escalation stage (modified interval 3+3 design), a maximum tolerated dose and/or recommended dose (MTD/RD) of XL102 will be established (primary endpoint) for use alone (solid tumors) and then for use in combination with standard dose fulvestrant (HR+BC) or abiraterone/prednisone (mCRPC); dose escalation will require ̃36 pts for the single-agent cohort and ̃15 pts for each combination cohort. Pts enrolled in the dose-escalation stage must have an unresectable or metastatic tumor for which available therapies are intolerable, ineffective, or do not exist. Upon determining the MTD/RD for each regimen, the cohort-expansion stage will enroll according to Simon’s Two-Stage Minimax design, assuming a power of 80% and one-sided α of 15%, for single-agent XL102 (HR+BC, TNBC, EOC, and mCRPC) and XL102 in combination therapy (HR+BC and mCRPC); the expansions will enroll ̃36 pts for each single-agent cohort and ̃44 pts for each combination cohort. Pts enrolled in the expansion stage must have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), adequate organ function, and exposure to prior therapy, with specific therapy requirements based on the disease cohort. The primary endpoint of the expansion stage is objective response rate (ORR) of XL102 alone and in combination therapy as assessed by investigator per RECIST v1.1. Secondary endpoints are safety, tolerability, and pharmacokinetics. Exploratory endpoints include duration of response (DOR) and progression-free survival (PFS) as assessed by the investigator per RECIST v1.1, overall survival, and correlation of tumor and blood biomarkers with response. ORR, DOR, and PFS may also be assessed by blinded independent radiology committee in selected expansion cohorts. The study began enrolling pts in February 2021 and is ongoing. Total enrollment is estimated to be up to 298 pts. Clinical trial information: NCT04726332.

A phase 1b study (STELLAR-002) of XL092 administered in combination with nivolumab (NIVO) with or without ipilimumab (IPI) or bempegaldesleukin (BEMPEG) in patients (pts) with advanced solid tumors.

TPS4600 Background: XL092 is a novel oral inhibitor of receptor tyrosine kinases, including MET, VEGFR2, and TAM kinases (AXL, MER), which are implicated in tumor growth, metastasis, angiogenesis, and immune suppression of the tumor microenvironment. XL092 has a relatively short half-life (̃21h) to support convenient daily dosing and help manage tolerability. Preclinical studies of XL092 with an anti‒PD-1 immune checkpoint inhibitor (ICI) demonstrated antitumor activity in tumor models, and BEMPEG (IL-2 pathway agonist) showed synergy with anti‒PD-L1 and anti‒CTLA-4 agents. This phase 1b trial will evaluate the safety and clinical activity of XL092 alone and in combination with NIVO (anti‒PD-1 mAb) ±IPI (anti‒CTLA-4 mAb) or ±BEMPEG in pts with advanced solid tumors including genitourinary cancers. Presented here is the study design. Methods: This multicenter phase 1b, open-label study (NCT05176483) will enroll pts with unresectable advanced or metastatic solid tumors in dose-escalation and expansion stages. In the dose-escalation stage, ̃36 pts will be enrolled in three XL092 combination therapy cohorts using a rolling 6 design. Cohort A: XL092 (starting dose [SD] 100 mg PO QD) + NIVO (360 mg IV Q3W); Cohort B: XL092 (SD 80 mg PO QD) + NIVO (3 mg/kg IV Q3W × 4, then 480 mg IV Q4W) + IPI (1 mg/kg Q3W × 4); Cohort C: XL092 (SD 100 mg PO QD) + NIVO (360 mg IV Q3W) + BEMPEG (0.006 mg/kg IV Q3W). The primary objective of the dose-escalation stage is to determine the recommended doses of XL092 with the NIVO regimens to be used in the expansion stage. The expansion stage will include cohorts of advanced genitourinary tumors: Cohort 1, clear-cell renal cell carcinoma (ccRCC), no prior systemic therapy; Cohort 2, ccRCC, 1 prior ICI combination regimen; Cohort 3, metastatic castration-resistant prostate cancer (mCRPC), 1 prior novel-hormonal therapy; Cohort 4, urothelial carcinoma (UC), 1 prior platinum-based regimen, ICI-naïve; Cohort 5, UC, ≤2 prior systemic regimens, ICI-experienced; Cohort 6, non-ccRCC, no prior systemic therapy. In each cohort, pts will be randomized to one of the following treatments (based on tumor cohort): single-agent XL092 (Cohorts 2‒6); XL092+NIVO (Cohorts 1‒6); NIVO+IPI (Cohort 1); XL092+NIVO+IPI (Cohorts 1, 3, 6); NIVO+BEMPEG (Cohort 1), XL092+NIVO+BEMPEG (Cohort 1, 2, 4‒6). Thirty pts will be enrolled in each single-agent XL092 arm and 40 pts in each combination therapy arm. Expansion stage objectives are to assess preliminary efficacy, safety, and pharmacokinetics of XL092 alone or in combination in each tumor-specific cohort. Primary efficacy endpoints include objective response rate by investigator per RECIST v1.1 and progression-free survival by blinded independent radiology committee per Prostate Working Group 3 criteria (mCRPC cohort only). The study is currently enrolling pts. Clinical trial information: NCT05176483.

Cabozantinib (C) versus placebo (P) in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on prior VEGFR-targeted therapy.

6083 Background: Based on the results of the phase 3 COSMIC-311 trial, the multikinase inhibitor C was recently approved by the FDA for the treatment of RAIR DTC pts who progress after prior VEGFR-targeted therapies, such as lenvatinib (L) or sorafenib (S), and for whom there was no standard of care (Brose et al. Lancet Oncol. 2021). In an extended follow-up of the intent-to-treat (ITT) population, C-treated pts achieved a median (m) progression-free survival (PFS) of 11 months (mo) vs 1.9 mo with P (HR 0.22, 96% CI 0.15–0.32, P &lt;.0001); here we present outcomes for prespecified subgroups who received prior L, S, or both. Methods: Pts were randomized 2:1 to C (60 mg QD) or P. P pts could cross over to open-label C upon disease progression per confirmation by blinded independent radiology committee (BIRC). The primary endpoints were PFS (ITT) and objective response rate (first 100 randomized pts), per RECIST v1.1 by BIRC. Pts must have received L or S and progressed during or after 1–2 prior VEGFR inhibitors. Results: After a median follow-up of 10.1 mo, 258 pts (170 C, 88 P) had been randomized (data cutoff 8 Feb 2021); 96 (̃37%) had received prior S (no L), 102 (̃40%) prior L (no S), and 60 (̃23%) prior S and L. Median PFS was 16.6 for C vs 3.2 mo for P in prior S (no L) (HR 0.13, 95% CI 0.06–0.26); 5.8 vs 1.9 mo in prior L (no S) (HR 0.28, 95% CI 0.16–0.48), and 7.6 vs 1.9 mo in prior S and L (HR 0.27, 95% CI 0.13–0.54). In the C arm, 21% of pts in prior S (no L), 3% in prior L (no S), and 8% in S and L subgroups had confirmed partial response, and 1 pt had a confirmed complete response in prior L (no S); there were no responses with P. Stable disease as best response was 67% for C vs 45% for P in prior S (no L), 68% vs 32% in prior L (no S), and 74% vs 38% in prior S and L. Median duration of C-exposure was 7.0 mo in prior S (no L), 5.6 mo in prior L (no S) and 5.9 mo in prior S and L. Grade 3/4 treatment-emergent adverse events (TEAE) occurred in 63% pts in prior S (no L), 57% in prior L (no S), and 69% in prior S and L. Discontinuations of C due to TEAE occurred in 16% of pts in prior S (no L), 13% in prior L (no S), and 23% in prior S and L. There were no treatment-related deaths. Conclusions: In the extended follow-up, C maintained its superior PFS vs P irrespective of prior L and/or S. AEs in each subgroup were consistent with that of the overall population. This is also the first phase 3 study demonstrating a clinical benefit with C after prior L in RAIR DTC pts. Clinical trial information: NCT03690388.

Cabozantinib versus placebo in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on histology subtypes.

6081 Background: DTC comprises multiple histology subtypes, the most common being papillary and follicular. Based on results of the phase 3 COSMIC-311 trial, the multikinase inhibitor cabozantinib was recently approved by FDA for the treatment of pts with RAIR DTC who progressed after prior VEGFR-targeted therapy (Brose et al. 2021). In an extended follow-up, median (m) progression-free survival (PFS) was 11 months (mo) for cabozantinib vs 1.9 mo for placebo (HR 0.22, 96% CI 0.15–0.32, P&lt;.0001) in the intent-to-treat (ITT) population (Capdevila et al. ESMO 2021. Abstr LBA67). Here we present outcomes for prespecified subgroups based on the baseline histology subtypes of papillary and follicular thyroid cancers. Methods: Pts were randomized 2:1 to cabozantinib (60 mg QD) or placebo. Placebo pts could cross over to open-label cabozantinib upon disease progression per blinded independent radiology committee (BIRC). Primary endpoints were PFS (ITT) and objective response rate (ORR, first 100 randomized pts), per RECIST v1.1 assessed by BIRC. Results: After a median follow-up of 10.1 mo, 258 pts (170 cabozantinib, 88 placebo) had been randomized (data cutoff 8 Feb 2021); 150 pts (96 cabozantinib, 54 placebo) had papillary thyroid cancer (PTC) and 113 pts (78 cabozantinib, 35 placebo) had follicular thyroid cancer (FTC), with the PTC and FTC subgroups each including 5 pts with both PTC and FTC. Sixty-three pts (̃56%) within the FTC subgroup had Hurthle cell and poorly differentiated variants. mPFS was 9.2 mo for cabozantinib vs 1.9 mo for placebo in the PTC subgroup (HR 0.27, 95% CI 0.17–0.43) and 11.2 mo vs 2.6 mo in the FTC subgroup (HR 0.18, 95% CI 0.10–0.31). The mPFS was 11.1 mo for cabozantinib and 1.9 mo for placebo for pts with Hurthle cell and poorly differentiated variants (HR 0.12, 95% CI 0.05–0.27). The ORR was 15% for cabozantinib vs 0% for placebo in the PTC subgroup and 8% vs 0% in the FTC subgroup. Median duration of cabozantinib exposure was 5.5 mo for the PTC subgroup and 7.3 mo for FTC. Grade 3/4 treatment-emergent adverse events (TEAE) in the cabozantinib arm occurred in 59% of pts in the PTC subgroup and 68% of pts in the FTC subgroup; discontinuations due to TEAE occurred in 17% and 15% of pts, respectively. Conclusions: In the extended follow-up, cabozantinib maintained superior efficacy vs placebo irrespective of histology subtype, including the aggressive Hurthle cell and poorly differentiated variants. The moderately higher rates of grade 3/4 TEAE in the FTC vs the PTC subgroup could be attributed to the longer median duration of exposure of cabozantinib in the FTC subgroup. Clinical trial information: NCT03690388.

A Randomized, Double-Blind Noninferiority Study to Evaluate the Efficacy of the Cabozantinib Tablet at 60 mg Per Day Compared with the Cabozantinib Capsule at 140 mg Per Day in Patients with Progressive, Metastatic Medullary Thyroid Cancer.

Background:Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC.Methods:In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics.Results:At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm (n = 123) and the 140 mg/day capsules arm (n = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90–1.70; p = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points.Conclusions:PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs.Clinical Trial Registry:ClinicalTrials.gov NCT01896479.

Trilynx: A Phase 3 Trial of Xevinapant and Concurrent Chemoradiotherapy (CRT) for Locally Advanced Head and Neck Cancer

Purpose/Objective(s) Concurrent CRT is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, and CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements for xevinapant versus placebo in addition to standard CRT for locoregional control (LRC) rate at 18 months, progression-free survival (PFS) and overall survival (OS). The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. Materials/Methods TrilynX is a multinational, phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-SCCHN. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharyngeal, laryngeal and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ∼90% power to detect the expected hazard ratio benefit of 0.73. Secondary endpoints include OS, PFS, LRC, objective response rate, health-related quality of life, and safety. Patients will be followed up for a minimum of 60-months. PK sparse sampling will be performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and is ongoing. Results TBD Conclusion TBD Concurrent CRT is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, and CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements for xevinapant versus placebo in addition to standard CRT for locoregional control (LRC) rate at 18 months, progression-free survival (PFS) and overall survival (OS). The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. TrilynX is a multinational, phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-SCCHN. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharyngeal, laryngeal and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ∼90% power to detect the expected hazard ratio benefit of 0.73. Secondary endpoints include OS, PFS, LRC, objective response rate, health-related quality of life, and safety. Patients will be followed up for a minimum of 60-months. PK sparse sampling will be performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and is ongoing. TBD TBD

Abstract OT1-12-02: Trial in progress: Phase 2, open-label study to evaluate the safety and efficacy of praluzatamab ravtansine in metastatic HER2 non-amplified breast cancer as monotherapy and combination with pacmilimab

Abstract Background: Probody® therapeutic candidates (Pb-Tx) are masked antibodies designed to be conditionally activated in the tumor microenvironment by tumor-associated proteases. This allows Pb-Tx to address previously undruggable targets that are highly expressed in both tumor and normal tissues. Praluzatamab ravtansine is a masked antibody-drug conjugate targeting CD166 with a DM4 payload. A phase 1 monotherapy study showed safety and durable clinical activity (clinical benefit rate at 24 weeks [CBR24] 28%) in patients (pts) with metastatic HR-positive/HER2 non–amplified breast cancer (mHR+/HER2− BC) or metastatic triple-negative breast cancer (mTNBC). Pacmilimab, a masked PD-L1 inhibitor, demonstrated monotherapy activity in pts with TNBC with an acceptable tolerability profile.Trial design: This phase 2, open-label study with 3 parallel arms (~40 evaluable/arm) will evaluate praluzatamab ravtansine monotherapy (7 mg/kg Q3W) in pts with mHR+/HER2− BC or mTNBC, and praluzatamab ravtansine (7 mg/kg Q3W) combined with pacmilimab (1200 mg Q3W) in pts with mTNBC. Adult pts with an ECOG PS 0–1, measurable disease, and willingness to receive ocular prophylaxis for DM4-related toxicities will be enrolled. Key eligibility criteria for the mHR+/HER2− BC cohort include 2–4 prior regimens in the metastatic setting (excluding single-agent endocrine therapy). No CD166 screening required for HR+/HER2− BC but mTNBC must be CD166+. Pts with mTNBC must have received 1–3 prior metastatic regimens. For mTNBC pts who receive the doublet, key exclusion criteria include known PDL1 negative tumor, history of autoimmune disease, and progression within 120 days of 1st dose of an immuno-oncology agent. Pts with corneal disorders will be excluded. Primary endpoint is overall response rate (ORR) assessed by an independent radiology committee per RECIST v1.1. Secondary endpoints include ORR by investigator, duration of response, CBR16 &amp; 24, progression-free survival, and overall survival. This study will also evaluate safety and tolerability, pharmacokinetics, and antidrug antibodies with praluzatamab ravtansine as monotherapy and in combination with pacmilimab. This trial is enrolling (NCT04596150). Citation Format: Kathy Miller, Leisha A. Emens, Sara M. Tolaney, Sara A. Hurvitz, Erika Hamilton, Virginia Paton, Alison Hannah, Valentina Boni. Trial in progress: Phase 2, open-label study to evaluate the safety and efficacy of praluzatamab ravtansine in metastatic HER2 non-amplified breast cancer as monotherapy and combination with pacmilimab [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-02.

SURPASS-2 trial design: A phase 2, open-label study of ADP-A2M4CD8 SPEAR T cells in advanced esophageal or esophagogastric junction cancers.

TPS363 Background: ADP-A2M4CD8 is an autologous specific peptide enhanced affinity receptor (SPEAR) mixed CD4 and CD8 T-cell product that expresses an engineered T-cell receptor (TCR) designed to target the MAGE-A4 antigen in HLA-A*02-positive patients. These SPEAR T-cells also express wild-type CD8α co-receptors, designed to provide additional functionality to CD4 T-cells. MAGE-A4 expression has been described in several solid tumors, including esophageal and esophagogastric junction (EGJ) cancers[1]. In an ongoing phase 1 study (NCT04044859) of ADP-A2M4CD8 in patients with different tumor types, most adverse events have been consistent with those typically experienced by patients undergoing chemotherapy and/or adoptive T-cell therapies, and as of 2 August 2021, among evaluable patients with esophageal and EGJ cancers, best overall responses were 1 partial response (EGJ), 4 stable disease (2 EGJ, 2 esophageal), and 1 progressive disease (EGJ)[2]. Methods: SURPASS-2 (NCT04752358) is a phase 2, open-label, single-arm trial to assess safety and efficacy of ADP-A2M4CD8 SPEAR T-cells in HLA-A*02–positive patients with advanced esophageal or EGJ cancers that express MAGE-A4 antigen. A total of 45 patients between the ages of 18 and 75 years old will be treated across sites in North America and Europe. Key eligibility criteria include measurable disease per RECIST v1.1; ECOG performance status of 0 or 1; no active autoimmune or immune-mediated disease; no leptomeningeal disease, carcinomatous meningitis, or symptomatic CNS metastases; and ≤2 prior lines of combination or single agent systemic treatment for advanced or metastatic disease before treatment with ADP-A2M4CD8 as the next therapy. Leukapheresis can be performed before initiating or at the end of second-line treatment. Collected T-cells will be transduced with a self-inactivating lentiviral vector expressing the high affinity MAGE-A4-specific TCR and the CD8α co-receptor. Lymphodepleting chemotherapy, consisting of intravenous (IV) cyclophosphamide 600 mg/m2/day for 3 days and IV fludarabine 30 mg/m2/day for 4 days, will be given approximately 1 week prior to treatment with ADP-A2M4CD8. ADP-A2M4CD8 dose will range between 1 x 109 to 10 x 109 transduced cells administered by a single IV infusion. The primary endpoint is overall response rate per RECIST v1.1 by an independent radiological assessment committee. Safety evaluations will include adverse events (AEs); serious AEs; incidence, severity, and duration of the AEs of special interest; replication competent lentivirus; and T-cell clonality and insertional oncogenesis. All patients receiving ADP-A2M4CD8 cellular therapy will be followed for 15 years from time of last T-cell infusion for observation of delayed AEs. To date, one site is activated. [1] Ishihara et al. BMC Cancer 20, 606 (2020). [2] Hong et al. E-poster 540P: ESMO (2021). Clinical trial information: NCT04752358.