Prior Adjuvant Therapy Research Articles

Colorectal cancer metastatic dMMR immunotherapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer 9NRG-GI004/SWOG-S1610).

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

Phase IB/II first line panitumumab, irinotecan, trifluridine/tipiracil in RAS wild-type patients with metastatic colorectal cancer: PIT study.

e15532 Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently used in later line therapy. Preclinical data have demonstrated synergistic activity when panitumumab (Pmab) or irinotecan (Ir) are combined with TT supporting use in combination schedules in early line protocols. PIT was a phase IB/II study determining the maximum tolerated dose (MTD), safety and tolerability of substituting FP with TT, combined with Pmab and Ir in RAS wild-type mCRC. Methods: Phase IB 3+3 design dose escalation study (Dose level 1: TT 20mg/m2 oral BD, Ir 150mg/m2 IV, Pmab 6mg/m2). Primary objective was MTD of the combination in RAS WT mCRC patients, either 1st or 2nd line. Treatment was administered in 14-day cycles. Pmab and Ir were administered intravenously on day 1 with TT dosed orally, bid, days 1-5. Once MTD was established the phase II expansion study was to enrol 50 previously untreated mCRC patients. Primary endpoint was modified to toxicity. Results: The study closed due to slow recruitment. 14 patients were enrolled from 6/18 to 10/21. Med follow up 23 months. Med age 59 yrs (range 37-74yrs). 60% were male. One patient each was BRAF MT and right sided. ECOG 0/1 50%/50%. Thirteen patients had PIT as first line, 57% had prior adjuvant therapy. There was one DLT in first 3 patients however based on additional toxicity data (Clin Cancer Res. 2020 Apr 1:1555) a decision was made to not dose escalate beyond level 1 and commence phase II. Overall Gd 3 toxicity: Acne/rash 46%, Diarrhoea 31%, Fatigue 8%, neutropenia 15%, hypomagnesaemia 23%. One patient had Gd 4 neutropenia and there was one treatment related death (neutropenic sepsis). 12 patients had evaluable disease, 58% PR, 42% SD. Survival: Med PFS 14.1 mths, Med OS 40.6mths and 12 mth OS 64%. Conclusions: The MTD was deemed TT 20mg/m2, irinotecan 150mg/m2 and panitumumab 6mg/kg. Toxicity was manageable however significant grade 3 diarrhoea and rash was seen. There was one toxic death contributed to therapy. Small numbers do make interpretation difficult however there is a signal of activity. The slow recruitment illustrates difficulty in exploring novel combinations in early lines and potentially the reluctance to consider first line anti-EGFR therapy. Clinical trial information: ACTRN12617001190392.

A phase 3 trial of fixed dose combinations of fianlimab (anti–LAG-3) + cemiplimab (anti–PD-1) versus relatlimab + nivolumab in patients with unresectable or metastatic melanoma.

TPS9611 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. Concurrent LAG-3 blockade may enhance the efficacy of anti–PD-1 therapies. Relatlimab (anti–LAG-3) + nivolumab (anti–PD-1) monoclonal antibodies demonstrated benefit in progression-free survival (PFS) in advanced melanoma (Mel) patients compared with nivolumab alone in the RELATIVITY-047 study. In a multicohort Phase 1 study (NCT03005782), fianlimab + cemiplimab demonstrated reproducibly high clinical activity (objective response rate [ORR]: 61%, N=98) in three independent cohorts of advanced PD-(L)1–naïve metastatic Mel patients with an acceptable safety profile. Methods: This is a randomized, open-label, multicenter Phase 3 study (NCT06246916) comparing the fixed dose combination (FDC) of fianlimab + cemiplimab to the FDC of relatlimab + nivolumab in patients with unresectable or metastatic Mel. The primary objective is to demonstrate superiority of fianlimab + cemiplimab compared with relatlimab + nivolumab as measured by ORR assessed by blinded independent central review (BICR). This study will be conducted at approximately 80 sites across North America. Key inclusion criteria are: (1) aged ≥18 years; (2) histologically confirmed unresectable stage III or IV (metastatic) Mel; (3) no prior systemic therapy for unresectable or metastatic Mel; patients with adjuvant and/or neoadjuvant systemic therapies are eligible with a treatment-free and disease-free interval of >6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) Eastern Cooperative Oncology Group performance status of ≤1; (6) adequate bone marrow, hepatic, and kidney function. Approximately 560 patients will be randomized in a 1:1 ratio to two treatment arms: Arm A: FDC of fianlimab (Dose 1) + cemiplimab (Dose 2) every 3 weeks intravenously (IV); Arm B: FDC of relatlimab 160 mg + nivolumab 480 mg every 4 weeks IV. All patients will be stratified based on metastatic stage (stage III vs M1a–b vs M1c–d), baseline lactate dehydrogenase level (≤ vs > upper limit of normal), and prior adjuvant and/or neoadjuvant systemic therapy. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, a study withdrawal criterion is met, or the sponsor terminates the study. The primary endpoint is ORR and key secondary endpoints are PFS and overall survival. Additional secondary endpoints are duration of response, disease control rate, investigator-assessed ORR and PFS, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT06246916 .

Efficacy and safety of triplet nivolumab, relatlimab, and ipilimumab (NIVO + RELA + IPI) in advanced melanoma: Results from RELATIVITY-048.

9504 Background: NIVO (anti–PD-1 antibody) is approved as monotherapy and in combination with either RELA (anti–LAG-3 antibody) or IPI (anti–CTLA-4 antibody) for the treatment of patients (pts) with advanced melanoma. RELATIVITY-048 (NCT03459222) is a phase 1/2, nonrandomized trial evaluating immuno-oncology (I-O) triplets, including NIVO + RELA + IPI, for pts with select solid tumors. This analysis from RELATIVITY-048 focused on NIVO + RELA + IPI use in the advanced melanoma cohort and is the first disclosure from the study. Methods: Pts with advanced melanoma were treated with first-line NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W until progression or unacceptable toxicity. Prior neoadjuvant/adjuvant therapy, including I-O agents, was permitted if completed > 6 mo before enrollment. Pts with controlled brain metastases were allowed to enroll. Primary endpoints were safety and confirmed objective response rate (ORR), disease control rate (DCR), and median duration of response (DOR) per investigator. The secondary endpoint was progression-free survival (PFS) per investigator (median and 6-mo/12-mo rates). Exploratory endpoints included overall survival (OS; median and 12-mo/24-mo rates). Results: In total, 46 pts were treated. Median follow-up was 49.4 mo (range, 0.4–55.0; database lock, Nov. 1, 2023). Median age was 61.0 y, 8.7% had cutaneous acral melanoma, 50.0% were BRAF positive, 73.9% were LAG-3 positive (≥ 1%), 26.1% were tumor cell PD-L1 positive (≥ 1%), and 6.5% had received prior adjuvant therapy. Median duration of treatment was 5.0 mo (range, 0.0–49.0). NIVO + RELA + IPI had a confirmed ORR of 58.7% and a 48-mo OS rate of 71.7% (table). Any-grade and grade 3/4 treatment-related adverse events (TRAEs) occurred in 44 pts (95.7%) and 18 pts (39.1%), respectively. Any-grade TRAEs led to treatment discontinuation in 19 pts (41.3%). Deaths due to TRAEs occurred in 2 pts (4.3%; rectal hemorrhage and dyspnea [n = 1], immune-mediated myositis [n = 1]). Conclusions: In RELATIVITY-048, NIVO + RELA + IPI demonstrated encouraging efficacy, with a confirmed ORR of 58.7% and a 48-mo OS rate of 69.1%. There were no new safety signals with NIVO + RELA + IPI, and the safety profile was generally consistent with I-O combinations. Given the small sample size, additional studies are needed to confirm the efficacy and safety of NIVO + RELA + IPI. Clinical trial information: NCT03459222 . [Table: see text]

Dostarlimab (Jemperli)

We recommend that Jemperli in combination with carboplatin and paclitaxel be reimbursed by public drug plans for the first-line treatment of adult patients with primary advanced or recurrent mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) endometrial cancer who are candidates for systemic therapy if certain conditions are met. Jemperli in combination with carboplatin and paclitaxel should only be covered to treat adult patients who have primary stage III or IV endometrial cancer, experience a first disease recurrence and have not previously received systemic anticancer therapy for advanced disease, and/or have received prior neoadjuvant adjuvant systemic anticancer therapy and experience a first recurrence at a minimum of 6 months after completion of treatment. Eligible patients should have confirmed dMMR or MSI-H status of their tumours before starting treatment with Jemperli and have a good performance status. Jemperli should only be reimbursed in combination with carboplatin and paclitaxel if prescribed by clinicians with expertise in advanced uterine cancer. Treatment should be supervised and administered in institutions with expertise in systemic therapy delivery. The cost of Jemperli should be reduced.

Abstract PO3-16-10: Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial

Abstract Background: Ribociclib (RIB), a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET) yielded significant improvement in progression-free survival (PFS) and overall survival (OS) across three phase III MONALEESA trials including patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC) in first-line (1L) and second-line (2L) setting. In the previous interim analyses of REACH AUT trial, 1L RIB + ET showed tolerable safety and favorable PFS results in a real-world setting. Results from the preplanned fourth interim analysis are reported here. Methods: REACH AUT is a noninterventional study conducted in Austria reporting data on the real-world clinical experience of RIB + ET (aromatase inhibitor [AI] or fulvestrant [FUL]) in premenopausal, perimenopausal, or postmenopausal pts with HR+, HER2– MBC. Pts with no prior ET for advanced disease and maximum up to 1 prior line of chemotherapy (CT) in the advanced setting were included. Results: At data cutoff (March 27, 2023) with a median duration of follow-up of 23.8 months, out of 281 analyzed pts (12.5% of premenopausal/perimenopausal and 85.1% of postmenopausal, 2.5% of unknown status) 31.7% of pts were receiving ongoing treatment. The most common reasons for treatment discontinuations (68.3%) were disease progression (39.1%) and adverse events (AEs, 22.1%). The median age was 63 years (< 65 years, n=156, 55.5%; ≥65 years, n=125, 44.5%) and ECOG PS ≥2: 1.8%. In 106 pts (37.7%), de novo metastatic disease was reported. Visceral metastases (lung, liver) were present in 116 pts (41.3%) and bone-only metastases in 80 pts (28.5%). Prior adjuvant therapy was received by 139 pts (49.5%): AI ± GnRH: n=80 (26.7% without and 1.8% with GnRH); tamoxifen ± GnRH: n=74 (21.7% without and 4.6% with GnRH); CT: n=56 (19.9%); antibody therapy n=3 (1.1%). In the metastatic setting, 1L RIB was prescribed in combination with an AI in 223 pts (79.4%; letrozole: n=139 [49.5%]; anastrozole: n=48 [17.1%]; exemestane: n=47 [16.7%]) and with FUL in 52 pts (18.5%). Prior CT for MBC was received by 5 pts (1.8%). The median PFS was 29.7 months in the overall population; 28.3 months in pts with bone only and 26.9 months in pts with visceral metastatic disease. In pts evaluable for response, the objective response rate and clinical benefit rate were 31.3% and 60.9%, respectively. The OS rates were 91.9%, 81.7%, and 63.7% at 12 months, 24 months, and 36 months, respectively. The trial is ongoing with ~40% of subjects end of documentation and ~27% of deaths. In total, 69.4% of pts had RIB dose interruptions and 48.8% of pts had a RIB dose reduction. The majority of all reported AEs were grade 1 (50.1%) or grade 2 (31.2%); the median time to first AE was 0.5 months. The most common AE was neutropenia (all grades: n=143, 50.9%; grade 1: n=39, 13.9%; grade 2: n=68, 24.2%; grade 3: n=98, 34.9%; grade 4: n=5, 1.8%). QTc prolongation of any grade was observed in 32 pts (11.4%; grade 1: n=24, 8.5%; grade 2: n=11, 3.9%; grade 3: n=1, 0.4%). Hepatobiliary toxicity of any grade was observed in 42 pts (14.9%; grade 1: n=12, 4.3%; grade 2: n=18, 6.4%; grade 3: n=22, 7.8%; grade 4: n=3, 1.1%). Overall, currently 101 pts (35.9%) received a follow-up therapy after progression on RIB + ET. The most common first subsequent therapies were targeted therapies + ET (40.0%), followed by cytotoxic chemotherapy (22.0%) and endocrine monotherapy (19.0%). Conclusion: 1L RIB + ET continues to show favorable efficacy and a tolerable safety profile in the routine clinical practice. The results are consistent with the data from MONALEESA trials. The OS is showing a positive trend but is still immature during this study follow-up. Efficacy Outcomes With RIB + ET in Patients With HR+, HER2– MBC (Overall Population, Nf281) XX XX Citation Format: Christian F. Singer, Daniel Egle, Richard Greil, Edgar Petru, Leopold Oehler, Marija Balic, Laurenz Schöffmann, Georg Pfeiler, Maximilian Marhold, Christine Brunner, Karin Haider, Arik Galid, Ursula Pluschnig, Ferdinand Haslbauer, Michael Hubalek, Andreas Redl, Julia Flatschacher, Shanow Uthman, Bernhard Mraz, Rupert Bartsch. Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-10.

Abstract CT090: DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas

Abstract Background Neuroendocrine carcinomas (NECs) have limited treatment options. DLL3 is highly expressed in NECs and is a promising treatment target. In an ongoing phase 1 trial (NCT04429087), BI 764532, a DLL3/CD3 IgG-like T-cell engager, was tolerable with clinical activity in patients with DLL3-positive (+) tumors, including those with small cell lung cancer and other NECs. Purpose DAREON™-7 (NCT06132113), a phase 1, open-label, dose-escalation (Part A) and dose-expansion (Part B) trial, aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE)/recommended phase 2 dose (RP2D), and the safety and efficacy of BI 764532 + platinum and etoposide in patients with DLL3+ NEC. Experimental design Part A: ~25 patients will receive intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide (CE) until intolerable toxicity, or progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or for a maximum of 36 months. BI 764532 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Part B: 2 cohorts (~15 patients each) will receive BI 764532 at the RDE/RP2D + CE or cisplatin/etoposide (carboplatin/etoposide or cisplatin/etoposide are the most-used standard of care [SOC] regimens). Key inclusion criteria: patients must have no prior systemic treatment for DLL3+ locally advanced or metastatic NEC (extrapulmonary or unknown primary) or large cell NEC of the lung except for 1 cycle of standard platinum/etoposide regimen as first-line treatment prior to entering the treatment period of the trial; patients with localized NEC or resectable disease who received prior adjuvant therapy can participate in the trial if they experienced a treatment-free interval of >6 months prior to the diagnosis of metastatic disease; and patients must have at least 1 measurable lesion as defined per RECIST v1.1. Patients must be adequate candidates to receive platinum/etoposide as the SOC treatment. Primary endpoints: occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation (Part A) and on-treatment (Part B) periods. Secondary endpoints: occurrence of DLTs and adverse events during the on-treatment period (Part B), and efficacy measured by objective response and duration of response (Part B). Enrollment is ongoing. Citation Format: Jaume Capdevila, Timon Vandamme, Patricia Niccoli, Saori Mishima, Ken Kato, Yiyuan Ma, Ping Sun, Lijiang Geng, Ulrich M. Lauer. DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT090.

Abstract 6428: Transcriptome analysis of tissues and peripheral blood revealed potential biomarkers for chemo/radio-immunotherapy in non-small cell lung cancer

Abstract Background: Combination of anti-PD-(L)1 antibody with chemotherapy has shown promising efficacy in advanced/metastatic non-small cell lung cancer (NSCLC). Dynamics of peripheral blood mononuclear cells (PBMC) might have impact on repertore of immune cells further resulting different immune infiltration in tumor microenvironment. Thus, monitoring changes in PBMC during therapy or measuring tumor microenvironment provides the possibility to predict the efficacy of tumor immunotherapy. Methods: Patients diagnosed with NSCLC (Stage III-IV)were enrolled in this study. Anti-PD-L1 and chemo/radio combination therapy was performed as adjuvant therapy. Tumor samples were obtained prior to adjuvant therapy PBMC samples were obtaind at multiple time points, including prior adjuvant therapy, 3 months after adjuvant therapy, and 3 months after adjuvant therapy. Tumor and PBMC mRNA sequencing were performed by Amoy Diagnostics Co Ltd. (Xiamen, China). Patients who achieved CR/PR/SD and PFS > 6 months were defined as well responders. Pathway enrichment and GSEA analyses were performed by clusterProfiler (version 4.0.5) on GO, KEGG, and from six different gene sets. Correlations between immune cellular signature ES scores and gene expression were estimated using Pearson correlation. Results: 28 patients were enrolled; mean age was 60.38±7.86 years, 27 (96.4%) patients were male. 21 (75.0%) patients were identified as responder and 7 (25.0%) were non-responder. In the baseline tumor samples, immune infiltration was more extensive in responders compared to non-responders. Cytotoxic lymphocytes, activated CD8+ T cell, and NK cells were significantly enriched in responders. High expression of CCL17 and down regulation of CTSG/PLK1/PRTN3, a signaling axis that inhibits histone H3 hydrolysis and promotes monocyte to macrophage differentiation, was significant in responders. Dynamic monitoring of PBMC before and after treatment showed significant upregulation of immune infiltration-related pathways in responders, including effector cells, NK cells and CD8+ T cells. In the non-responder group, the up-regulated pathways after treatment were mainly enriched in tumor growth rate, EMT, and matrix remodeling. Multi-time point analysis showed that CEACAM5/MKI67 level and tumor proliferation rate in non-responders were higher than those in responders at each time point after treatment. Conclusion: Baseline tumor transcripton signatures and dynamic changes in PBMC could be applied to develop novel biomarkers for immune-related therapy. Patients with stronger immune infiltration signals in baseline tumor samples and PBMC after treatment had better immune response. The upregulation of proliferation-related signals in PBMC predicts poor immune response. Citation Format: Jing Hu, Jianguo Zhang, Peng Cheng, Yanhua Chen, Changbin Zhu, Feilin Yi, Conghua Xie. Transcriptome analysis of tissues and peripheral blood revealed potential biomarkers for chemo/radio-immunotherapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6428.

Subgroup analyses from READY: Real-world data from an Italian compassionate use program (CUP) of avelumab first-line maintenance (1LM) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC).

558 Background: A multicenter CUP provided early access to avelumab 1LM in Italian patients (pts) with Ia/mUC before reimbursement. Real-world pt characteristics and outcomes with avelumab 1LM from READY were reported previously. Here, we report updated data and subgroup analyses of effectiveness with avelumab 1LM. Methods: This prospective, noninterventional CUP included pts with la/mUC who were progression free after 1L platinum-based chemotherapy (PBC; 4-6 cycles, starting avelumab 1LM 4-10 wk after last PBC dose). Pts were enrolled from Jan 18, 2021 to Mar 7, 2022. Avelumab was provided per physician request and after approval by local ethics committees, per Italian compassionate-use regulations. Pts who had a relapse within 12 mo of prior adjuvant or neoadjuvant systemic therapy, including immune checkpoint inhibitors, were excluded. Results: 464 pts were included (78.45/21.55% male/female; median age, 70.0 y [interquartile range, 63.0-76.0]). At data cutoff (July 30, 2023), median follow-up from start of avelumab 1LM in 411 evaluable pts was 20.24 mo (95% CI, 19.78-20.93); median overall survival (OS) and progression-free survival (PFS) from start of avelumab were 26.22 mo (95% CI, 19.97-not estimable [NE]) and 7.63 mo (95% CI, 5.79-9.24), respectively. In pts aged <60 y (n=53), 60-70 y (n=150), and >70 y (n=208), median OS (95% CI) was not reached (NR; 12.86 mo-NE), NR (24.21 mo-NE), and 24.01 mo (16.94-NE), and median PFS was 5.20 mo (2.83-6.71), 7.70 mo (5.26-10.07), and 8.82 mo (6.05-12.93), respectively. In pts who received 1L cisplatin + gemcitabine (n=183) and 1L carboplatin + gemcitabine (n=219), median OS (95% CI) was NR (16.05 mo-NE) and 25.10 mo (19.97-NE), and median PFS was 6.61 mo (5.30-9.18) and 8.42 mo (6.05-12.73), respectively. The table shows OS and PFS in other subgroups defined by best response to 1L PBC and number of 1L PBC cycles received. Conclusions: Real-world outcomes with avelumab 1LM in this CUP in Italy show clinical benefit across various subgroups. These data are clinically relevant and are consistent with other real-world country-based studies and the phase 3 JAVELIN Bladder 100 trial. Findings further support the use of avelumab 1LM as standard of care in pts with la/mUC who are progression free after PBC. [Table: see text]

Phase III randomized trial of stereotactic ablative radiotherapy (SAbR) for oligometastatic advanced renal carcinoma (EA8211-SOAR).

TPS489 Background: Optimal strategies for managing oligometastatic renal cell carcinoma (RCC) are unclear. While systemic therapy is the accepted standard, Stereotactic Ablative Radiation (SAbR) is a promising alternative based on retrospective and limited prospective data1-3. SAbR may spare patients from systemic therapy toxicity, but progression of occult micrometastasis remains a concern. This prospective ECOG-ACRIN phase 3 randomized trial will compare SAbR to systemic therapy for oligometastatic RCC. Co-primary endpoints are overall survival (OS) and toxicity. Methods: Patients with RCC (any histology except for sarcomatoid) with an ECOG performance 0-2, International Metastatic RCC Database Consortium (IMDC) favorable and intermediate-risk, and 2-5 extracranial metastases are eligible. The exclusion criteria include prior systemic therapy (except for adjuvant therapy) and brain metastases. Patients with intact primary are eligible after definitive treatment of the primary site. Stratification factors include 1) number of metastases (2-3 vs 4-5), 2) histology (clear cell vs non-clear cell), 3) IMDC (0 vs 1-2), 4) prior adjuvant systemic therapy (yes vs no), and 5) time from treatment of primary disease (<1yr vs >1yr). Patients will be randomized to up front systemic therapy (the type of systemic therapy will be chosen at the discretion of the investigator) versus SAbR (and additional SAbR of up to a total of 6 metastasis while disease remains amenable) followed by systemic therapy. Co-primary endpoints are OS and toxicity (≥grade 3). Target accrual goal is 472 patients which will provide 85% power to test non-inferiority in OS from a non-inferiority hybrid design, assuming a null hazard ratio of 1.24 and alternative hazard ratio of 0.85. If it is concluded that SAbR arm has non-inferior OS, superiority in toxicity will be tested. Secondary endpoints include health-related quality of life (QOL) as measured with NFKSI-19 and EQ-5D-5L and progression free survival (PFS). Exploratory endpoints include PFS of 1st line systemic therapy, local control with SAbR and cost-effectiveness. The trial has been open for enrollment since September 2023.

Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.

TPS231 Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Upon AtezoTRIBE subgroup analysis of the 8 pts with dMMR mCRC treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first patient having progression ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+/-atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow up have been reduced; as has measurable disease per RECIST. The primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). The sample size has been modified with the accrual goal of 120 patients randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228 .

Alliance A022102: Randomized phase III trial of mFOLFIRINOX +/- nivolumab vs. FOLFOX +/- nivolumab for first-line treatment of metastatic HER2-negative gastroesophageal adenocarcinoma (GEA).

TPS4175 Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score > 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .

Real-world outcomes in advanced melanoma patients treated with first-line nivolumab plus ipilimumab.

e21552 Background: Nivolumab plus ipilimumab (NIVO+IPI), a first-in-class combination immunotherapy, has dramatically changed the treatment paradigm for melanoma in recent years. The aim of this study was to analyze treatment patterns, treatment response, survival, safety, and healthcare resource utilization with this first-line combination therapy in patients (pts) with advanced melanoma under real-world conditions. Methods: This retrospective analysis included pts with stage 3 unresectable and stage 4 melanoma treated 01/2021-06/2022 with NIVO+IPI at 6 centers in Poland according to uniform criteria. Pts received up to 4 cycles of IPI 3 mg/kg + NIVO 1 mg/kg Q3W followed by maintenance NIVO (240 mg Q2W or 480 mg Q4W) until disease progression, unacceptable toxicity or at the request of the patient or physician. Kaplan-Meier estimator and Log-rank test were used in survival analysis. Results: A total of 291 adults were identified. The median age was 53 years, 42.5% of pts were female, 47% were BRAF-mutated, and 24% of pts received prior adjuvant treatment. At baseline, 19.5% of pts had stage III disease, 14.1% stage M1a, 13.7% stage M1b, 30.1% stage M1c and 23% had M1d disease. Median follow-up time was 11.9 months. The median number of cycles of NIVO+IPI administered was 3, with 47.9% of pts completing 4 cycles. Maintenance NIVO was continued in 52.7% pts who discontinued the combination therapy due to toxicity. Median progression-free survival (mPFS) was 9.8 months (95% CI 6.9–13.4). The longest mPFS was observed in pts with stage M1a (15 months; 95%Cl 3.1–NA) and the shortest in stage M1d pts (5 months; 95%CI 2.8–NA). We observed a statistically significant longer mPFS in pts who continued NIVO monotherapy after discontinuation of combination therapy due to toxicity (13 months, 95% Cl 10.4–NA) compared to those who discontinued immunotherapy (7.1 months, 95% Cl 3.4 –12; p < 0.0001). Median overall survival (OS) was not achieved, with an OS rate of 70% at 12 months (95%Cl 64–76). The objective response rate (ORR) was 39%, with 7.8% of pts achieving a complete response. For pts who received prior adjuvant therapy, the ORR was 24.2%. Treatment-related adverse events (TRAEs) of any grade were observed in 97% of pts and grade 3/4 TRAEs occurred in 29.6% of pts. The most common TRAEs were liver toxicity, colitis, hyperthyroidism, hypothyroidism, and hypopituitarism; the treatment-related hospitalization rate was 23.8% and the median length of hospital stay was 9 days. Conclusions: This real-world study confirms the high efficacy of NIVO+IPI in real-world settings with grade 3/4 toxicity lower than observed in clinical trials. Maintenance of NIVO despite early toxicity during combination treatment appears to have a beneficial effect on patient survival. Therefore, it is extremely important to carefully monitor pts for toxicity, as early intervention helps to avoid severe toxicity and premature discontinuation of treatment.

Multi-omics fusion analysis models with machine learning predict survival of HER2-negative metastatic breast cancer: a multicenter prospective observational study.

Multi-omics fusion analysis models with machine learning predict survival of HER2-negative metastatic breast cancer: a multicenter prospective observational study.

Abstract P4-01-37: Discontinuation of HER2+ targeted therapy among cancer survivors with metastatic HER2+ breast cancer: A case report

Abstract Background: Anti-HER2 directed therapy (aHER2tx) has significantly improved survival outcomes in patients with HER2-positive metastatic breast cancer (HMBC). Current United States (US) and European oncology practice guidelines recommend continuing aHER2tx until intolerable side effects or disease progression. It is estimated that 10-15% of treated patients (pts) may achieve prolonged complete remission (CR). Currently, the optimal duration of aHER2tx in patients achieving a CR is unknown. A PubMed literature search identified 7 case reports outside of the US that describe pts who remain in CR after discontinuation of aHER2tx. To our knowledge, this is the first analysis of similar cases in the US. Method: We identified pts with a diagnosis of HMBC who discontinued aHER2tx between January 1, 2010, to June 30, 2021, at a large integrated healthcare system in the US. Pts were included if they had discontinued aHER2tx for at least one year. Data collection included demographics, histology, confirmed sites of metastatic disease (mets), local and systemic treatment (tx) before and after aHER2tx discontinuation, documented radiographic response, and reason to discontinue aHER2tx. Data collection ended on June 30, 2022. Results: Our case report identified 15 pts (mean age at diagnosis 53.0 ± 13.2) based on inclusion criteria. Baseline demographics and characteristics are listed in Table 1. Common clinical characteristics of the cohort include mean age at mets diagnosis is 56 years, postmenopausal status (67%), invasive ductal carcinoma (87%), ER-negative (60%), HER2-positive 3+ by IHC (93%), de-novo mets (60%), multiple sites (93%) and multi-organ mets (87%). Among the cohort, 6 pts (40%) received prior adjuvant therapy, then later recurred, and of these only one had received HER2-based adjuvant tx. In all pts, first line therapy for mets included chemotherapy and aHER2tx, except one pt received endocrine therapy (ET) and aHER2tx. A CR was achieved in all but one pt (93%) with one line of aHER2tx consisting of trastuzumab (H) ± pertuzumab (P). One pt (7%) received local tx to all metastatic sites. In 13 pts, the median time to first radiologic complete response (RCR) after first line therapy for mets was 4 months (Interquartile (IQR) 3-15). Two cases were not included as we were unable to determine time to initial response after tx. All pts had confirmed RCR at the time of aHER2tx discontinuation. Median duration of aHER2tx was 8.3 years (IQR 4.8-9.5), including a median of 6.3 years (IQR 2.8-8.8) on maintenance aHER2tx. Twelve pts (80%) were off all therapy, and 3 pts (20%) continued ET for ER+ disease at the last follow-up (f/u). Patient preference (47%) was the most common reason for stopping aHER2tx. The median disease-free survival off aHER2tx was 4.8 years (IQR 3.1-6.2) and all pts were alive without evidence of disease at last f/u. Conclusion: A subset of HMBC pts successfully discontinued aHER2tx without experiencing recurrence with a median of 4.8 years off therapy in a US cohort. In this case report, common clinical features like strong HER2 overexpression, no prior aHER2tx, and achieving RCR while on first line aHER2tx with H ± P are potential indicators for prolonged CR after discontinuing aHER2tx. Future studies with a comparator group are needed to fully understand the pt population who may safely stop aHER2tx after a CR. Table 1: Baseline Demographics and Clinical Characteristics Citation Format: Lai Fong Hui, Nina N. Shah, Rita L. Hui. Discontinuation of HER2+ targeted therapy among cancer survivors with metastatic HER2+ breast cancer: A case report [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-37.

Updated outcomes in TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan (SG) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI).

526 Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, a topoisomerase-I inhibitor, via a proprietary hydrolyzable linker. SG received accelerated FDA approval in April 2021 in pts with mUC who previously received PT-based therapy and a CPI based on the primary analysis of the pivotal TROPHY-U-01 Cohort 1 study. With 9.1 mo median (med) follow-up, SG monotherapy demonstrated a 27% objective response rate (ORR) and med overall survival (OS) of 10.9 mo in 113 pts with locally advanced or mUC progressing after receiving at least a PT-based therapy and a CPI (Tagawa, et al. J Clin Oncol. 2021). Here we report updated Cohort 1 outcomes. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase 2 study. Cohort 1 pts (≥18 y) had progression of mUC following PT (as first-line metastatic therapy or as (neo)adjuvant therapy with recurrence/progression ≤12 mo) and CPI, had ECOG PS 0-1, and creatinine clearance ≥30 mL/min. Pts received 10 mg/kg of SG intravenously on D1 and D8 of 21-D cycles. The primary endpoint was ORR per central review by RECIST 1.1. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), OS, and safety. Results: As of July 26, 2022, med follow-up was 10.5 mo (range, 0.3-40.9) for treated pts (N=113). As previously reported, pts (78% men; med age, 66 y; 66% with visceral metastases, 34% liver), were heavily pretreated with a med of 3 prior therapies (range, 1-8). Med time since last prior therapy was 1.5 mo (range, 0-60.0). At data cutoff, per central review, ORR was 28% (95% CI, 20.2-37.6); CBR was 38% (95% CI, 29.1-47.7), med DOR was 6.1 mo (95% CI, 4.7-9.7, n=32) and med PFS was 5.4 mo (95% CI, 3.5-6.9). Med time to response was 1.6 mo (range, 1.2-5.6) and med OS was 10.9 mo (95% CI, 8.9-13.8). DOR, PFS, and OS rates (95% CI) at 12 mo were 30% (13.6-48.8), 14% (7.2-23.3), and 45% (35.4-53.8), respectively, with 7 (6%) pts still receiving SG at 12 mo. In pts who received prior enfortumab vedotin (n=10) and prior PT in the (neo)adjuvant setting (n=39), results were consistent with the overall population. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 65% of pts and were similar to prior reports; the most common Grade ≥3 TRAEs were neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%). One treatment-related death occurred due to febrile neutropenia-related sepsis. Conclusions: At 10.5-mo med follow-up, the response rate remains high in pts with heavily pretreated mUC, including pts with visceral metastases, prior EV therapy and prior (neo)adjuvant PT therapy. No new safety signals were observed. These data support the use of SG in pts with mUC who received PT and a CPI and further evaluation of SG in earlier lines of therapy. Clinical trial information: NCT03547973 .

READY: Real-world data from an Italian compassionate use program of avelumab first-line maintenance (1LM) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC).

469 Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1) 1LM plus best supportive care (BSC) in patients (pts) with la/mUC whose disease did not progress after 1L platinum-based chemotherapy (PBC) significantly extended overall survival (OS) vs BSC alone, and it is now recommended internationally as standard of care with level 1 evidence. We report real-world descriptive pt characteristics and outcomes data from a large, multicenter, Italian compassionate use program (CUP) assessing avelumab 1LM in pts with la/mUC. Methods: This prospective, noninterventional CUP was initiated on Jan 18, 2021, to provide early access to avelumab before reimbursement by the Italian Medicines Agency for pts with la/mUC. Avelumab was provided upon physician request and after approval by local ethics committees in accordance with the Italian compassionate use regulation. Avelumab 800 mg IV was administered every 2 weeks per local prescribing information to adult pts aged ≥18 years with la/mUC who were progression-free following PBC (4-6 cycles, starting 4-10 weeks after last dose of PBC). Pts who had a relapse within 12 months of prior adjuvant or neoadjuvant systemic therapy, including immune checkpoint inhibitors, were not eligible. Results: As of Aug 16, 2022, 464 pts (78.4% male, 21.6% female) were included from 140 Italian centers from Jan 2021-Mar 2022. Median age at inclusion was 70 years (IQR, 63-76 years). At the start of 1L PBC, 346 pts (73.9%) had metastatic disease and 40 (8.6%) had unresectable locally advanced disease (disease stage not defined [N/D] in 78 pts [16.8%]). ECOG PS was 0 in 321 pts (69.2%), 1 in 140 (30.2%), and N/D in 3 (0.7%). Primary tumor site was upper tract in 148 pts (31.9%) and lower tract in 309 (66.6%) (N/D in 7 [1.5%]). 1L PBC comprised carboplatin + gemcitabine in 241 pts (51.9%), cisplatin + gemcitabine in 214 (46.1%), and other PBC in 9 (1.9%); 225 pts (48.5%) received 4 cycles of PBC, 54 (11.6%) received 5 cycles, and 177 (38.2%) received 6 cycles (other or N/D in 8 [1.7%]). Complete response to 1L PBC was achieved in 51 pts (11.0%), partial response in 266 (57.3%), and stable disease in 147 (31.7%). For 391 pts currently evaluable for OS and progression-free survival (PFS) from the start of avelumab, the 12-month OS rate was 69.1% (95% CI, 64.4%-73.6%), while median OS was not reached. The 12-month PFS rate was 38.9% (95% CI, 34.0%-43.7%) and median PFS was 6.6 months (95% CI, 5.6-8.9 months). Grade 3-4 adverse events occurred in 33 pts (7.1%). Conclusions: This CUP included a large pt population representative of daily clinical practice in 140 Italian oncology centers and the results are consistent with those of previous studies. Overall, these real-world data strengthen the findings of JAVELIN Bladder 100 and provide further support for avelumab 1LM as a standard of care in eligible pts with la/mUC.

The Contemporary Presentation and Diagnosis of Endometrial Cancer Recurrence: When, Where, and How?

ABSTRACT Endometrial cancer (EC) is the most common gynecologic cancer in the United States. Despite a favorable prognosis in many, EC is one of the few cancers with rising mortality rates. This is in part due to recurrence rates, being as high as 50% in patients at high risk. Survival differences between locoregional and distant disease recurrence have prompted increased focus on multimodality adjuvant treatment. Disease surveillance using routine imaging for early detection of recurrence has not shown a survival benefit in those at low risk, and a more accurate profile of recurrence pattern and presentation may aid the screening current infrastructure. This retrospective review aimed to examine patterns of recurrence, presentation, and method of diagnosis of recurrent EC in a large contemporary cohort from a single, high-volume institution. Patients who underwent surgery for an EC diagnosis between June 2014 and December 2020 at Ohio State University Comprehensive Cancer Center were included. Disease recurrence was defined as evidence of disease after a 3-month disease-free interval following primary treatment. In the setting of metastatic disease, only those with a complete radiographic response after adjuvant therapy were eligible for recurrence. Locoregional recurrence was confined to the vaginal vault or pelvis. Multiple logistic regression analysis was used to assess the impact of covariates on the likelihood of receipt of treatment for recurrent disease, overall survival, and time from recurrence to death. A total of 1723 patients were included in the study cohort with a median follow-up time of 2.3 years. A total of 201 participants (11.6%) were included in the recurrence analysis. Of these patients, 120 (59.7%) were symptomatic, with abdominal and pelvic pain being the most common symptoms. Among asymptomatic recurrence cases, 15.4% were diagnosed by imaging at provider discretion, 13.4% were diagnosed by pelvic examination, and 7.5% were diagnosed by CA-125 at provider discretion. Patients diagnosed by pelvic examination were more likely to be at an early stage (66.7% vs 34.5%; P = 0.001), of endometrioid histology (66.7% vs 36.8%; P = 0.003), and without prior adjuvant therapy (48.2% vs 17.9%; P = 0.001). Patients who received adjuvant therapy experienced significantly more locoregional recurrences (60.5% vs 19.7%; P ≤ 0.001), but there was no difference in the median time to recurrence of 12.7 months. Patients with asymptomatic recurrence were more likely to be able to receive treatment than those with symptomatic presentations (91.3% vs 76.7%; P = 0.005). Age at initial diagnosis was associated with receipt of treatment for recurrence. Patients with symptomatic recurrence had a significantly shorter median time from recurrence to death (6.5 vs 11.1 months; P = 0.0053) than asymptomatic patients; however, this was driven by receipt of treatment. Overall survival did not differ significantly between mode of presentation or method of diagnosis. The results of this study find that recurrence for EC was observed in 12% of women, the majority of whom experienced symptoms, and symptomatic patients were less likely to receive treatment, which contributed to a shorter time from recurrence to death. These findings in the context of an increasing mortality for EC suggest improvements in providing timely treatment for recurrent disease are essential.

NRG-GI004/SWOG-S1610: Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).

TPS258 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% v 12.3%) with mean PFS of 13.7 mos, with ~45% of pts in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data, which showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. A recent randomized trial subgroup analysis of 8 pts with dMMR metastatic colon cancer treated with FOLFOXIRI+bev+atezo, with the first patient having progression ~16 mos (AtezoTRIBE). Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy (48% PFS at 24 mos as assessed by site investigator), we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, and duration of response. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Clinical trial: NCT02997228. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT05080673 .

C-Reactive Protein and Lymphocyte-to-Monocyte Ratio Predict Recurrence in Stage III Melanoma Patients with Microscopic Sentinel Lymph Node Metastasis.

Although adjuvant therapies with immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors improve recurrence-free survival (RFS) in stage III melanoma patients significantly, prognostic factors are needed to identify patients with a high risk of disease recurrence. Therefore, the aim of our study was to investigate the prognostic potential of routinely collected blood parameters for stage III melanoma patients with microscopic sentinel lymph node (SLN) metastasis. Altogether, we retrospectively analyzed 138 stage III melanoma patients who were diagnosed with microscopic SLN metastasis at the skin cancer center of the University Hospital Cologne between 2011 and 2020 and who did not receive prior adjuvant therapy with ICI or BRAF/MEK-inhibitors. Univariate and multivariate Cox regression analyses, Kaplan-Meier survival analyses and receiver operating characteristic (ROC) curves were performed to assess the impact of preoperatively collected blood parameters and blood ratios on recurrence-free survival (RFS; primary endpoint) and overall survival (OS). A high neutrophil-to-lymphocyte ratio (NLR), low lymphocyte-to-monocyte ratio (LMR) and high C-reactive protein (CRP) value were significantly associated with shorter RFS in multivariate analysis. For LMR (cut-off 3.5) and for CRP (cut-off 3.0) this effect remained after dichotomization. CRP showed a stronger association with RFS than NLR or LMR, with the highest association being detected for the combination of low LMR and high CRP. Additionally, derived NLR ≥ 2.0 was significantly associated with shorter OS in multivariate analysis. In summary, our data suggest that CRP in combination with LMR should be considered as a marker for melanoma recurrence in stage III melanoma patients with microscopic SLN metastasis.