Objective Response Rate In Pts Research Articles

Abstract CT054: Amivantamab in wild-type advanced non-small cell lung cancer after disease progression on checkpoint inhibition and chemotherapy: Results from the phase 1b CHRYSALIS study

Abstract Background: Overexpression of EGFR and MET has been observed in wild-type (WT) adenocarcinoma and squamous non-small cell lung cancer (NSCLC; Huang L. J Thorac Oncol. 2014). Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, demonstrated pre-clinical activity against WT tumors overexpressing EGFR and MET. We examined ami monotherapy activity in WT-NSCLC after disease progression on platinum-based chemotherapy and anti-PD-1 or PD-L1 therapy. Methods: The WT-Ad and WT-Sq cohorts of the CHRYSALIS study enrolled pateints (pts) with adenocarcinoma or squamous cell carcinoma histology, respectively, without evidence of EGFR, ALK, and MET Exon 14 skipping activating mutations. Pts received ami monotherapy at the approved dose (1050 mg; 1400 mg if ≥80 kg) weekly for the first 4 weeks and biweekly thereafter. Response was assessed by the investigator per RECIST v1.1. Plasma samples were collected pre-treatment, with ctDNA analyzed by Guardant Health (Redwood City, CA). Results: In the WT-Ad cohort, 41 pts received ami (30 with ≥1 post-baseline disease assessment; 11 discontinued due to adverse events [AEs], disease progression, or physician decision), with a median follow-up of 6.2 mo. The median age was 62 years, 63% were men, and 37% were Asian. The objective response rate (ORR) was 7% (3/41), the clinical benefit rate (CBR) was 29%, and the median duration of response (DoR) was 4.2 mo (95% CI, 4.1-not estimable [NE]). Among pts with detectable ctDNA (n=24), 9 pts had KRAS/HER2 mutations. The ORR for pts with and without KRAS/HER2 mutations was 0% (0/9) and 20% (3/15), respectively. The corresponding median PFS for pts with and without KRAS/HER2 mutations was 1.4 mo (95% CI, 1.4-NE) and 4.2 mo (95% CI, 1.6-NE), respectively. In the WT-Sq cohort, 14 pts received ami (12 with ≥1 post-baseline disease assessment; 2 discontinued), with a median follow-up of 6.3 mo. Median age in the WT-Sq cohort was 71 years, 57% were men, and 43% were Asian. ORR was 21% (3/14) with a median DoR that was NE and 2 pts with a DoR ≥6 mo. The overall CBR was 43% (6/14), median PFS was 4.0 mo (95% CI, 2.2-7.3), and median OS was NE. Most common treatment-emergent AEs in both cohorts were rash (grouped term; 66% for WT-Ad, 57% for WT-Sq) and infusion-related reactions (63% WT-Ad and 57% WT-Sq). Grade ≥3 treatment-related AEs (TRAEs) were reported in 17% of pts in the WT-Ad cohort and 21% the WT-Sq cohort. One (2%) pt in the WT-Ad cohort experienced grade 2 interstitial lung disease. Four pts in WT-Ad and 2 pts in WT-Sq cohort discontinued due to TRAEs. Conclusions: Ami demonstrated preliminary antitumor activity in pts with refractory WT squamous and adenocarcinoma NSCLC, particularly in those lacking KRAS/HER2 activating mutations. Safety profile was consistent with the previously reported monotherapy experience, and no new signals were identified. Citation Format: Byoung Chul Cho, Jonathan Goldman, Natasha Leighl, Filippo De Braud, Ki Hyeong Lee, François Ghiringhelli, Pilar Garrido, Julio Peguero, Benjamin Besse, Philippe Cassier, Nicolas Girard, Maria de Miguel, Rosa Alvarez, Alastair Greystroke, Yuichiro Ohe, Te-Chun Hsia, Joshua C. Curtin, Sanjib Chowdhury, Xuesong Lyu, Grace Gao, Siyang Qu, Patricia Lorenzini, Aastha Kapoor, Priya Kim, Mahadi Baig, Meena Thayu, Roland E. Knoblauch, Sandrine Hiret, Pascale Tomasini. Amivantamab in wild-type advanced non-small cell lung cancer after disease progression on checkpoint inhibition and chemotherapy: Results from the phase 1b CHRYSALIS study [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 CT054.

Abstract CT179: Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study

Abstract Background: JSKN003 is a bispecific HER2-directed antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor (TOP1i) via a dibenzocyclooctyne tetrapeptide linker on the glycan of a humanized bispecific antibody. Pre-clinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian patients (pts) with advanced/metastatic solid tumors. Pts (ECOG PS 0-1) with histologically documented HER2-expressing (IHC ≥ 1+) or pts with HER2-mutant cancers who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15th December 2023, 32 pts (15 breast cancers, 5 ovarian cancers, 3 bladder cancers, 2 esophageal cancers, 2 non-small cell lung cancers, 1 gastric cancer, 1 head and neck cancer, and 3 other cancers) were enrolled and received JSKN003 across 7 dose levels (1.0, 2.1, 4.2, 5.2, 6.3, 7.3, and 8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. Treatment-related adverse events (TRAEs) occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%),which were all grade 1-2. Only 1 pt experienced interstitial lung disease (7.3mg/kg, Grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg.Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved partial response as per RECIST 1.1 by investigator. The objective response rate (ORR) and disease control rate (DCR) was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2+ BC and HER2-low BC, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 amplified tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 Citation Format: Claire Beecroft, Bo Gao, John Park, Kate Wilkinson, Karl Zhang, Xiangyun Yan, Yuan Lv. Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study [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 CT179.

Efficacy of lenvatinib (LEN) vs sorafenib (SOR) in the first-line (1L) treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC): A post hoc analysis of patients with nonviral etiology from REFLECT.

4078 Background: The randomized phase 3 REFLECT trial demonstrated that LEN was non-inferior to SOR in overall survival (OS; primary endpoint) in 1L uHCC (median: 13.6 months [95% CI, 12.1–14.9] vs 12.3 months [95% CI, 10.4–13.9]) (HR, 0.92; 95% CI, 0.79–1.06). Median progression-free survival (PFS) by independent imaging review (IIR) per mRECIST was 7.3 months (95% CI, 5.6–7.5) for pts in the LEN arm and 3.6 months (95% CI, 3.6–3.7) for pts in the SOR arm (HR, 0.64; 95% CI, 0.55–0.75; p<0.0001). Objective response rate (ORR) by IIR per mRECIST was 40.6% for pts in the LEN arm and 12.4% for pts in the SOR arm (odds ratio, 5.01; 95% CI, 3.59–7.01; p<0.0001) [Kudo 2018, Lancet]. Since REFLECT, combination therapies with immunotherapy have become part of the therapeutic arsenal for the treatment of uHCC, and many studies are ongoing. Recent data suggest that viral/nonviral etiology may impact treatment outcomes [Pfister 2021, Nature; Rimini 2022, ESMO Open]. To add to the current body of evidence, this post hoc analysis evaluated efficacy in pts with nonviral etiology in REFLECT. Methods: In REFLECT, pts with uHCC who had not received treatment for advanced disease were randomized to LEN (12 mg/day for bodyweight ≥60 kg; 8 mg/day for bodyweight <60 kg) or SOR (400 mg twice-daily) in 28-day cycles. This post hoc analysis included pts without hepatitis B or C (based on medical history) who were randomized to receive LEN or SOR. PFS, ORR (by IIR per mRECIST), and OS were analyzed. OS and PFS were estimated with the Kaplan-Meier method. Results: Of 478 pts randomized to LEN and 476 pts randomized to SOR, 127 and 108 pts, respectively, had nonviral etiology. Among randomized pts with nonviral etiology, median OS was 13.8 mos (95% CI, 10.5–18.7) in the LEN arm and 13.9 months (95% CI, 11.7–17.5) in the SOR arm (HR, 1.03; 95% CI, 0.75–1.43). Median PFS was 7.4 months (95% CI, 5.5–8.7) in pts randomized to LEN with nonviral etiology and 4.0 months (95% CI, 3.6–5.5) in pts randomized to SOR with nonviral etiology (HR, 0.60; 95% CI, 0.42–0.87). ORR was 39.4% (95% CI 30.9–47.9) in pts randomized to LEN with nonviral etiology and 20.4% (95% CI 12.8–28.0) in pts randomized to SOR with nonviral etiology. Fewer (n=34 [26.8%]) pts with nonviral etiology randomized to LEN received anticancer medication during survival follow-up than those randomized to SOR (n=46 [42.6%]). Conclusions: In this post hoc analysis, OS, PFS, and ORR in pts randomized to LEN with nonviral etiology were consistent with the overall population of pts randomized to LEN. This post hoc analysis, along with the results of the primary analysis of REFLECT [Kudo 2018, Lancet], demonstrates the efficacy of LEN regardless of etiology in uHCC, and supports LEN as a standard of care option for pts with 1L uHCC. Treatment efficacy by etiology should be assessed prospectively in future uHCC trials. Clinical trial information: NCT01761266 .

A multicenter, open-label, single-arm, phase II trial to evaluate the efficacy and safety of geptanolimab (GB226) in the treatment of patients (pts) with programmed cell death ligand 1 (PD-L1)–positive recurrent or metastatic cervical cancer, for whom prior platinum-containing chemotherapy has failed.

5535 Background: Geptanolimab (GB226) is a novel anti-programmed cell death 1 (PD-1) antibody, exhibiting good tolerance and promising efficacy in pts with advanced/recurrent solid tumor/lymphoma in previous phase I/II studies. This study is a two-part, multicenter, single-arm phase II study of GB226 in pts with recurrent or metastatic cervical cancer recruited from 28 clinical sites in China. In Part 1, we observed encouraging antitumor activity of GB226 with 11 PRs in 46 PD-L1 positive (combined positive score, CPS≥1) pts. Here we report the efficacy and safety results from Part 2 of this trial. Methods: In part 2, PD-L1 positive (CPS≥1) pts with recurrent or metastatic cervical cancer who had received one or more lines of platinum-containing chemotherapy were enrolled and treated with GB226 (intravenous infusion, 3 mg/kg) once every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by Independent Review Committee (IRC) per RECIST 1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Results: In Part 2, 123 pts were enrolled. As of July 28, 2022, after a median follow-up of 16.69 months (95%CI: 11.07, NR), 100 pts who met the study population criteria were eventually included in the full analysis set (FAS). 46% (46/100) of pts had received ≥2 lines of prior systemic therapy and 90% (90/100) had squamous cell carcinoma. The ORR was 18.0% (18/100; 95%CI: 11.03%, 26.95%) assessed by IRC, including 5 pts with CR (5.0%) and 13 pats with PR (13.0%); Median DOR was not reached (95%CI: 7.16, NR), median PFS was 1.91 months (95%CI: 1.87, 3.55), and median OS was 16.69 months (95%CI: 11.07, NR). Clinical benefit was observed across most patient subgroups, with a trend of higher ORR in pts with squamous cell carcinoma, no previous bevacizumab use and higher CPS. Among 123 safety-evaluable pts, 97 (78.9%) pts experienced a treatment-related adverse event (TRAE). The most common TRAE (≥10%) were hypothyroidism (24.4%), anemia (21.1%) and hyperthyroidism (13.8%), most of which were grade 1 and 2. Treatment-related grade 3/4 adverse events occurred in 25 (20.3%) and 2 (1.6%) pts, respectively. No grade 5 TRAEs occurred. 7 (5.7%) pts discontinued treatment due to a TRAE. The most common immune-related adverse events (irAE, ≥5%) were hypothyroidism 27 (22.0%) and hyperthyroidism 16 (13.0%). Conclusions: GB226 demonstrated durable antitumor activity and manageable safety profile in pts with recurrent or metastatic cervical cancer. Clinical trial information: NCT03808857 .

A phase I study of KL590586, a next-generation selective RET inhibitor, in patients with RET-altered solid tumors.

3007 Background: KL590586 (A400/EP0031) is a potent next-generation selective RET inhibitor (SRI) with activity against acquired resistance mutations to first-generation SRIs, and brain metastases (mets). Here we present preliminary data of the phase Ⅰ part from a phase I/II study (KL400-I/II-01, NCT05265091) in patients (pts) with RET-altered advanced tumors to define safety, pharmacokinetics (PK) and efficacy. Methods: The phase Ⅰ of KL400-I/Ⅱ-01 consisted of dose-escalation (Bayesian Optimal Interval design) and dose-expansion. Primary endpoints were to determine the maximum tolerated dose (MTD) and/or Recommended Phase II Dose. Secondary endpoints included safety, PK, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) as per RECIST 1.1. Results: As of Dec. 30, 2022, 87 pts with RET-altered tumors were treated at 6 doses levels (10 to 120 mg QD). No DLTs were observed, and MTD was not reached. Incidence of treatment-related adverse events (TRAEs, any grade) was 93.1% (81/87), most (74.7%) were grade 1-2, reversible and included (>25%): AST increase (50.6%), ALT increase (48.3%), creatinine increase (33.3%), bilirubin increase (32.2%), constipation (32.2%) and headache (31%). 24.1% of pts had grade ≥3 TRAEs, the most common (occurring in >2% of pts) were ALP increase (2.3%), GGT increase (2.3%), ileus (2.3%). TRAEs led to dose reduction or treatment discontinuation in 4.6% and 6.9% of pts, respectively. Hypertension, QT interval prolongation, platelets decrease and lymphocytes decrease (leading to 1st gen SRI dose delays and modifications frequently) were rare (<5%) and low-grade. The exposure increased dose-dependently and the mean half-life was found to be 34.1-99.8 h. Clinical responses were observed from 40mg onwards. 69 pts treated at the 40-120mg dose levels (57 NSCLC, 10 MTC, 1 pancreatic cancer, 1 ovarian cancer) were evaluable for efficacy analysis, ORR was 64% (NSCLC, MTC and pancreatic cancer). Most pts (58/69) remained on treatment, with the longest >11 months. The ORR in pts with systemic pretreated NSCLC (median prior treatment: 2, range 1-9, 28% pretreated with anti-PD1/PD-L1 therapy) was 63%(20/32, 1 CR), DCR 91% with median DoR not reached. 9 pts received prior 1st gen SRI, 7 with tumor shrinkage of -10% to -69%, with 3 PR and 4 SD. 11 pts with brain mets (without radiotherapy):4/5 with measurable brain disease had 100%, 100%, 80%, and 47% shrinkage. Overall CNS DCR was 100%.The ORR in treatment naïve NSCLC was 76% (19/25, 1 CR), DCR 92% and median DoR not reached. 3/4 pts with brain mets (without radiotherapy) had complete or partial disappearance of baseline brain lesions. Conclusions: KL590586 was well-tolerated, and associated with robust clinical activity in RET-altered tumors regardless of tumor type, including NSCLC pts with resistance to1st gen SRIs and with CNS mets. Pivotal studies are planned. Clinical trial information: NCT05265091 .

Abstract CT228: Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials

Abstract Background: NTRK gene fusions are oncogenic drivers in various tumor types. Laro, a highly selective and central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, is approved for the treatment of patients (pts) with TRK fusion cancer. Laro demonstrated an objective response rate (ORR) of 69% in 244 pts with solid (non-primary CNS) tumors (Drilon et al. ASCO 2022). Here, we report on the concordance between baseline local tissue-based testing with central tissue-based and liquid biopsy-based ctDNA testing to identify NTRK gene fusions. Methods: Pts with non-primary CNS TRK fusion cancer who underwent independent review committee assessments by July 15, 2019, in three laro clinical trials (NCT02122913, NCT02576431, and NCT02637687) were included. Tumor NTRK gene fusion status was determined locally by a variety of methods, and centrally by next-generation sequencing in both tissue (using Illumina TruSight™ Oncology Comprehensive) and ctDNA (using Guardant360® or GuardantOMNI®) at baseline. Data cut-off: July 20, 2021. Results: Of the 164 pts with NTRK fusions identified by local testing, 117 had evaluable tissue samples for central testing, and 99 had evaluable liquid biopsy samples. In total, 81.2% (95/117) of tumors had the fusion confirmed by central tissue testing. ctDNA testing detected NTRK gene fusions in 33.3% (33/99) of patients. Positive predictive values for each NTRK gene fusion are shown in the Table. The ORR for pts with NTRK gene fusions determined by local and central testing will be presented. Conclusions: A high proportion of tumors with locally identified NTRK gene fusions were confirmed centrally. At present, analysis of ctDNA is significantly less sensitive at detecting NTRK gene fusions. A negative ctDNA result requires next-generation sequencing testing of a tissue biopsy. Further research is needed to improve the sensitivity of ctDNA gene fusion detection. Table NTRK gene fusion Tissue-based LT Tissue-based CT ctDNA-based CT with LB Fusion confirmed, n Fusion confirmed, n Fusion not detected, n Unavailable samples, n† PPV‡: CT vs tissue-based LT, % Fusion confirmed, n Fusion not detected, n Unavailable samples, n† PPV‡: LB vs tissue-based LT, % NTRK1 68 35 14 19 71.4 20 34 14 37.0 NTRK2 4 3 1 0 75.0 0 4 0 0 NTRK3 92§ 57 7 28 89.1 13 28 51 31.7 †Includes no sample available and sample QC failed. ‡Calculated as a percentage of the number of confirmed fusions over the number of available samples. §Includes 9 inferred NTRK3 fusions. CT, central testing; ctDNA, circulating tumor DNA; LB, liquid biopsy; LT, local testing; NTRK, neurotrophic tyrosine receptor kinase; PPV, positive predictive value; QC, quality control. Citation Format: Erin R. Rudzinski, Marc Ladanyi, Lauren L. Ritterhouse, Felix Sahm, Ricarda Norenberg, Hong Zheng, Chi Chen, Vadim Bernard-Gauthier, Nicoletta Brega, Cornelis M. van Tilburg, Jessica J. Lin, Marcia S. Brose, Ulrik N. Lassen, Ray McDermott, Theodore W. Laetsch, David S. Hong, Alexander Drilon, Sinchita Roy-Chowdhuri. Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT228.

Phase 2 study of tislelizumab monotherapy in previously treated, locally advanced, unresectable or metastatic microsatellite instability-high/mismatch repair-deficient solid tumors: Gynecological cancer subgroup (127)

<b>Objectives:</b> Primary results from this Phase II study (NCT03736889) showed that tislelizumab (TIS), an anti-PD-1 antibody, was generally well tolerated and demonstrated a clinically meaningful improvement in the objective response rate (ORR) in patients (pts) with previously treated, locally advanced, unresectable or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors compared with the historical control rate (45.9% vs 10 %, respectively) [1]. Here, we report results from the updated analysis for pts with gynecologic MSI-H/dMMR tumors. <b>Methods:</b> Eligible pts received TIS 200 mg intravenously once every three weeks until disease progression, unacceptable toxicity, or withdrawal. ORR, duration of response (DoR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS) (all assessed by independent committee review per RECIST v1.1), overall survival (OS), and safety were evaluated in pts with gynecologic tumors. <b>Results:</b> At the time of the latest data cut-off (July 8, 2021), 80 pts were enrolled, and 75 pts were included in the efficacy analysis set, of whom 15 had gynecologic tumors (median age: 55 years; range: 41-67 years): 13 had endometrial cancer, one had cervical cancer, and one had ovarian cancer. ORR in pts with gynecologic tumors was 53.3% (95% CI: 26.6-78.7). Three pts had complete responses (all had endometrial cancer), five pts had a partial response (three pts with endometrial cancer, one pt with cervical cancer, and one pt with ovarian cancer), one pt had stable disease (endometrial cancer), and four pts had progressive disease (endometrial cancer). At a median follow-up duration of 17.5 months, me dian OS was not reached; median PFS and median DoR were also not reached. Median TTR was 9.1 weeks, and DCR was 60.0% (95% CI: 32.3-83.7). TIS was generally well tolerated in pts with gynecologic tumors (Table 1); the most common treatment-emergent adverse events were increased alanine aminotransferase (86.7%), increased aspartate aminotransferase (46.7%), decreased white blood cell count (46.7%), and anemia (46.7%). <b>Conclusions:</b> This subgroup analysis demonstrates that TIS was clinically active in pts with gynecologic MSI-H/dMMR tumors and was generally well tolerated with no new safety signals. These data support TIS as a potential new treatment option for pts with gynecologic MSI-H/dMMR tumors and further investigation with a larger population is warranted to further confirm the clinical benefit of TIS in these pts. [1] J Li, et al. J Clin Oncol 2021;39(15_suppl):2569 <b>Acknowledgments:</b> This study is sponsored by BeiGene Ltd. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Claire White, Ph.D., of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene Ltd.

Taxanes plus cetuximab with or without platinum chemotherapy after progression on immune checkpoint inhibitors in patients with squamous cell carcinoma of the head and neck.

6036 Background: Salvage chemotherapy after progression on immune checkpoint inhibitors (ICIs) was associated with an objective response rate (ORR) of 30% in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We aimed to investigate the efficacy of taxanes + cetuximab (TC) +/- platinum chemotherapy in pts with R/M SCCHN who failed ICIs in palliative setting. Methods: A retrospective study was conducted at 7 French university hospitals. Eligibility criteria were pts treated with ICI for R/M SCCHN, who progressed after treatment with ICI and received TC +/- platinum salvage chemotherapy between August 2017 and December 2021. Clinical and radiological data and outcome were collected from review of medical records. Results: Ninety-nine pts met eligibility criteria: 63 pts received TC and 36 pts received triplet regimen (TR). The median age was 61 years (range 24-78) and 79% of pts were male. Forty-two pts (42%) had platinum-refractory disease (PRD) after multimodal treatment, 13 pts received prior taxanes and 24 pts received prior cetuximab. The median PS at salvage chemotherapy was 1 (range 0-3). ICIs were given as first-line treatment in 70% of pts including those with PRD. The ORR of the entire cohort was 62% (61/99) including 5 complete responses (CR) and the disease control rate was 79% (78/99). The median progression-free survival of the entire cohort was 4.4 months and the median overall survival (OS) was 7.5 months. The 5 pts who had CR as best response are still in remission after a median follow-up of 24 months (range 8-58). The ORR of TC subgroup was 57% (36/63) and the ORR of TR subgroup was 69% (25/36). Furthermore, the ORR in the PRD subgroup of pts was 54% (39/72), and the ORR in the subgroup of pts who were not chemo naïve was 54% (39/72). The ORR in pts who previously received cetuximab was 50% (12/24) vs 75% (49/75) in those who did not. The ORR in pts who previsouly received taxanes was 38% (5/13) vs 65% in those who did not. Finally, the ORR in PRD pts and treated with TR was 50% (7/14) and the ORR in pts who previously received platinum-based treatment or PRD and treated with TR was 55% (11/20). Conclusions: TC +/- platinum chemotherapy was highly effective in pts R/M SCCHN who progressed on ICIs with an ORR of 62% and DCR of 79%. Further investigations are warranted.

Tumor agnostic efficacy and safety of erdafitinib in patients (pts) with advanced solid tumors with prespecified fibroblast growth factor receptor alterations (FGFRalt) in RAGNAR: Interim analysis (IA) results.

3007 Background: Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat locally advanced or metastatic urothelial carcinoma (UC) in adults with susceptible FGFR3/2alt who have progressed during or after ≥ 1 line of platinum containing chemotherapy . FGFRalt are observed across a wide range of malignancies and may function as oncogenic drivers independent of the underlying tumor type. RAGNAR (NCT04083976) is an ongoing phase 2 open label, single arm tumor agnostic trial investigating the efficacy and safety of erda in pretreated adult and pediatric pts with advanced solid tumors and FGFRalt. Here, we report results from a planned IA of RAGNAR. Methods: Pts aged ≥ 6 y with advanced or metastatic solid tumors of any histology (except UC) with predefined FGFR1-4alt (mutations/fusions based on local/central test) and documented disease progression on ≥ 1 prior line of systemic therapy (tx) and no alternative standard tx received oral erda until disease progression or intolerable toxicity. The primary end point is objective response rate (ORR) by independent review committee (IRC). Secondary end points include investigator assessed ORR, duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), PFS, OS, and treatment emergent adverse events (TEAEs). Results: As of the IA data cutoff, 178 pts were treated (median age 56.5 y [range 12-79], median 2 prior systemic tx). Only 9.0% of pts responded to last line of tx prior to study entry. ORR by IRC was 29.2% (95% CI, 22.7-36.5). Investigator assessed ORR was 26.4% (95% CI, 20.1-33.5). Responses were observed in 14 distinct tumor types, including gliomas, thoracic, gastrointestinal, gynecological, and rare tumors (Table). ORR in pts with FGFR mutations vs fusions was comparable (26.8% vs 27.0%, respectively). Median DOR, PFS, and OS were 7.1 mo (95% CI, 5.5-9.3), 5.2 mo (95% CI, 4.0-5.6), and 10.9 mo (95% CI, 7.9-14.3), respectively; DCR was 75.3% and CBR was 48.9%. All pts experienced TEAEs, including 69.1% with grade ≥ 3. Treatment-related serious TEAEs occurred in 7.3% of pts. Conclusions: RAGNAR data show, for the first time, evidence of efficacy for erda in heavily pretreated pts with a variety of hard to treat advanced FGFR+ malignancies, including glioblastoma, pancreatic, and salivary gland cancers. Safety was consistent with the known erda safety profile. Clinical trial information: NCT04083976. [Table: see text]

Update on phase 1 study of tazemetostat, an enhancer of zeste homolog 2 inhibitor, in pediatric patients with relapsed or refractory integrase interactor 1–negative tumors.

10040 Background: A defining feature of malignant rhabdoid tumors (MRTs), epithelioid sarcoma (ES), and poorly differentiated chordomas (PDC) is loss of integrase interactor 1 (INI1) expression, which induces dependence on enhancer of zeste homolog 2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the US Food and Drug Administration for patients (pts) aged ≥16 y with metastatic or locally advanced ES ineligible for complete resection. Pediatric dose escalation and interim efficacy and safety data for the dose expansion were previously reported. Updated efficacy, safety, subgroup analyses, and translational results are reported here. Methods: NCT02601937 is a phase 1 multicenter study evaluating TAZ monotherapy ≤2400 mg/m2 daily in pediatric pts with relapsed or refractory INI1− tumors (MRT, atypical teratoid rhabdoid tumor [ATRT], select tumors with rhabdoid features, other INI1− tumors, and SS18-SSX synovial sarcoma). Primary endpoint for dose expansion was objective response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), progression-free survival (PFS), and overall survival. Selected exploratory flow data using 250,000 cells from peripheral blood were available for up to 25 pts. Results: Phase 1 enrolled 109 pts (escalation, n=46; expansion, n=63; Table) with mean ages of 5.4 y in the dose escalation and 7.4 y in the dose expansion. ORRs were 7% (3/46) in the dose escalation and 14% (9/63) in the dose expansion. Per tumor category in the dose expansion, ORRs were 24% (5/21) ATRT, 33% (2/6) PDC, 22% (2/9) ES, and 0% in non–CNS RTs (n=21) and other tumors (n=6). ORR for pts with prior radiotherapy was 14% (11/80) vs 3% (1/29) with prior radiotherapy ( P&gt;0.05). In the dose expansion, median PFS was 8 wk (95% CI: 8–13), OS was 21 wk (95% CI: 13–38), and DOR was 35 wk (95% CI: 24–121). Grade 3–4 treatment-related treatment-emergent adverse event rates were 15% (7/46) in the dose escalation and 22% (14/63) in dose expansion. Differences between responders (R) and nonresponders (NR) at C1D1 for neutrophil counts were significant ( P&lt;0.05). All R (6/6) had &lt;125,000 total neutrophils at C1D1 vs 42% (8/19) of NR; 50% (3/6) of R had &gt;50,000 total CD3 T cells vs 0% (0/19) of NR. Conclusions: TAZ showed promising antitumor activity in ATRT, ES, and PDC. Potential synergism between prior radiotherapy and TAZ requires further investigation. TAZ was generally well tolerated. The biological/clinical significance of differences in peripheral blood cell counts between R and NR at C1D1 needs further investigation. Clinical trial information: NCT02601937. [Table: see text]

Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC).

9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to &lt;50% 3+) and for the SQ cohort as ≥75% 1+ by IHC. The planned enrollment was up to approximately 150 pts in Stage 1 and 160 pts in Stage 2. Teliso-V was dosed at 1.9 mg/kg IV Q2W. The primary endpoint is objective response rate (ORR) by independent central review. Secondary endpoints include duration of response (DOR). Results: As of data cutoff (27 May 2021), 136 pts were treated with Teliso-V; 122 were evaluable for ORR. ORR was 36.5% in the NSQ EGFR WT cohort (52.2% in c-Met high group and 24.1% in c-Met intermediate group), but was modest in the NSQ EGFR mutant and SQ cohorts. Efficacy data in groups/cohorts are in the Table. The most common any-grade adverse events (AEs) were peripheral sensory neuropathy (25.0%), nausea (22.1%), and hypoalbuminemia (20.6%). Grade 5 AEs considered possibly related to Teliso-V occurred in 2 pts (sudden death and pneumonitis in 1 pt each in the SQ cohort). Conclusions: Teliso-V demonstrated a promising ORR in pts with previously treated c-Met OE NSQ EGFR WT NSCLC; this cohort is currently expanding in Stage 2. ORR was modest in the cohorts of pts with c-Met OE NSQ EGFR mutant NSCLC and with c-Met OE SQ NSCLC; both cohorts have now met the protocol-specified stopping criteria and are no longer enrolling. The safety profile observed was consistent with IA3. Clinical trial information: NCT03539536. [Table: see text]

Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

7520 Background: Zilovertamab (Zilo) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anti-cancer agents, including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), multiple doses were examined. Zilo 600 mg IV starting q2wks x3 then q4wks + Ibr qD was selected as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Zilo+Ibr vs. Ibr alone). Results: As of 18Jan2022 data cutoff, 26 evaluable RR MCL pts, including pts who received prior Ibr (5) or auto-SCT (7), and 34 evaluable CLL pts (12 TN and 22 RR) were enrolled into Parts 1&amp;2. In Part 3, 22 evaluable pts were randomized (2:1) to receive either Zilo+Ibr (15) or Ibr (7). Safety: Treatment-emergent adverse events (TEAEs) (≥30%, N = 84), regardless of relationship, included fatigue (41.7%), contusion (39.3%), and diarrhea (38.1%). Most common (≥5%) Grade ≥3 TEAEs included hypertension (10.7%), pneumonia (7.1%), atrial fibrillation, fatigue, and neutropenia (all 6.0%). Grade ≥3 neutrophil decrease observed in 9.4% or 17.6%, platelet decrease in 12.5% or 2.9%, or hemoglobin decrease in 9.4% or 0% of pts with MCL or CLL, respectively in Parts 1&amp;2. Investigators scored TEAEs as due to Ibr in 78.1% or 85.3%, or to Zilo in 15.6% or 23.5% of pts with MCL or CLL, respectively. Efficacy (MCL): Objective response rate (ORR) was 80.8% (34.6% CR, 46.2% PR). ORR for pts with prior Ibr was 80% (2CR, 2PR) and median duration of response (mDOR) was 13.7 months (M) (95%CI: 11.93, NE). ORR was 100% in pts who had prior SCT+/- CAR-T (5CR, 2PR), and mDOR was 34.1 M (95% CI 13.84, NE). Overall median PFS (mPFS) was 35.9 M (95% CI: 17.3, NE) at median follow-up of 15.0 M. For MCL pts with TP 53 aberrancy (6), Ki67 &gt; 30% (13), ≥ 3 prior lines of therapies (4), blastoid histology (3), bulky disease ≥5 cm (4), intermediate MIPIb (6), or high MIPIb (11), the mPFS (in M) was 17.3 (95% CI: 2.85, NE), Not Reached (NR) (95% CI: 2.85, NE), 35.9 (95% CI: 16.52, NE), NR (min 9.18, max 27.87), 26.6 (95% CI: 0.03, NE), 35.9 (min 8.30, max 35.9) or 16.5 (95% CI: 2.72, NE). Efficacy (CLL): In Parts 1&amp;2 ORR was 91.2% (8.8% CR, 82.3% PR/PR-L), and 8.8% had stable disease (SD). At median follow-up of 31.4 M, mDOR was 33.5 M and mPFS was NR (95% CI: 36.3, NE); the mPFS (in M) for pts with 1, 2, or ≥ 3 prior therapies was NR (min 19.3, max 41.3), NR (min 31.3, max 36.8) or 36.3 (95% CI: 15.7, NE). At median follow-up of 21.1 M in Part 3, mPFS was NR for TN or RR in both Zilo+Ibr and Ibr arms. Conclusions: Zilo+Ibr is well-tolerated. Striking responses were observed in MCL pts, with mPFS of 35.9 M (95% CI: 17.3, NE) and CR of 34.6%, which compares favorably to mPFS of 12.8 M (95% CI 8.5, 16.6) and CR of 20% reported for single agent Ibr (Rule 2017). For CLL, ORR and PFS compare very favorably to Ibr monotherapy data (Byrd 2019). Clinical trial information: NCT03088878.

Plasma RAS dynamics and anti-EGFR rechallenge efficacy in patients with RAS/BRAF wild-type metastatic colorectal cancer: REMARRY and PURSUIT trials.

3518 Background: Rechallenge with anti-EGFR monoclonal antibody (EGFR mAb) showed certain activities in patients (pts) with RAS/ BRAF V600E wild-type (wt) metastatic colorectal cancer (mCRC), particularly in pts with negative plasma RAS (p RAS) mutation by circulating-tumor DNA (ctDNA) assay at ‘just before’ the rechallenge therapy. However, the efficacy is unknown in pts with RAS/ BRAF wt mCRC whose p RAS was converted to positive once during or after EGFR mAb. Therefore, we conducted REMARRY, a prospective longitudinal study to investigate the p RAS dynamics, and PURSUIT trials, a phase II trial to investigate the efficacy of EGFR mAb rechallenge in pts with p RAS wt just before rechallenge therapy. Methods: The eligibility criteria of REMARRY trial included RAS/ BRAF V600E wt mCRC; ECOG PS 0-1; CR or PR during EGFR mAb; and a refractory ≤ 2 months from the last administration of EGFR mAb. p RAS status by the BEAMing method was prospectively monitored at timepoints of progression on EGFR mAb and each subsequent therapy. The eligibility criteria of PURSUIT trial included enrollment in the REMARRY trial with confirmed p RAS wt prior to enrollment in PURSUIT trial; being refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; and ≥ 4 months of EGFR mAb-free interval. Study treatment was rechallenge with panitumumab + irinotecan (6 mg/kg + 150 mg/m2 q2wks). Primary endpoint was a confirmed objective response rate (ORR) according to RECIST v1.1. The required number of pts was 45, with a null ORR of 10%, an expected ORR of 25%, power of 85%, and one-sided α of 0.05. Results: Between May 2019 and May 2021, 183 pts with 343 timepoints (median, 2) were enrolled in REMARRY trial from 27 institutions, and 50 pts were enrolled in PURSUIT trial; median age, 68 years; left-sided primary, 44 pts; prior EGFR mAb, 1st/2nd/≥3rd lines was 28/6/16 pts; and p RAS status at progression on prior EGFR mAb, wt/mutant (mt)/unknown in 31/7/12 pts. Confirmed ORR and disease control rate were 14% (90% CI, 7.8%–23.9%) and 80% (95% CI, 67.0%–88.8%), respectively. In addition, 4 pts showed an unconfirmed PR. With a median follow-up time of 8.7 months, median progression-free survival was 3.6 months (95% CI, 3.0 – 4.7 months). The subgroup analysis showed a significantly higher confirmed ORR in pts with a longer EGFR mAb-free interval than a shorter one (&gt; vs. &lt; 365 days, 44.4% vs. 7.3%, p = 0.0037). Without any unexpected safety signals, 58.5% of pts had ≥ grade 3 adverse events. Of 31 patients with wt p RAS at progression on prior EGFR mAb, 5 had a confirmed response (ORR, 16%), whereas no response was observed in patients with 7 p RAS mt (ORR, 0%) (p = 0.25). Conclusions: The primary endpoint of confirmed ORR was not met; however, pts with p RAS wt at progression on prior EGFR mAb may benefit from rechallenge with, implying a lack of or worse response if p RAS becomes positive even once during or after EGFR mAb. Clinical trial information: REMARRY: UMIN000036424 PURSUIT: jRCTs031190096.

A phase Ib/II study of the combination of lenvatinib (L) and eribulin (E) in advanced liposarcoma (LPS) and leiomyosarcoma (LMS) (LEADER): Efficacy updates.

11506 Background: There are limited treatment options for advanced LPS and LMS, the two most common histologies in soft tissue sarcoma. Patients (pts) treated with E had an improved overall survival (OS) compared to dacarbazine but with an unsatisfactory 4% objective response rate (ORR). Early studies of L, a multi-targeted anti-angiogenic inhibitor, had suggested efficacy in sarcoma pts. We hypothesized that the L+E could potentiate the treatment efficacy in advanced LMS and LPS. Methods: LEADER was a single-arm phase Ib/II study for advanced adult LMS and LPS pts who had received no more than 2 lines of systemic chemotherapy (NCT03526679). The phase Ib part (starting dose: L 18mg/day, E 1.1mg/m2) had been reported and the recommended phase 2 dose (RP2D) was determined at L 14mg/day and E 1.1mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was ORR by RECIST 1.1, secondary endpoints included progression-free survival (PFS), 6-month PFS rate, and OS. Pts in phase Ib/II part were analyzed together for efficacy. Results: As of Nov 15 2021, 30 pts (F/M 20/10) had been treated with at least one cycle of L + E; 21 were LMS (9 uterine, 12 non-uterine) and 9 were LPS (5 dedifferentiated, 2 myxoid round cell, 2 pleomorphic). The median age was 59 (range 29-73); the median lines of treatment(s) received before enrollment was 1 (range 0-3). The ORR by RECIST 1.1 was 20 % (6/30) (95% CI 10-53%); the ORR for pts received L 18mg/day (2/6) and L 14mg/day (4/26) were not significantly different (p = 0.23). After a median FU time of 20.1 months, the median PFS and 6-month PFS rate was 8.56 mos (95% CI 4.40-not reached (NR)) and 59%, respectively. The median PFS for LMS (8.56 mos, 95% CI 4.17- NR) and LPS (11.36 mos, 95% CI 4.4-NR) were not significantly different (p = 0.73). The median OS and 12-month OS rate was 26.2 mos (95% CI 21.4-NR) and 89%, respectively, but LPS pts had significantly worse OS (HR 3.5, p = 0.04). Twenty pts experienced at-least one grade (gr) 3 or 4 adverse event (AE); gr 3 or 4 AEs occurred in &gt; 1 pt included hypertension (n = 4); hand-foot-syndrome (HFS) (n = 5), proteinuria (n = 3), febrile neutropenia (n = 3), neutropenia (n = 11, without G-CSF support). Compared to L 18mg/day, pts treated with RP2D were associated with lower gr3/4 HFS and hypertension. There were no sustained grade 3/4 AEs for pts receiving long-term L+E. Conclusions: L + E had shown promising efficacy in advanced LMS and LPS. L at 14mg (vs 18mg) had a better AE profile without compromising activity. Future randomized study to confirm the efficacy of the combination is warranted. Clinical trial information: NCT03526679.

Updated analysis from a phase 2 study of tislelizumab (TIS) monotherapy in patients (pts) with previously treated, locally advanced, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) solid tumors.

e14556 Background: TIS is an anti-programmed cell death protein-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. Primary results from this single-arm, multicenter, open-label, Phase 2 study evaluating TIS in pts with MSI-H/dMMR solid tumors, showed a clinically meaningful improvement in the objective response rate (ORR) for this patient population. Here we report results from the updated analysis (NCT03736889). Methods: Eligible adult pts with previously treated, locally advanced, unresectable/metastatic histologically confirmed MSI-H/dMMR solid tumors with ≥ 1 measurable lesion (RECIST v1.1) and an Eastern Cooperative Oncology Group performance status of ≤ 1 were enrolled. Pts received TIS 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. The efficacy analysis set were all pts who received any dose of TIS with measurable disease per independent review committee (IRC) at baseline. The primary endpoint was IRC-assessed ORR (RECIST v1.1). Secondary endpoints included duration of response (DoR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS) (all IRC-assessed [RECIST v1.1]), overall survival (OS), and safety. Programmed death ligand 1 (PD-L1) immunohistochemistry assay (Ventana SP263) was applied retrospectively. Results: Between Sep 2018–Jul 2021, 80 pts were enrolled (median age 53 years; range 19–81 years) and 75 were included in the efficacy analysis set. In this updated efficacy analysis set, at a median follow-up of 15.2 months, ORRIRC was 46.7% (n = 35; 95% CI 35.1, 58.6) in all tumor types (1-sided p &lt; 0.0001), including 5 complete responses (CR) and 30 partial responses (PR). ORRIRC was 39.1% (n = 18; 95% CI 25.1, 54.6) in colorectal cancer (CRC) pts (N = 46), 55.6% (n = 5; 95% CI 21.2, 86.3) in G/GEJC pts (N = 9), and 60.0% (n = 12; 95% CI 36.1, 80.9) in other pts (N = 20). Of the pts who responded (n = 35), one patient had disease progression. Median DoR was not reached, median TTRIRC was 11.9 weeks (range 8.4–98.9) and DCR was 72.0% (95% CI 60.4, 81.8). Median PFSIRC was not reached (95% CI 7.5, not estimable [NE]). Median OS (safety analysis set) was not reached (95% CI 28.7, NE). No clear association was observed between PD-L1 expression and clinical efficacy. Treatment-emergent adverse events (TEAEs) ≥ Grade 3 occurred in 48.8% (n = 39) of pts. The most common ≥ Grade 3 TEAE was anemia, 10.0% (n = 8). Immune-mediated TEAEs ≥ Grade 3 were 8.8% (n = 7). Conclusions: With a longer follow up time, TIS demonstrated clinically meaningful improvement in ORR in pts with MSI-H or dMMR solid tumors. TIS was generally well tolerated, with no new safety signals. These data support TIS as a new treatment option for this patient population. Clinical trial information: NCT03736889.

Updated analysis from a phase 2 study of tislelizumab (TIS) monotherapy in patients (pts) with previously treated, locally advanced, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) solid tumors.

1 Background: TIS is an anti-programmed cell death protein-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. Primary results from this single-arm, multicenter, open-label, Phase 2 study evaluating TIS in pts with MSI-H/dMMR solid tumors, showed a clinically meaningful improvement in the objective response rate (ORR) for this patient population. Here we report results from the updated analysis (NCT03736889). Methods: Eligible adult pts with previously treated, locally advanced, unresectable/metastatic histologically confirmed MSI-H/dMMR solid tumors with ≥1 measurable lesion (RECIST v1.1) and an Eastern Cooperative Oncology Group performance status of ≤1 were enrolled. Pts received TIS 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. The efficacy analysis set were all pts who received any dose of TIS with measurable disease per independent review committee (IRC) at baseline. The primary endpoint was IRC-assessed ORR (RECIST v1.1). Secondary endpoints included duration of response (DoR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS) (all IRC-assessed [RECIST v1.1]), overall survival (OS), and safety. Programmed death ligand-1 (PD-L1) immunohistochemistry assay (Ventana SP263) was applied retrospectively. Results: Between Sep 2018–Jul 2021, 80 pts were enrolled (median age 53 years; range 19–81 years) and 75 were included in the efficacy analysis set. In this updated efficacy analysis set, at a median follow-up of 15.2 months, ORRIRC was 46.7% (n = 35; 95% CI 35.1, 58.6) in all tumor types (1-sided p &lt; 0.0001), including 5 complete responses (CR) and 30 partial responses (PR). ORRIRC was 39.1% (n = 18; 95% CI 25.1, 54.6) in colorectal cancer (CRC) pts (N = 46), 55.6% (n = 5; 95% CI 21.2, 86.3) in G/GEJC pts (N = 9), and 60.0% (n = 12; 95% CI 36.1, 80.9) in other pts (N = 20). Of the pts who responded (n = 35), one patient had disease progression. Median DoR was not reached, median TTRIRC was 11.9 weeks (range 8.4–98.9) and DCR was 72.0% (95% CI 60.4, 81.8). Median PFSIRC was not reached (95% CI 7.5, not estimable [NE]). Median OS (safety analysis set) was not reached (95% CI 28.7, NE). No clear association was observed between PD-L1 expression and clinical efficacy. Treatment-emergent adverse events (TEAEs) ≥Grade 3 occurred in 48.8% (n = 39) of pts. The most common ≥Grade 3 TEAE was anemia, 10.0% (n = 8). Immune-mediated TEAEs ≥Grade 3 were 8.8% (n = 7). Conclusions: With a longer follow up time, TIS demonstrated clinically meaningful improvement in ORR in pts with MSI-H or dMMR solid tumors. TIS was generally well tolerated, with no new safety signals. These data support TIS as a new treatment option for this patient population. Clinical trial information: NCT03736889.

Clinical outcomes in patients (pts) with a history of central nervous system (CNS) metastases receiving talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 EMBRACA trial.

1090 Background: In the EMBRACA trial (NCT01945775) of pts with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (ABC), the poly(ADP-ribose) polymerase (PARP) inhibitor TALA significantly improved progression-free survival (PFS) vs PCT (8.6 vs 5.6 mo; HR [95% CI] 0.54 [0.41-0.71]; P &lt; 0.0001). Patient-reported outcomes favored TALA, and most common adverse events included anemia, fatigue, and nausea. Previous subgroup analyses found that pts with a history of CNS metastases had improved PFS for TALA vs PCT (HR [95% CI] 0.32 [0.15-0.68]; P = 0.0016) and improved objective response rate (ORR) 63.2% vs 15.8%, respectively (odds ratio [95% CI] 8.95 [1.86-52.26]; P = 0.0013). This retrospective subgroup analysis further explored the clinical characteristics and outcomes in pts with a history of CNS metastases in EMBRACA. Methods: Pts were randomized 2:1 to TALA or PCT. Pts with adequately treated and stable CNS metastases not requiring corticosteroids were included. This analysis assessed intracranial ORR and best overall response (BOR) based on investigator assessment per RECIST 1.1 in pts with intracranial disease at baseline (data cutoff 15-Sep-17), and overall survival (OS; data cutoff 30-Sep-19). Results: In the intent-to-treat (ITT) population, 63 pts (43/287 [15.0%] TALA and 20/144 [13.9%] PCT) had a history of CNS metastases, of which 33 (11.5%) pts (TALA) and 15 (10.4%) pts (PCT) had intracranial disease at baseline. Additional baseline characteristics are shown in the table. Intracranial ORR in pts with intracranial disease at baseline and unconfirmed complete or partial response was 18.2% (TALA) vs 20.0% (PCT) (odds ratio [95% CI] 0.78 [0.13-5.80]; P = 0.765). In pts with intracranial disease at baseline, an intracranial BOR of stable disease was 69.7% for TALA vs 33.3% for PCT. Median OS in pts with a history of CNS metastases was 12.9 mo (95% CI 9.4-15.6) for TALA and 13.4 mo (95% CI 8.8-17.6) for PCT (HR [95% CI] 0.67 [0.37-1.2]; P = 0.1936 [stratified log-rank test]). In the safety population ([n = 43, TALA]; [n = 19, PCT]), median treatment duration (range) with TALA was 5.0 (0.1-36.0) mo compared with 2.1 (0.4-6.9) mo for PCT. Conclusions: In this subgroup analysis, baseline characteristics between pts with a history of CNS metastases treated with TALA or PCT were comparable. More pts with intracranial disease at baseline treated with TALA vs PCT experienced stable disease. Intracranial ORR in pts with intracranial disease was 18.2% for TALA vs 20.0% for PCT. Treatment options for pts with a history of CNS metastases are limited and further investigation in larger data sets is warranted. Clinical trial information: NCT01945775 .[Table: see text]

Outcomes with KTE-X19 in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) in ZUMA-2 who had progression of disease within 24 months of diagnosis (POD24).

7547 Background: KTE-X19 is an autologous anti-CD19 CAR T-cell therapy approved in the US and EU for the treatment of R/R MCL. In the ZUMA-2 study of KTE-X19 in R/R MCL, the objective response rate (ORR) at a median 17.5-mo follow-up was 92% (67% complete responses [CR]; Wang et al. ASH 2020 #1120). Here, we report results in pts with or w/o POD24, an indicator of poor outcomes (Visco et al. Br J Haematol 2019). Methods: Eligible pts with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19. Efficacy results are reported for the 60 treated pts with ≥1 y of follow-up (median 17.5 mo); safety results are presented for all 68 treated pts. Results: High-risk disease characteristics were common in pts with (n=33) and w/o POD24 (n=35), although pts with POD24 had higher tumor burden and lactate dehydrogenase (LDH) levels, and more had blastoid type MCL (Table). ORR in pts with (n=28) and w/o POD24 (n=32) was 93% and 91%, with CR rates of 61% and 72%. In pts with and w/o POD24, median progression-free survival (PFS) was 11.3 mo (range, 0.9–30.3) and 29.3 mo (range, 0–35.9). Medians for duration of response (DOR) and overall survival (OS) were not reached in either group. Most common Grade ≥3 adverse events (AEs) in pts with vs w/o POD24 were neutropenia (91% vs 80%), thrombocytopenia (61% vs 46%), and anemia (55% vs 51%); Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 9% vs 20% and 27% vs 34%, respectively. There were no cases of Grade 5 CRS, KTE-X19–related secondary cancers, or replication-competent retrovirus in either group. In pts with vs w/o POD24, median peak CAR T-cell levels and median area under the curve were 53.4 cells/µL (range, 0.2–2566) and 583.4 cells/µL (range, 1.8–27,743.6) vs 112.4 cells/µL (range, 0.2–2589) and 1588.3 cells/µL (range, 3.8–27,238.7); by 12 mo, B cells were detectable in 8/11 (73%) vs 7/15 pts (47%) in ongoing response. Conclusions: KTE-X19 provided a high CR rate across all pts, with median DOR and OS not reached. Pts with POD24 had more aggressive high-risk disease characteristics (tumor burden, LDH levels, and blastoid MCL) and generally lower CAR T-cell expansion and PFS vs pts w/o POD24. Earlier intervention with CD19-directed CAR T-cell therapy may benefit pts with MCL with known high-risk factors. Clinical trial information: NCT02601313. [Table: see text]

Efficacy of selpercatinib after prior systemic therapy in patients with RET mutant medullary thyroid cancer.

6074 Background: Selpercatinib is a first-in-class, CNS active, highly selective, and potent RET kinase inhibitor which has demonstrated durable antitumor activity in patients (pts) with RET altered thyroid cancer and is approved in multiple countries for the treatment of RET fusion+ lung or thyroid cancers. As response rates to cancer therapy usually decline on subsequent lines of therapy, the efficacy of selpercatinib was examined in the context of the last prior therapy received before trial enrollment. Methods: Pts with RET mutant medullary thyroid cancer (MTC) previously treated with multikinase inhibitors (cabozantinib and/or vandetanib) were enrolled in the global LIBRETTO-001 trial (NCT03157128). This post-hoc exploratory intrapatient analysis, based on March 30, 2020 data cutoff date, was performed to compare the retrospective physician-reported objective response rate (ORR) from the last systemic therapy prior to enrollment, as reported in pts case reports, to ORR by independent review committee per RECIST 1.1 with selpercatinib treatment, with each patient serving as his/her own control. Results: Efficacy-evaluable pts, 64% male, 90% white with a median age of 58 years, received prior therapy for MTC (n = 143). Pts had a median of 2 (range 1-8) prior systemic regimens. The ORR on selpercatinib (69%) was markedly higher than for the last prior therapy (10%) received before enrollment. ORR improvements with selpercatinib were observed regardless of prior therapy: cabozantinib (66% vs 14%) or vandetanib (71% vs 12%). Fewer pts had progressive disease as their best overall response with selpercatinib (2/143; 1.4%) compared to last prior therapy (33/143; 23.1%). Notably selpercatinib achieved 62% ORR in pts that did not respond to their previous line of therapy prior to enrolment. This shift from non-responder to responder on selpercatinib therapy was consistent regardless of prior cabozantinib or vandetanib treatment, where pts achieved 57% and 61% ORR respectively when subsequently treated with selpercatinib. In contrast, only 3% of patients did not respond to selpercatinib after a previous response to the immediate prior therapy. Similarly, 5% and 2% of patients were non-responders on selpercatinib after a prior response with cabozantinib and vandetanib therapy respectively. Conclusions: Prior to selpercatinib, response with previous multikinase therapy was rare. By contrast, selpercatinib demonstrated robust efficacy regardless of response to or specific prior therapy in pts with RET mutant MTC. Clinical trial information: NCT03157128.

Abstract PD3-08: Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status

Abstract Background Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (&amp;gt; 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-08.