Wainberg, Zev A.

TPS258 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action & are capable of forcing internalization, self-routing through intracellular compartments to the cytosol & inducing potent cell-kill via the enzymatic & permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2+ solid tumors. Its novel mechanism of action, via enzymatic ribosome inactivation, may not be subject to resistance mechanisms that exist for tyrosine kinase inhibitors, antibody-drug conjugates, or antibody modalities. MT-5111 binds an epitope on HER2, distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2-targeting agents. MT-5111 is a 55 kilodalton protein & may have improved tumor penetration capability. The objective of this trial will be to determine the safety, tolerability, & maximum tolerated dose (MTD) of MT-5111 in patients (pts) with advanced HER2+ solid tumors. Methods: This Phase 1, first-in-human, open-label, dose escalation & expansion study will evaluate MT-5111 monotherapy in pts with HER2-positive solid tumors. The primary objective is to determine the MTD; secondary objectives include pharmacokinetics, tumor response & immunogenicity. Part 1 consists of MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10µg/kg/dose) based on a modified 3+3 design (n≤42 pts); Part 2 (dose expansion) will evaluate MT-5111 at the MTD in ≤98 pts. All pts will be administered MT-5111 over 30 min via IV infusion on Days 1, 8, & 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent, or another reason for withdrawal. Part 1 will include pts with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastric or gastroesophageal junction adenocarcinomas (collectively referred as gastroesophageal adenocarcinomas [GEA]) & other HER2+ solid cancers. Immunohistochemistry (IHC) status must be 2+ or 3+, regardless of in situ hybridization (ISH) results; if no IHC is available for pts with BC or GEA, ISH criteria per the American Society of Clinical Oncology College of American Pathologists guidelines will be used. In metastatic cases, HER2 positivity must be demonstrated on metastatic lesions. Pts with HER2+ BC should have had ≥2 lines of HER2-directed therapy; pts with HER2+ GEA should have received or been intolerant to trastuzumab. Pts with evaluable disease may be included in Part 1; in Part 2, all pts must have ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment, which began in September 2019, is ongoing. Clinical trial information: NCT04029922.

TPS149 Background: METamp is a secondary, or co-driving, genetic change in pts with mCRC and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant pts with mCRC and METamp, MET inhibition + an anti-EGFR agent could achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI). Tepotinib + the EGFR TKI gefitinib demonstrated improved outcomes in pts with EGFR-mutant METamp non-small cell lung cancer and acquired EGFR TKI resistance vs chemotherapy (INSIGHT: NCT01982955). In these pts, progression-free survival (PFS) was 16.6 vs 4.2 months (HR = 0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). In pts with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp, tepotinib + anti-EGFR antibody cetuximab may be active and therefore provide an effective therapeutic option. Methods: This Phase II, multicenter, single-arm, open-label study will assess preliminary antitumor activity, safety and tolerability, and explore pharmacokinetic (PK) profiles of tepotinib + cetuximab in pts with RAS/BRAF wild-type left-sided mCRC and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp. A safety run-in (6-12 pts) will evaluate the recommended Phase II dose of tepotinib to be used in combination with cetuximab (endpoint:dose-limiting toxicities). Enrollment is based on a confirmed advanced left-sided CRC diagnosis, with RAS/BRAF wild-type, documented previous anti-EGFR therapy and acquired resistance on the most recent anti-EGFR antibody and METamp confirmed by liquid and/or tissue biopsy. Pts must be ≥18 years old and have an Eastern Cooperative Oncology Group performance status of 0/1 and normal organ function. The study will screen sufficient pts to account for setting-specific METamp heterogenicity. Approximately 42 pts are planned to receive study treatment: ~22 in Cohort A (tepotinib second-line, outside US) and 20 in Cohort B (tepotinib ≥third-line, US only). Primary endpoint:investigator-assessed objective response (RECIST 1.1). Secondary endpoints are investigator-assessed duration of response (DoR) and PFS (RECIST 1.1), OS, tolerability and safety (NCI-CTCAE v5.0) and cetuximab immunogenicity (measured by antidrug antibody assays at the start and end of treatment). Additional endpoints include assessment of tepotinib and cetuximab PK profiles and expression of biomarkers of resistance (from blood and/or tissue samples). Retrospective assessment of best overall response, DoR and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study. Clinical trial information: NCT04515394.

TPS4661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .

4009 Background: Interim analysis of a global, phase 2 KEYNOTE-059 study (NCT02335411) reported manageable safety and promising antitumor activity for pembro alone or pembro + chemo in pts with G/GEJ cancer. Here we report long-term efficacy and safety data of all cohorts. Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled in 3 cohorts. Cohort 1 pts (PD-L1–positive or –negative) received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts (PD-L1–positive or –negative) received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts (PD-L1–positive, combined positive score ≥1% using the PD-L1 IHC 22C3 pharmDx assay) received pembro alone as first-line. All pts received pembro 200 mg Q3W for up to 2 years. End points included safety, ORR, DOR, and OS. Results: At data cutoff (Aug 8, 2018), median (range) follow-up was 6 (1-38), 14 (2-40), and 21 (2-36) months for cohorts 1 (n = 259), 2 (n = 25), and 3 (n = 31), respectively. In cohort 1, confirmed ORR (95% CI) was 11.6% (8-16) overall, 15.5% (10-22) in PD-L1–positive, and 6.4% (3-13) in PD-L1–negative tumors. In cohort 2, confirmed ORR was 60.0% (39-79) overall, 73.3% (45-92) in PD-L1–positive, and 37.5% (9-76) in PD-L1–negative tumors. In cohort 3, confirmed ORR was 25.8% (12-45). Median (range) DOR in months was 16.1 (2-35+), 4.6 (3-37+), and not reached (2.1-32.5+) in cohorts 1, 2, and 3, respectively. OS at 1 year/2 years was 24.6%/12.5%, 52%/32%, and 63.6%/40.1% in cohorts 1, 2, and 3, respectively. In cohorts 1, 2, and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 20 (80%), and 8 (26%) respectively. TRAEs led to discontinuation in 6 (2%) and 3 (12%) pts in cohorts 1 and 2, respectively, and to death in 2 (1%) pts in cohort 1. No TRAEs led to discontinuation or death in cohort 3. Conclusions: These updated results demonstrate manageable safety, durable clinically meaningful activity of pembro in heavily pretreated pts, and promising efficacy of first-line pembro (alone or + chemo) in pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.

723 Background: The US FDA approved pembro for treating pts with 1) recurrent locally advanced or metastatic G/GEJ adenocarcinoma, whose disease has progressed on or after ≥2 prior therapies and whose tumors express PD-L1 (combined positive score [CPS] ≥1), and 2) unresectable or metastatic, microsatellite instability-high (MSI-H) solid tumors that have progressed after prior therapy and who have no fitting options. We report Asian subgroup analyses from cohort 1 of KEYNOTE-059 (NCT02335411), a global, phase 2 study in advanced G/GEJ cancer. Methods: Eligible pts had measurable recurrent or metastatic G/GEJ adenocarcinoma whose disease has progressed on ≥2 prior chemotherapy regimens. Pts received pembro 200 mg Q3W up to 2 y. PD-L1+ tumors had a CPS ≥1. Primary end points were ORR (RECIST 1.1, by central review) and safety. Results: Cohort 1 enrolled 259 pts; 57% had PD-L1+ tumors. MSI status was evaluable in 174 tumor samples; of these, 7 were MSI-H. At data cutoff (4/21/2017), median (range) follow-up was 6 mo (1-25). Overall ORR was 12% (95% CI, 8-17) and median (range) DOR was 14 mo (2-19+). PFS6-mo rate was 15% and OS6-mo rate was 46%. In pts with PD-L1+ tumors, ORR was 16% (95% CI, 11-23) and median (range) DOR was 14 mo (3+-19+). In pts with PD-L1+ tumors, PFS6-mo rate was 20% and OS6-mo rate was 50%. In pts with MSI-H tumors, ORR was 57% (95% CI, 18-90) and median (range) DOR was not reached (5-14+ mo). In cohort 1, 41 pts were Asian and 218 pts were non-Asian. PD-L1+ tumors occurred in 42% of Asian pts and 60% of non-Asian pts. ORR was 12% (95% CI, 2-36) in Asian pts with PD-L1+ tumors and 17% (95% CI, 11-24) in non-Asian pts with PD-L1+ tumors. One of 7 pts with MSI-H tumors was Asian; this pt had CR. Grade 3-5 treatment-related AEs occurred in 17% and 18% of Asian and non-Asian pts, similar to the overall cohort. Conclusions: Pembro showed durable clinical benefit in previously treated pts with advanced G/GEJ cancer, especially those with PD-L1+ or MSI-H tumors. Safety and efficacy were similar in Asian and non-Asian pts. These findings highlight pembro as a standard treatment option in Asian and non-Asian pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.

4003 Background: Pembro has shown promising antitumor activity and manageable safety in a phase 1 study of pts with previously treated advanced gastric cancer. We conducted a global, multicohort, phase 2 study of pembro in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (KEYNOTE-059;NCT02335411). Methods: Cohort 1 enrolled 259 pts, aged ≥18 y with measurable recurrent or metastatic G/GEJ adenocarcinoma who had progressed on ≥2 prior chemotherapy regimens and had ECOG PS 0-1. Pts received pembro 200 mg Q3W up to 2 y or up to disease progression, investigator/pt decision to withdrawal, or unacceptable toxicity. PD-L1+pts had expression in ≥1% tumor or stromal cells using IHC (22C3 antibody). Primary end points: ORR (RECIST 1.1, by central review), safety, and tolerability. Results: Of 259 pts in cohort 1, 76.4% were men; median age was 62.0 y. 51.7% and 48.3% received pembro as 3rd-line (3L) and 4L+ therapy, respectively. 57.1% had PD-L1+ tumors. At data cutoff (Oct 19, 2016), median duration of follow-up was 5.4 mo (range, 0.5 to 18.7). Overall ORR (CR + PR) was 11.2% (95% CI, 7.6-15.7); 1.9% of pts (95% CI, 0.6-4.4) had CR, 9.3% had PR (95% CI, 6.0-13.5), 17% (95% CI, 12.6-22.1) had SD, and 55.6% (95% CI, 49.3-61.7) had PD. Median DOR was 8.1 mo (range, 1.4+ to 15.1+). ORR was 14.9% (95% CI, 9.4-22.1) in 3L pts and 7.2% (95% CI, 3.3-13.2) in 4L+. In PD-L1+ pts, ORR was 15.5% (95% CI, 10.1-22.4) with 2.0% (95% CI, 0.4-5.8) CR and 13.5% (95% CI, 8.5-20.1) PR; in PD-L1– pts, ORR was 5.5% (95% CI, 2.0-11.6), with 1.8% (95% CI, 0.2-6.5) CR and 3.7% (95% CI, 1.0-9.1) PR. In 3L pts with PD-L1+ tumors, ORR was 21.3% (95% CI, 12.7-32.3), with 4.0% (95% CI, 0.8-11.2) CR; in 3L pts with PD-L1– tumors, ORR was 6.9% (95% CI, 1.9-16.7), with 3.4% (95% CI, 0.4-11.9) CR. Grade 3-5 treatment-related AEs (TRAEs) occurred in 43 pts (16.6%). TRAEs led to discontinuation in 2 pts (abnormal LFT, bile duct stenosis) and were fatal in 2 pts (acute kidney injury, pleural effusion). Conclusions: Pembro showed encouraging efficacy and manageable safety after ≥2 prior lines of therapy in pts with advanced G/GEJ cancer in this large phase 2 trial. Survival and additional biomarker data, including MSI status, will be presented. Clinical trial information: NCT02335411.