Bendell, Johanna C.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348 ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

10 Background: In colon cancer, tumor deposits (TD) have been associated with worse prognosis, but they are included in the TNM staging system only in the absence of lymph node metastasis (i.e., stage III pN1c tumors). Here we aimed at evaluating the prognostic value of TD and the impact of the addition of TD in the count of lymph node metastases in patients with stage III colon cancer from the CALGB/SWOG 80702 phase III trial (NCT01150045). Methods: Pathological reports of all patients were reviewed for the presence and the count of TD, primary tumor sidedness, lymphovascular invasion and perineural invasion. Cases without available pathological report or without specific information of TD were excluded. Prognostic associations were evaluated by multi-variable Cox models adjusting for treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. Results: Overall, 2028 patients were included, with 524 (26%) TD-positive and 1504 (74%) TD-negative stage III tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e., pN1c), 239 (46.1%) were pN1a/b and 200 (38.55%) were pN2. 17.2% and 37.0% of all pN1a/b and pN2 tumors had TD. Overall median follow-up was 69.3 months. The presence of TD was associated with poorer DFS (adjusted hazard ratio (aHR) = 1.59, 95%CI 1.28-1.91) and OS (aHR = 1.52, 95%CI 1.18-1.95) in the overall population. The negative effect of TD on DFS and OS was observed for both pN1a/b and pN2 groups and confirmed in multivariate Cox model. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Adding TD to the count of lymph node metastases, 104 of 1570 (6.6%) patients initially considered as pN1 were re-staged as pN2. Re-staged pN2 patients experienced worse DFS (3-year DFS rate: 65.5% versus 80.3%, P = .0003) and OS (5-year OS rate: 69.1 versus 87.8%, P = .0005) than patients confirmed as pN1. Re-staged pN2 patients had similar DFS than patients initially staged as pN2 (3-year DFS rate: 65.5% versus 63.1%, P = .1992). OS curves of these 2 groups crossed, with better outcomes during the first 3 years of follow-up but poorer 5-year estimates for re-staged pN2 patients (5-year OS rate: 69.1% versus 74.8%, P = .0436). Conclusions: TD are found in more than one fourth of stage III colon cancer specimens. The number of TD has a linear deleterious effect on patients’ prognosis. Adding the number of TD to the count of lymph node metastases improves the prognostication accuracy of the TNM staging. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01150045.

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the United States. Aberrant activation of the Wnt signaling pathway is associated with CRC progression. Ring finger protein 43 (RNF43) is a single-pass type 1 transmembrane protein and a key feedback regulator of Wnt. SC-006 is a RNF43 targeted antibody drug conjugate, linked to a pyrrolobenzodiazepine dimer DNA crosslinking agent. Budigalimab (ABBV-181) is a PD-1 targeting, humanized, recombinant immunoglobulin G1 monoclonal antibody with Fc mutations (L234A, L235A) shown to reduce Fc receptor interactions and limit effector function. This open-label, Phase 1 clinical trial assessed the safety and efficacy of SC-006 as monotherapy and in combination with budigalimab in patients with CRC (NCT03035279). Methods: Evaluable patients had histologically or cytologically confirmed advanced metastatic or unresectable CRC. The trial consisted of 2 parts: part A (SC-006-monotherapy, 2 to 12 µg/kg, IV) and part B (SC-006 in combination with budigalimab at a fixed dose of 375 mg/kg IV every 3 weeks [Q3W]). Efficacy was assessed per RECIST 1.1 by radiographic assessments. Results: As of April 2019, 29 patients were enrolled (n=20 in part A and n=9 in part B). All patients experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs (>20% of patients) are summarized in Table 1. Two patients (7%) had dose-limiting toxicities of grade 4 thrombocytopenia. All 29 patients discontinued from the study, with study drug being discontinued for 76% of patients due to progressive disease. One death occurred in part A due to gastrointestinal hemorrhage with possible relation to SC-006. Serious TEAEs occurred in 8 patients (28%); these included thrombocytopenia and malignant neoplasm progression in 2 patients (7%) each. Progressive disease occurred in 18 patients (62%), stable disease was reported in 10 patients (34%) and the response for 1 patient was not reported. Conclusion: SC-006 dose escalation was limited by thrombocytopenia observed below the predicted efficacious dose, leading to study termination. Table 1.Summary of the Most Common Treatment-Emergent Adverse EventsPart A: SC-006-monotherapyPart B: SC-006+budigalimabTEAEs (>20% patients), n (%)2 ug/kg4 ug/kg8 ug/kg4 ug/kg8 ug/kg12 ug/kg4 ug/kg Q6W+budigalimab8 ug/kg Q6W+budigalimabOverallQ3WQ3WQ3WQ6WQ6WQ6W(N=1)(N=3)(N=1)(N=2)(N=10)(N=3)(N=4)(N=5)(N=29)Thrombocytopenia01 (33)1 (100)1 (50)4 (40)3 (100)1 (25)4 (80)15 (52)Fatigue0001 (50)3 (30)2 (67)3 (75)3 (60)12 (41)Nausea0001 (50)5 (50)1 (33)2 (50)2 (40)11 (38)Edema peripheral01 (33)01 (50)4 (40)02 (50)1 (20)9 (31)Decreased appetite01 (33)01 (50)4 (40)002 (40)8 (28)Dyspnea00004 (40)3 (100)01 (20)8 (28)Vomiting0001 (50)3 (30)1 (33)2 (50)1 (20)8 (28)Constipation0001 (50)3 (30)01 (25)2 (40)7 (24) Citation Format: Katrina S. Pedersen, Amit Mahipal, Andrea Cercek, Susanna Ulahannan, Michael Rossi, Abraham Fong, Daniel Brickman, Johanna Bendell. First-in-human clinical trial of SC-006, a RNF43 targeted antibody-drug conjugate, as a monotherapy and in combination with budigalimab in patients with advanced colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT167.

4003 Background: Aspirin and cyclooxygenase-2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. CALGB/SWOG 80702 tested the effect of celecoxib, a COX-2 inhibitor, on reducing the risk of recurrence in stage III CC. Methods: CALGB/SWOG 80702 is a 2x2 randomized controlled phase III trial of 3 v 6 months of adjuvant FOLFOX (data previously reported as part of the IDEA collaboration) with concurrent celecoxib (400 mg daily) v placebo x 3 yrs for patients (pts) with resected stage III CC. The primary endpoint of the trial is disease-free survival (DFS), defined as time from randomization to recurrence or death from any cause. The trial was designed to provide 91% power to detect a hazard ratio (HR) of 0.79 in favor of celecoxib with 2-sided alpha = 0.05 (775 events required); due to slowing accumulation of events 4 years after complete accrual, power was lowered to 85% with same HR and alpha assumptions (696 events required). The DSMB released data on February 24, 2020 at median f/u of 5.6 yrs with 689 DFS events. Results: Between June 2010 and November 2015, 2,526 pts were consented and randomized to the trial. Treatment arms were well balanced by patient and tumor prognostic features, as well as low-dose aspirin use. Baseline characteristics included 45% female, 18% non-White, 8% Hispanic, 15% T4, 26% N2. 3-yr DFS for celecoxib was 76.3% v 73.3% for placebo (HR 0.89 [95% CI 0.77-1.04]; P = 0.14). 5-yr overall survival (OS) was 83.9% for celecoxib v 81.7% for placebo (HR 0.87 [95% CI 0.72-1.05]; P = 0.14). When considering the 4 treatment arms separately, 3-yr DFS was 77.0% for 12 months FOLFOX + celecoxib, 74.9% for 12 months FOLFOX + placebo, 75.5% for 6 months FOLFOX + celecoxib, and 71.9% for 6 months FOLFOX + placebo (log rank P = 0.22; P interaction = 0.64). There were no significant differences in grade 3-4 toxicity with celecoxib v placebo. Compliance with protocol celecoxib treatment, defined as 3 yrs of therapy completion or recurrence/death while on treatment, was 58.1% pts on celecoxib and 60.2% pts on placebo. Conclusions: The addition of celecoxib to standard chemotherapy did not significantly improve DFS or OS. Clinical trial information: NCT01150045 .

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.