Citations

TPS4205 Background: Multiple lines of evidence support the use of platinum-based chemotherapy for patients with homologous recombination deficiency-associated pancreatic adenocarcinoma (HRD PDAC; 15-20%). However, the impact of the specific platinum agent used remains uncertain. Mechanistically, oxaliplatin and cisplatin act distinctly on cancer cells, reflected in disparate toxicity profiles and target disease indications; furthermore, preclinical studies have shown that BRCA2-deficient cell lines and mice demonstrate significantly greater sensitivity to cisplatin compared to oxaliplatin. While oxaliplatin, part of the FOLFIRINOX regimen, represents the most commonly used platinum analogue for PDAC, clinical data shows that cisplatin (in combination with gemcitabine) can produce robust response rates (~70%) specifically in patients with germline BRCA/PALB2-mutated metastatic PDAC. We therefore designed a randomized clinical trial (PLATINUM) through the Alliance for Clinical Trials in Oncology cooperative group to assess the optimal chemotherapy regimen in patients with HRD-associated metastatic PDAC following front-line FOLFIRINOX and to test the hypothesis that a platinum switch strategy will be beneficial. Methods: The study consists of a seamless phase II/III design, with the primary endpoint of the phase III component being overall survival. Eligible patients will have metastatic PDAC, a confirmed pathogenic BRCA1/2 or PALB2 mutation (somatic or germline), and demonstrated disease progression on front-line FOLFIRINOX, with or without subsequent PARP inhibitor maintenance. Patients will be randomized 1:1 to receive (1) the de facto standard of gemcitabine plus nab-paclitaxel; or (2) the experimental 3-drug combination of gemcitabine, nab-paclitaxel, and cisplatin (NABPLAGEM), which has been previously studied in non-biomarker-selected patients with advanced biliary tract cancer (SWOG1815) and metastatic PDAC. Both treatment arms will use a once every other week dosing schedule. A total of 100 patients will be enrolled, which provides 90% power to detect an effect size of hazard ratio 0.5 (median OS of 18 vs 9 months) at a one-sided alpha of 0.05. Reports containing efficacy, adverse events, and administrative information will be provided to the Alliance DSMB every 6 months. Planned correlatives include ctDNA analysis for BRCA reversion mutations in all patients, as well as whole genome and transcriptome sequencing in an optional biopsy cohort. This study was activated in December 2023. Clinical trial information: NCT06115499 .

TPS4196 Background: Advanced BTC patients have poor prognosis. Up to 40% of BTCs have KRAS mutations and are associated with worse overall survival (OS). With a median OS of 7.7 months in KRAS wild-type compared to 1.7 months in KRAS mutated disease, these alterations are independent poor prognostic factors in BTC. Gemcitabine and cisplatin (GC) with or without immunotherapy are often used as 1st-line therapies. However, there is a lack of data on best 2nd-line regimens. mFOLFOX6 (5-fluorouracil [5-FU], leucovorin [LV], oxaliplatin) or liposomal irinotecan+5-FU+LV are options when no biomarkers are found (e.g., MSI-H, BRAFV600E, FGFR-fusions, IDH1-mutation, HER2-overexpression). Prior studies do not demonstrate benefit with MEK inhibitors (MEKi), but none of the studies had biomarker selection. Pre-clinical studies in BTC cell lines suggest synergy between MEKi and 5-FU. Thymidylate synthase (TS )levels induced by 5-FU are downregulated by addition of binimetinib. Early clinical studies show safety and tolerance of this combination. In this study, we will evaluate if the combination of mFOLFOX6+binimetinib improves OS for patients with BTC and MAPK mutations compared to mFOLFOX6 alone in 2nd-line therapy. Methods: EAY191-A6 is a treatment study arm of the NCI ComboMATCH master registration trial EAY191. The A6 trial has a randomized phase II design, enrolling a maximum of 66 patients. Patients with any MAPK pathway mutations except those with available therapies will be eligible. Patient must first enroll to the EAY191 master trial. Local molecular results may be used for enrollment. Submission of tissue at baseline is mandatory. Eligible patients will be randomized 1:1 to mFOLFOX6 vs mFOLFOX6 + binimetinib (45 mg oral twice a day every 14 days). Stratification factors include location and stage of disease. Primary efficacy analysis will compare OS in the intent-to-treat population. If the observed hazard ratio (HR) of experimental arm vs standard of care is < 0.545 (corresponding to an observed increase in OS by 5 months or longer), experimental treatment will be considered superior. An interim futility analysis at 50% of expected events will be conducted. If the observed HR is ≥ 1, experimental treatment will not be considered superior, and accrual maybe suspended. Secondary endpoints include progression-free survival, objective response rate, duration of response, disease control rate and toxicity of treatments. Exploratory objectives include prognostic modeling, correlations of genomic alterations with response or resistance and use of machine learning for outcome prediction. This study is active and open to accrual. Clinical trial information: NCT05564403 .

TPS3633 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101/NRG-GI009 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least 1 lesion. Patients receive first-line systemic therapy for 16-26 weeks and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver/lungs in at least 1 site. Patients in Arm 1 will receive TAT consisting of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov identifier: NCT05673148 Clinical trial information: NCT05673148 .

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045 ) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant ( Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.

TPS236 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG). Clinical trial information: NCT05673148 .

283 Background: The randomized phase II CALGB 80803 trial evaluated use of PET imaging for early assessment of induction chemotherapy (iCT) responsiveness to tailor therapy for patients with esophageal and gastroesophageal junction adenocarcinomas (EC) undergoing trimodality therapy. The primary endpoint of improving pathologic complete response rates using PET-adapted therapy was met. A companion QOL study aimed to characterize patients’ experience through iCT, chemoradiation (CRT) and surgery (S). Methods: Between 11/2011 and 5/2015, 241 eligible patients were randomized to an iCT regimen: modified oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) or carboplatin/paclitaxel (CP), followed by PET scan then CRT, either continuing on the same CT for PET-responders (PET-R) or crossing over to the alternative CT for PET-nonresponders (PET-NR). We prospectively collected QOL domains and symptoms at baseline (T1), after iCT (T2), after CRT (T3), and 3- (T4) and 6- months (T5) after S using the EORTC QLQ-C30, The Esophageal Cancer subscale (EORTC OES18), FACT Neurotoxicity Scale (FACT-NTX), and 6 questions from the PRO-CTCAE. QOL scores were compared between iCT groups and between PET-R and PET-NR at each time point using mixed models. The association of QOL scores at enrollment with overall survival (OS) was tested using Cox regression. Results: 189 patients enrolled on the QOL sub-study, 92 received induction FOLFOX and 97 induction CP. Of those, 110 were PET-R and 79 were PET-NR. 97.9% went on to CRT, and 83.6% underwent S. Global QOL and symptoms statistically significantly worsened from T1 to T2 in 14 of 25 domains, and remained significantly worsened from T1 at: T3 for 19 of 25 domains, T4 for 17 of 25 domains, and T5 for 6 of 25 domains. Changes from T1 significantly favored iFOLFOX (vs iCP) for ability to eat (at T3 and T4), GI symptoms (at T3 and T4), and talking (at T5). Changes from T1 significantly favored iCP (vs iFOLFOX) for neuropathy (at T2, T3, and T4) and coughing (at T5). Proportion of patients reporting worsened PRO-CTCAE scores did not differ between PET-R or PET-NR groups . Multiple QOL domains and symptoms were associated with OS including role functioning, global health status/QOL, appetite loss, pain, dysphagia, and ability to eat (all p<0.002). Conclusions: QOL was impacted most by CRT but returned to baseline 6 months after surgery for most domains. Observed symptom differences did not consistently favor one iCT regimen. Early interventions such as nutritional support and prehabilitation should be studied to improve QOL and OS. Clinical trial information: NCT01333033 .

Abstract Background: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. Methods:The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. Discussion: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC.

MSI-H identified by ctDNA: prevalence across 21 advanced cancers and outcomes from >700 patients.

TPS4204 Background: The role of neoadjuvant chemotherapy in resectable pancreatic cancer has yet to be defined. Recent phase II trial results demonstrate a median overall survival time (mOS) of only 22.4 months after treatment with perioperative modified FOLFIRINOX (mFOLFIRINOX) with 36% not reaching surgery due to disease progression during neoadjuvant therapy. While potential benefits and shortcomings of neoadjuvant chemotherapy have been well documented, to date, no phase III trial has directly compared a perioperative versus an adjuvant chemotherapy strategy in resectable pancreatic cancer. Alliance for Clinical Trials in Oncology A021806 is an actively accruing randomized controlled phase III trial evaluating the efficacy of perioperative chemotherapy with mFOLFIRINOX in patients with resectable pancreatic cancer. Methods: To qualify for enrollment, patients must have biopsy-proven localized resectable pancreatic adenocarcinoma as defined by the National Comprehensive Cancer Network. Patients must have good performance status (ECOG 0 or 1) and be candidates to receive mFOLFIRINOX treatment. All patients enrolled undergo central radiologic eligibility review for quality control and are then randomized to either Arm 1 which consists of 8 cycles of neoadjuvant mFOLFIRINOX followed by 4 cycles of adjuvant mFOLFIRINOX or Arm 2 which includes upfront surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary endpoint of the trial is overall survival with secondary endpoints evaluating disease-free survival, margin-negative resection rate, surgical complications, and chemotherapeutic adverse events. Additional correlative endpoints include quality of life and radiomic imaging assessments. A total enrollment of 352 patients is planned from the US and Canada; current enrollment for this trial is at 145 patients. An OS interim analysis will be performed when 50% of the events (124) are observed combining the two arms. If the trial continues after interim analysis, the final OS analysis will be performed with a total of 248 events (combined arms). If the Cox model (stratified by tumor location and ECOG PS) comparing OS between arms produces a one-sided p-value < 0.05, then we will conclude that the OS of the perioperative therapy arm is superior to adjuvant therapy. The Alliance A021806 phase III trial aims to define a new standard of care for patients with resectable pancreatic cancer. Clinical trial information: NCT04340141 .

TPS8603 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients (pts) who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude pts with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in pts with newly diagnosed peritoneal mesothelioma. Methods: Alliance for Clinical Trials in Oncology A092001 is a prospective, randomized phase 2 clinical trial. All pts with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Pts who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine if frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible pts per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 pts are enrolled. Stratification factors include eligibility for cytoreductive surgery at diagnosis and histologic subtype. Secondary endpoints include progression-free survival, overall survival and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Clinical trial information: NCT05001880 .