Post-baseline Tumor Assessment Research Articles

SYST-06 INTRACRANIAL ACTIVITY OF TEPOTINIB IN PATIENTS WITH MET EXON 14 (METEX14) SKIPPING NSCLC ENROLLED IN VISION

BACKGROUNDBrain metastases (BMs) occur in 20–40% of patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, demonstrated an objective response rate (ORR) of 49.1% and median duration of response (mDOR) of 13.8 months, in METex14 skipping NSCLC patients in the Phase II VISION study (Cohorts A+C; N=275). Here, we report the intracranial activity of tepotinib in VISION. METHODSPatients with METex14 skipping NSCLC received oral tepotinib 500 mg QD (450 mg active moiety). Patients with BM (asymptomatic and symptomatic/stable) were eligible. Primary endpoint was systemic ORR (RECIST v1.1); a subgroup analysis in patients with BM was predefined (data cut-off: February 1, 2021). An ad-hoc retrospective analysis of brain lesions was conducted by an IRC using RANO-BM criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For those with only non-target lesions (NTLs) per RANO-BM (enhancing and non-enhancing NTLs), disease control was defined as non-complete response (CR)/nonprogressive disease (PD). Data cut-off: July 1, 2020. RESULTSFifty-one patients had baseline BM (Cohorts A+C). Systemic efficacy was consistent with the overall population (ORR 52.9% [95% CI: 38.5, 67.1], mDOR 9.0 months [95% CI: 5.6, not estimable]). Fifteen patients were evaluable by RANO-BM (Cohort A); 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and PD (n=3). Seven patients had target CNS lesions per RANO-BM (all with prior radiotherapy); intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL. 13/15 patients achieved intracranial disease control. CONCLUSIONSTepotinib demonstrated robust systemic activity in patients with METex14 skipping NSCLC with BM, complemented by intracranial activity in an ad-hoc analysis using RANO-BM.

LIO-1: Initial phase 2 experience of lucitanib + nivolumab in patients with metastatic or recurrent cervical cancer (NCT04042116; ENGOT-GYN3/AGO/LIO) (034)

<b>Objectives:</b> Lucitanib is a potent, selective inhibitor of the tyrosine kinases VEGFR1-3, PDGFRα/ß, and FGFR1-3 that is being investigated in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab in four recurrent gynecologic malignancies (cervical, endometrial, ovarian, and ovarian/endometrial clear-cell cancers) in an ongoing phase II study, using a Simon's two-stage design. To maximize lucitanib exposure and potential clinical benefit of the combination, individualized lucitanib dose titration is utilized. We presented initial data from the cervical cancer cohort. <b>Methods:</b> Patients with metastatic or recurrent cervical cancer of squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma histology, who received ≥1 prior platinum-based chemotherapy regimen, with or without bevacizumab, were enrolled. Prior treatment with a PD-1 or programmed cell death ligand-1 (PD-L1) inhibitor was prohibited. All patients-initiated treatment with lucitanib 6 mg orally once daily (QD) + nivolumab 480 mg intravenously every 28 days. Lucitanib dose was escalated from 6 mg to 8 mg and up to 10 mg QD in patients who met safety-based titration criteria. Tumor response was assessed by investigators per RECIST v1.1. Data cut-off was September 1, 2021. <b>Results:</b> Twenty patients have been treated to date (median treatment duration: 85 days, range: 1-343+); 15 (75%) remain on treatment (13 remain on the combination and two on nivolumab monotherapy). Eleven (55%) patients received ≥2 prior anticancer regimens; nine (45%) had prior bevacizumab. To date, 17 (85%) patients have completed ≥1 cycle; two patients have escalated lucitanib to a dose of 8 mg, and three to the maximum dose of 10 mg. The most frequent anygrade treatment-emergent adverse events (TEAEs) have been hypertension (<i>n</i>=13, 65%), decreased appetite (<i>n</i>=11, 55%), asthenia/fatigue (<i>n</i>=10, 50%), and nausea (<i>n</i>=10, 50%). The most frequent grade ≥3 TEAE has been hypertension (<i>n</i>=4, 20%). Three (15%) patients discontinued lucitanib due to a related TEAE (colonic fistula, hypertension, and proteinuria). As of the data cut-off, 17 patients had at least one post-baseline tumor assessment, with four confirmed partial responses (PRs), eight patients with stable disease (7 remain ongoing), and five patients with the best response of progressive disease reported. The durations of PR range from 1.8+ to 9.3+ months. Of the four responding patients, three had received prior bevacizumab. <b>Conclusions:</b> Promising signs of antitumor activity in patients with metastatic or recurrent cervical cancer were noted in this initial analysis. Toxicity has been manageable and is consistent with that previously reported for lucitanib and nivolumab, and other agents of both classes. Having met Simon's two-stage stage I requirements (≥3 confirmed responses), study accrual continues in stage II of the cervical cancer cohort. Additional and more mature data, including biomarker analyses, will be presented at the meeting.

Abstract CT034: Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study)

Abstract Background: METex14 mutations was reported in 3~4% of NSCLC patients and became a new target in the treatment of NSCLC. SCC244 is a highly selective and potent oral MET inhibitor. This is the first report of data from an ongoing single-arm phase II study of SCC244 in NSCLC patients with METex14 mutations (GLORY study). Methods: GLORY study is an open label, international, multi-center, single-arm phase II study to evaluate the efficacy and safety of SCC244 in patients with locally advanced or metastatic NSCLC harboring METex14 mutations which was confirmed by central laboratory. The enrolled patients have either failed one or two prior lines of systemic therapies or been not eligible/refused chemotherapy after being well-informed. SCC244 was taken orally at a dose of 300 mg once daily in 21-day treatment cycles until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks for the first 8 treatment cycles and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC) per RECIST 1.1, secondary endpoints include ORR by investigator assessment (INV), duration of response (DoR), time to response (TTR) and safety etc. Post-hoc analysis was done to explore the intracranial anti-tumor activity. Results: At data cut-off on May 6th, 2021, a total 73 patients screened from 163 patients in 42 sites were treated at 300 mg QD dose and had ≥2 post-baseline tumor assessments or discontinued for any reason. 69 of them were with METex14 mutation confirmed by central laboratory. In the 69 patients, ORR by BIRC was 60.9% (95% CI: 48.4%, 72.4%) overall, 66.7% (95% CI: 50.5, 80.4) and 51.9% (95% CI: 31.9, 71.3) in treatment naïve and previously treated patients respectively. Median DoR was 8.2 months (95% CI: 4.8, NE) and median PFS was 7.6 months (95% CI: 4.2, NE), tumor response from 30 of 42 responders was still ongoing. The response occurred fast with a median TTR of 1.4 months (range: 1.2, 4.2). Partial response was observed in 8 of 10 patients with brain metastasis. 5 patients who had brain metastasis selected as targeted lesion had intracranial response by INV with a median intracranial tumor shrinkage of 57% (range: 34%, 71%). The most common (≥20%) treatment-related adverse events (TRAEs) of any grade were peripheral edema, headache, nausea, loss of appetite, hypoalbuminemia, ALT increase and vomiting. The incidence of ≥ grade 3 TRAEs was 43.8%. TRAEs leading to treatment discontinuation occurred in 6.8% patients, among which peripheral edema was the most common (4.1%). Conclusions: The data shows high and robust efficacy of SCC244 in NSCLC patients with METex14 mutations across treatment lines and encouraging intracranial anti-tumor activity. The safety profile was favorable with manageable toxicity. The data supports SCC244 as a valuable targeted treatment option for METex14 NSCLC patients. Citation Format: Shun Lu, Yongfeng Yu, Jianya Zhou, Koichi Goto, Xingya Li, Jun Sakakibara-Konishi, Kazumi Nishino, Tanaka Kentaro, Lin Wu, Xuhong Min, Wei Zhang, Dingzhi Huang, Yongqian Shu, Chengzhi Zhou, Min Li, Xiaorong Dong, Chong Bai, Lu Li, Jiuwei Cui, Li Zhang, Lejie Cao, Xiaoling Li, AiMin Zang, Haruki Kobayashi, Yiping Zhang, Yan Yu, Xiuwen Wang, Terufumi Kato, Shoichiro Yamamoto, Yuki Shinno, Xiaoyan Lin, Yanqiu Zhao, Yanping Hu, Qitao Yu, Ziping Wang, Masahiro Kodani, Jian Fang, Jialei Wang, Meiqi Shi, Diansheng Zhong, Wen Dong, Hiroshi Tanaka, Yasuto Yoneshima, Minghui Sun, Jun Zhou, Qiuxia Wu, Meng Li. Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT034.

Abstract CT029: Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC)

Abstract Introduction: ZN-c3 is a selective, orally bioavailable small molecule inhibitor of WEE1, a crucial component of the G2/M cell cycle checkpoint, which prevents cells from entering mitosis to allow repair of DNA damage. ZN-c3 has demonstrated significant in vitro antitumor activity in multiple cell lines and xenograft models. Methods: ZN-c3-001 (NCT04158336) is an open label, multicenter, Phase I dose escalation and expansion study evaluating the safety and clinical activity of ZN-c3 in subjects with advanced or metastatic solid tumors, refractory to standard therapy or for whom no standard therapy is available. Oral, daily ZN-c3 dosing was escalated from 25 mg to 450 mg once daily (QD), with a recommended phase 2 dose of 300 mg QD. Here we report preliminary safety and efficacy results for subjects with USC who received ZN-c3 at doses ≥300 mg QD. Results: As of October 28, 2021, a total of 78 subjects were enrolled across all tumor types. For USC, there were 12 subjects who received ZN-c3 at doses ≥300 mg QD and were evaluated for safety. Median duration of treatment was 12 weeks (range, 2 - 33 weeks). The safety profile for this subgroup is comparable to the overall patient population with 11 of 12 subjects reporting at least one treatment-related adverse event (TRAE). TRAEs grades 1-4 occurring in ≥3 subjects, by decreasing frequency, included nausea, vomiting, fatigue, diarrhea, decreased appetite, dehydration, and anemia. Grade ≥3 TRAEs occurring in ≥2 subjects included anemia and thrombocytopenia. These hematologic events were limited to 2 subjects each. Nine of the 12 subjects had measurable disease and at least 1 post-baseline tumor assessment; 3 subjects (33.3%) had confirmed partial response and 5 (55.6%) had stable disease as their best overall response. Disease control rate, defined as those with complete response, partial response, and stable disease, was 88.9%. One subject with partial response achieved complete response at subsequent tumor assessment. Conclusions: ZN-c3 appears to be safe and well-tolerated as a single agent at oral doses ≥300 mg QD and demonstrated clinical activity in subjects with recurrent or advanced USC. Safety results in these subjects were consistent with those of the full study population. The ongoing dose expansion study is enrolling USC patients. The preliminary efficacy signal will be confirmed in a dedicated phase 2 study (ZN-c3-004, NCT04814108) in this patient population. Citation Format: Funda Meric-Bernstam, Pavani Chalsani, Hirva Mamdani, Cheng Zheng, Marcus Viana, Ruth Lambersky, Philippe Pultar, Anthony W. Tolcher. Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT029.

Interim results of a phase II multicenter study with the oral histone deacetylase inhibitor abexinostat in patients with relapsed/refractory follicular lymphoma.

7513 Background: Follicular lymphoma (FL) is generally considered incurable with patients (pts) often experiencing multiple relapses requiring varying lines of subsequent treatments. Abexinostat (Abx) is a novel potent oral pan- Histone Deacetylase Inhibitor (HDACi) with a pharmacokinetic profile that allows maintenance of sufficient drug concentrations for anti-tumor activity with twice daily (BID) dosing. In prior phase 1/2 studies, Abx was shown to be well-tolerated with significant clinical activity and durable responses in patients with Relapsed/Refractory (R/R) FL. Methods: This open label, single arm study is being conducted to assess the efficacy and safety of Abx in pts with R/R FL. Adults with histologically confirmed grade 1, 2 or 3a FL who have previously received at least 2 lines of therapies, and ECOG PS of 0-2 are being recruited. Abx is administered orally at 80 mg BID 4 hours apart in “one week on, one week off” schedule (Days 1 to 7 &amp; 15 to 21 of a 28-day cycle). Pts undergo efficacy assessment by enhanced CT/MRI every 8 weeks for the first 24 weeks, and every 12 weeks thereafter, and PET-CT at weeks 12 and 24 and to confirm a complete response, in accordance with the Lugano 2014 criteria. The primary endpoint is overall response rate (ORR) assessed by independent review committe (IRC), defined as the % of pts who achieve complete response (CR) or partial response (PR). Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. In a planned interim futility analysis conducted with the first 37 pts, if &lt;12/37 (32%) responded (CR or PR), the study was to be terminated. Results: Between June 17, 2020 and Jan 28, 2022, 41 pts received Abx. 37 pts underwent at least one post baseline tumor assessment. Median age was 55 (range 34 – 79), 46% of pts were male, 70% had stage IV disease and 24% had &gt;3 FLIPI-2. Pts had a median of 3 prior lines of therapy (range 2-6), and 22% were refractory to the last prior treatment. As of the data cutoff date on Jan 31, 2022, of 37 pts evaluable for efficacy, the ORR was 70% (26/37 pts), 16% CR (6/37) and the disease control rate was 92% (34/37). The median time to response was 10.8 weeks. The study has met the pre-defined stage I criteria and has entered stage II, aiming to enroll up to 81 evaluable pts. Of 41 pts evaluable for safety, the most common treatment emergent adverse events (TEAEs) (≥ 30%) were thrombocytopenia (85%), diarrhea (61%), neutropenia (54%), leukopenia (49%), asthenia (39%), nausea (37%), and anemia (34%). Grade ≥ 3 TEAEs (≥ 5%) included thrombocytopenia (41%), neutropenia (27%), leukopenia (7%), lymphopenia (7%), prolonged QT (7%), and anemia (5%). One pt discontinued treatment due to AEs. Conclusions: Oral Abx demonstrated promising efficacy and was well tolerated in patients with R/R FL. Clinical trial information: NCT03934567.

IBI110 (anti-LAG-3 mAb) as a single agent or in combination with sintilimab (anti-PD-1 mAb) in patients with advanced solid tumors: Updated results from the phase Ia/Ib dose-escalation study.

2650 Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. A phase Ia/Ib dose-escalation study evaluated IBI110 ± sintilimab in patient with advanced solid tumors; initial efficacy and safety data were previously presented (C Zhou et al. ASCO 2021; NCT04085185). Here, we reported the updated results. Methods: Eligible patients were ECOG PS 0-1 and had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Patients received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5/8/10 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from monotherapy to combination therapy was allowed at progression. The primary objectives were safety, tolerability, and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 28 patients (median age of 60.5 years [range 35-72], ECOG PS of 0 [n = 14] and 1 [n = 14]) were enrolled. Dose escalation was completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The safety profile was generally consistent with the initial. By investigator-assessment, best response was 1 confirmed partial response (PR) and 6 stable diseases (SD) with monotherapy. After crossing to combination therapy at progression, 8 patients who failed prior anti-PD-(L)1 mAb therapy achieved SD. Phase Ib: Overall, 45 patients (median age: 60.0 yr [range 33-74]; ECOG PS: 0 [n = 14], 1 [n = 31]) were enrolled in all dose levels. Dose escalation was completed and no DLT was observed. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (28.9%), anaemia (24.4%), and alanine aminotransferase increased (22.2%). TRAEs ≥ grade 3 occurred in 10 (22.2%) patients. Immune-related AE (irAE) incidence was 31.1%, and the most common irAE was hypothyroidism (15.6%). In 43 patients who had undergone at least 1 post-baseline tumor assessment, the investigator-assessed best response included 6 PRs (1 endometrial cancer, 4 NSCLC, and 1 SCLC patients) and 23 SDs. Three patients showed a progression-free survival &gt; 1 year and continued treatment. Conclusions: IBI110 alone or plus sintilimab demonstrated acceptable safety profile and promising antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04085185.

A multicenter, open-label, single-arm, phase 1 dose-escalation study to evaluate the safety, tolerability, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1.

3011 Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease that increases susceptibility to malignant tumors. Up to 50% of patients with NF1 present with plexiform neurofibroma (PN). Surgery, a common treatment strategy for patients with PN, has limited efficacy. NF1 is caused by mutations in the gene that encodes neurofibromin; the NF1 mutation then leads to tumorigenesis via dysregulation of the Ras/Raf/MEK/ERK pathway. FCN-159 is anti-tumorigenic via highly potent, selective inhibition of MEK1/2. This study aims to assess the safety of FCN-159 in patients with NF1-related PN. Methods: This is a multicenter, open-label, single-arm, phase 1 dose-escalation and phase 2 dose-expansion study (NCT04954001). Patients with NF1-related PN that was not completely resectable or not suitable for surgery were enrolled in the study; they received FCN-159 monotherapy continuously in 28-day cycles. Here, we report safety and clinical efficacy data from adults enrolled in phase 1. Results: As of the data cutoff of December 1, 2021, 19 adults from 3 hospitals in China have been enrolled in the phase 1 dose-escalation study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. The most common neurofibroma-related complications were disfigurement and pain, occurring in 10 patients (52.6%) and 4 patients (21.1%) at baseline, respectively. Four patients experienced dose-limiting toxicity; G3 folliculitis was reported in 1 patient (16.7%) receiving the 8-mg dose and 3 (100%) patients receiving the 12-mg dose. The maximum tolerated dose was determined to be 8 mg. Study-drug-related treatment-emergent adverse events (TEAEs) were observed in all 19 patients (100%); the majority were grade 1 or 2 in severity. Nine (47.4%) patients reported grade 3 study drug-related TEAEs; 4 patients experienced paronychia and 5 experienced folliculitis, which were the most common causes of dose reduction (42.1%) and drug interruption (21.2%). One patient experienced a serious adverse event of rhegmatogenous retinal detachment, but this was considered unrelated to the study drug as it was preexisting at baseline. Of the 16 patients with at least 1 post-baseline tumor assessment, all (100%) had reduced tumor size and 6 (37.5%) had a reduction in tumor size of &gt; 20%. Three out of 6 patients with a second tumor assessment result had further tumor shrinkage; tumor volumes in the remaining 3 patients were similar to those at first assessment. The largest reduction in tumor size was 84.2%. Conclusions: Overall, FCN-159 at 8 mg is well tolerated, with easy to manage adverse events, and showed promising anti-neurofibroma activity in phase 1; this warrants further investigation in a phase 2 study on efficacy and safety in this indication. Clinical trial information: NCT04954001.

A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER+) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Monotherapy results from EMBER.

1021 Background: Imlunestrant is a novel, orally bioavailable SERD with pure antagonistic properties that result in sustained inhibition of ER-dependent gene transcription and cell growth. In dose escalation, imlunestrant showed favorable safety, pharmacokinetics (PK) and preliminary efficacy in patients with ER+, HER2- aBC and ER+ EEC (Phase 1a EMBER, Jhaveri 2021). Here we present updated data from the dose escalation (Phase 1a) and dose expansion (Phase 1b) of imlunestrant monotherapy in EMBER (NCT04188548). Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior ET sensitivity; ≤3 prior therapies for aBC in Phase 1a following protocol amendment and ≤2 in Phase 1b) and ER+ EEC (prior platinum therapy; no prior fulvestrant or aromatase inhibitor). Premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included recommended phase 2 dose (RP2D) determination, safety and tolerability, PK, objective response rate per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease and ≥1 post-baseline tumor assessment or discontinued prior to tumor assessment, and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of January 14, 2022, 138 patients (n = 114 aBC, n = 24 EEC) received imlunestrant monotherapy at doses ranging from 200-1200 mg QD. Median age was 62.0 years (range 32-95). Median number of prior therapies for aBC and EEC was 2 (range 0-8) and 1 (0-5), respectively. aBC patients had received a prior ET (94.7%), CDK4/6 inhibitor (92.1%), fulvestrant (50.9%) and chemotherapy (26.3%). No dose-limiting toxicities were observed. Most treatment-emergent adverse events (TEAEs) were grade 1. At the RP2D (400 mg QD, n= 69), the most common all grade TEAE’s were nausea (33.3%), fatigue (27.5%), and diarrhea (23.2%). Across all doses, the incidence of treatment-related grade 3 AEs was low (3.6%). No patient discontinued due to a TEAE. In evaluable aBC patients, ORR was 8.0% (6/75) and CBR was 40.4% (42/104). In evaluable EEC patients, ORR was 5.0% (1/20 had a PR- ongoing pending confirmation) and CBR was 47.1% (8/17). Clinical benefit was observed regardless of baseline ESR1 mutation status as determined by ctDNA sequencing. Additional biomarker analyses will be presented at the meeting. Conclusions: Imlunestrant continues to demonstrate a favorable side effect profile, with no cardiac or opthalmic safety signals, and has continued evidence of clinical activity in heavily pre-treated ER+ aBC and EEC patients. Clinical trial information: NCT04188548.

Phase I/II trial of RVU120 (SEL120), a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors.

e15091 Background: CDK 8 /CDK19 are kinases involved in transcriptional control of embryonic development and cellular homeostasis via the mediator complex. They are also described to maintain tumor dedifferentiation and stem cell properties. A variety of cancer cells hijack the mediator complex and targeting cancer-specific gene transcription via CDK8/19 inhibition has potential for treatment of solid tumors. RVU120 (SEL120) is a selective CDK8/19 inhibitor with preclinical efficacy in hematologic malignancies and a variety of solid tumor types (Rzymski et al. 2017). RVU120 showed strong anticancer activity in preclinical triple-negative breast cancer (TNBC) models, especially in the mesenchymal stem-like (MSL) molecular subtype (Rzymski et al SABCS 2021). Methods: A Phase I/II clinical trial of RVU120 in solid tumors is currently ongoing (NCT05052255). Patients with metastatic or advanced solid tumors without available treatments receive increasing doses of RVU120 as a single oral dose every other day (QOD) for a total of 7 doses on Days 1, 3, 5, 7, 9, 11 and 13, in a 3-week treatment cycle. Primary objectives of the study are safety / tolerability of RVU120 as single agent and determination of the recommended Phase II dose (RP2D) via a 3+3 dose escalation design. Secondary objectives include objective response rate (ORR) (RECIST criteria v1.1) and PK of RVU120. Results: As of 11FEB 2022, 5 pts have been enrolled into the trial: 3 into cohort 1, 75 mg dose, 2 into cohort 2, 100 mg. None of the pts experienced a DLT, SAEs or &gt; Grade 3 AE. Treatment-related AEs were all G1 except for G2 diarrhea and weakness. Cohort 1 patients had at least 1 post-baseline tumor assessment. A 62 YO patient, stage IV esophago-gastric junction carcinoma, metastases to the liver, retroperitoneum, adrenal gland and portocaval lymph nodes, progressing after 4 lines of previous therapy, achieved a SD with a +4% change of target lesion size and progressed in cycle 6. A 65 YO patient, stage IV adenoid cystic carcinoma of the trachea, metastases to the lung and refractory to antiandrogens and radiotherapy, achieved a SD with -4% change of target lesion size after 3 cycles and is currently ongoing in cycle 5. A 43 YO pt stage IV thymic carcinoma, metastases to the lung, mediastinum, pleura and lymph nodes, progressing under cisplatin/etoposide, stopped study drug at the end of cycle 3 for PD in non-target lesions, target lesions increased by 11%. Cohort 2 patients, a 65 YO pt with pancreatic cancer stage IV, metastases to liver and lung, and a 55 YO pt with TNBC stage IV, metastases to the lung, will be evaluated end of cycle 3. Conclusions: In the first dose escalation level with single agent RVU120, no DLTs or ≥G3 AEs were observed in patients with previously progressive solid tumors. Initial assessments in 3 pts demonstrated stable disease in 2 patients. Collection of further data at higher doses is ongoing with 2 patients enrolled at 100 mg. Clinical trial information: NCT05052255.

A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors.

3089 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancer (NSCLC), 1-2% of colorectal cancer (CRC) and other solid tumors in China. JAB-21822 (Jacobio, Beijing, PRC) is a highly selective, covalent oral inhibitor of KRAS G12C. Methods: NCT05009329 is an ongoing first-in-human, open label phase I/II study of JAB-21822 in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of JAB-21822. Other objectives include preliminary efficacy, pharmacokinetics, and biomarkers. Here we report the results from the dose escalation phase of the trial. Results: As of January 28th, 2022, 53 patients with a median age of 62 years (39-79) were enrolled in 5 different dose levels: 200mg QD, 400mg QD, 800mg QD, 400mg BID and 400mg TID. Most patients (55%) had ≥ 2 prior lines of therapy. No dosing-limiting toxicities were observed. Two treatment-related adverse events (TRAEs) were G4 neutropenia (1 in 400mg BID and 1 in 400mg TID). The most common TRAEs (≥ 10%) included anemia (24.5%), total bilirubin increase (20.8%), direct bilirubin increase (15.1%), proteinuria (13.2%) and indirect bilirubin increase (11.3%). Only Grade 1 and 2 TRAEs were observed in the QD cohorts. A total of 33 patients (22 NSCLC, 9 CRC and 2 pancreatic cancer) had at least 1 post-baseline tumor assessment; in the 800mg QD cohort, overall response rate (ORR) and disease control rate (DCR) were 50% (5/10) and 100% (10/10), respectively, including 4 non-confirmed partial response (PR); in the 400mg QD cohort had an ORR and DCR of 80% (4/5) and 100% (5/5) respectively, including 2 non-confirmed PR. Patients with NSCLC (400mg QD and 800mg QD), the ORR and DCR were 70% (7/10) and 100% (10/10), respectively, including 5 non-confirmed PR. With respect to the pharmacokinetics analysis, JAB-21822 was rapidly absorbed with an average Tmax of 2 hr and reached higher plasma exposures (Cmax and AUC0-24h) after a single dose and multiple doses at C1D8. Conclusions: JAB-21822 was well tolerated with impressive preliminary efficacy in patients with heavily treated solid tumors harboring KRAS G12C mutation. The study is enrolling patients in the expansion phase. Multiple JAB-21822-based combination trials are also ongoing. Clinical trial information: NCT05009329.

A study of relacorilant in combination with nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma.

4140 Background: Pancreatic cancer remains the third-leading cause of cancer-related death in the US. Average overall survival is only one year, and no standard therapies exist beyond second line. Chemotherapy resistance is one reason for the poor outcomes in pancreatic cancer, which can be caused by, among other factors, excess tumor expression of the glucocorticoid receptor (GR). Nonclinical and clinical data indicate that GR antagonism may enhance or restore chemotherapy sensitivity. Here, we report the interim analysis of RELIANT, a trial evaluating the efficacy and safety of relacorilant, a selective GR modulator, with nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: RELIANT (NCT04329949) was a single-arm, open-label, multicenter study of relacorilant (100 mg QD) + nab-paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 28-day cycle) in patients with histologically confirmed mPDAC. Based on tolerability, relacorilant doses were escalated up to 150 mg. Patients with 2+ prior lines of therapy, including prior gemcitabine- and fluoropyrimidine-based therapy, were enrolled. Planned enrollment was 80 patients. The study included a planned interim analysis after approximately 40 patients had completed 12 weeks of treatment or discontinued study treatment due to disease progression or toxicity. Objective response rate (ORR) by blinded independent central review was the primary endpoint. At the interim analysis, ORR was assessed by the investigator. Results: At the interim analysis, 43 heavily pretreated patients with a median age of 64 years (range: 43–78; 56% male) had been enrolled. 27/43 (63%) patients had received ≥2 prior lines of therapy (range: 2–5), and all but 3 patients had received prior treatment with nab-paclitaxel. Twelve patients (28%) did not have a post-baseline radiographic tumor assessment and were hence not efficacy evaluable. Most common reasons for discontinuation from relacorilant were disease progression (n = 16), adverse event (AE, n = 8), and patient decision (n = 9). Relacorilant + nab-paclitaxel demonstrated antitumor activity with 15/43 (35%) patients showing decreases in target lesion size, 10/43 (23%) achieving disease control for at least 12 weeks, and 17/43 (40%) having decreases in CA 19-9. Of note, one patient has been on study treatment for &gt; 15 months. No confirmed responses by RECIST (CR or PR) were observed, and enrollment was thus stopped after the interim analysis. No new safety signals were identified. The most common AEs were fatigue, nausea, and decreased appetite. Suppression of GR target genes was also observed. Conclusions: Modest antitumor activity of relacorilant + nab-paclitaxel was observed in this heavily pretreated patient population, with a safety profile similar to that observed for relacorilant in other oncology studies. Clinical trial information: NCT04329949.

Association of early tumor growth rate and survival outcomes in first-line metastatic non–small cell lung cancer (mNSCLC).

9063 Background: Tumor growth rates ( g) estimated using imaging measurements, have been associated with overall survival (OS) and progression-free survival (PFS) in patients with mNSCLC, including those treated with first-line immunotherapy (1L IO) or chemotherapy (chemo). Here, we evaluated whether early g estimates within 18 weeks of first treatment dose are associated with survival outcomes for 1L treatment in mNSCLC. Methods: This was a retrospective analysis of data from patients randomized to either nivolumab+ipilimumab (NIVO+IPI) or chemo in CheckMate 227 Part 1 (NCT02477826), or NIVO+IPI+chemo or chemo alone in CheckMate 9LA (NCT03215706). Tumor assessments were performed by blinded independent central review using RECIST v 1.1 at baseline, every 6 weeks for the first 48 weeks and then every 12 weeks until disease progression. The analysis included patients with at least 3 measurable timepoints, including baseline, week 6, week 12, and/or week 18. If a patient did not have a week 18 measurement, the first three measurements alone were used. To derive the median early g, sum of longest diameters (SLD), based on baseline, weeks 6, 12 and/or 18 assessments, and time relative to baseline were fitted to the model defined by sum of exponential growth (g) and decay (d): SLD (t) = exp (–d x t) + exp (g x t) – 1. OS and PFS were estimated using Kaplan-Meier methodology. Results: In the two studies, 865/1166 (75%) of randomized patients in CheckMate 227 Part 1 and 562/719 (78%) in CheckMate 9LA had evaluable tumor growth rate data (Table). The median early g at weeks 12 and 18 was numerically lower for the IO-containing arm vs chemo arm in both studies (Table). Patients with lower growth rate at week 12 or week 18 ( g in first quartile [Q1]) had better OS relative to those with higher rate ( g in fourth quartile [Q4]) across all treatment arms (Table). A similar trend was observed for PFS. Conclusions: Early g estimates based on 2 or 3 post-baseline tumor assessment timepoints were associated with longer-term survival outcomes for 1L treatment of mNSCLC and could discern efficacy outcomes. These findings provide the foundation for further research, which may incorporate volumetric segmentations of measurable lesions and radiomic feature changes to further explore indicators of patient outcomes that could inform future clinical trials and clinical practice.[Table: see text]

The efficacy and safety of taletrectinib in patients with TKI-naïve or crizotinib-pretreated ROS1-positive non–small cell lung cancer (NSCLC).

8572 Background: Taletrectinib (AB-106 / DS-6051b) is a next-generation, potent, CNS- penetrant, selective ROS1 tyrosine kinase inhibitor. The ongoing TRUST study (NCT04395677) is a multicenter, open-label, single-arm, Phase 2 study of taletrectinib in Chinese ROS1-positive NSCLC patients who are TKI -naïve or crizotinib-pretreated. Here we present the updated efficacy and safety results of the study. Methods: The eligible ROS1-positive NSCLC patients were enrolled into either TKI-naïve or crizotinib-pretreated cohorts, and treated with taletrectinib 600mg once daily. The study endpoints included overall response rate (ORR), duration of response (DOR), disease control rate (DCR), overall intracranial response rate (IC-ORR), progression-free survival (PFS), and safety profile. Results: As of the data cutoff date of September 7, 2021, 61 of the 86 stage IV patients enrolled in the study have at least three postbaseline tumor assessment of which 40 patients in the TKI-naïve cohort, and 21 patients in the crizotinib-pretreated cohort (50% patients having at least one prior chemotherapy). In the TKI -naïve cohort, the confirmed ORR by investigators per RECIST 1.1 was 90.0%: [95%CI: 76.3%; 97.2%] (36/40); and the DCR was 95% [95%CI: 83.1%; 99.4%] (38/40). In the crizotinib-pretreated cohort, the confirmed ORR by investigators was 47.6% [95%CI: 25.7%; 70.2%] (10/21); and DCR was 76.2%: [52.8%; 91.8%] (16/21). The mDOR and mPFS are not reached yet for both cohorts. Of 6 patients having brain metastasis and measurable target brain lesions at baseline, the intracranial ORR and IC-DCR were 83.3% and 100%, respectively. Of 4 patients with ROS1 G2032R mutation, 3 patients achieved partial response (PR), and 1 patient achieved stable disease (SD). The most common treatment-related adverse events (TRAEs) include diarrhea, nausea, vomiting, transaminase elevation, anemia, neutrophil count decrease, etc. were Grade 1 or 2, and the most common AEs (below 10%) were ALT/AST increased but reversible. Conclusions: Taletrectinib demonstrated meaningful clinical efficacy in both TKI-naïve and crizotinib-pretreated ROS1 positive NSCLC patients. In particular, taletrectinib showed clinical effectiveness in patients with ROS1 secondary G2032 mutations and patients with brain metastasis. Taletrectinib was well tolerated in this patient population. Clinical trial information: NCT04395677.

A multicenter, randomized, double-blind phase III clinical study to evaluate the efficacy and safety of KN046 combined with nab-paclitaxel and gemcitabine versus placebo combined with nab-paclitaxel and gemcitabine in patients with advanced pancreatic cancer (ENREACH-PDAC-01).

TPS4189 Background: Pancreatic cancer is biologically aggressive, and the majority of pts was diagnosed as locally advanced or metastatic disease. Nab-paclitaxel and gemcitabine is a frequently used regimen for advanced pancreatic cancer, but chemoresistance is unavoidable. The combination of immunotherapy with chemotherapy have shown efficacy for certain types of cancer, but no similar results have been obtained in pancreatic cancer. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. In a phase Ⅱ clinical trial (NCT04324307), as of August 10, 2021, 53 pts with unresectable advanced pancreatic cancer had received one cycle KN046 combined AG regimen treatment and 31 subjects had received post-baseline tumor assessment at least once. Objective response rate (ORR) was 45.2% (95% CI: 27.3%, 64.0%) and disease control rate (DCR) was 93.5% (95% CI: 78.6%, 99.2%)，excellent preliminary results have been achieved. Based on this, a phase III pivotal study (ENREACH-PDAC-01) is conducting now in China to verify the efficacy and safety of KN046 plus nab-paclitaxel and gemcitabine as first-line treatment for advanced pancreatic cancer (NCT05149326). Methods: This nationwide multicenter phase III clinical trial enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic ductal adenocarcinomas with a WHO performance score of 0 or 1 and expected survival period of more than 3 months. Eligible pts will be randomized 1:1 to intervention group or control group and receive 4-6 cycles of KN046 (5mpk Q2W) or placebo combined with nab-paclitaxel (initial dose: 125mg/m2 D1,8,15 Q4W) and gemcitabine (initial dose: 1000mg/m2 D1,8,15 Q4W) followed by KN046 (5mpk Q2W) or placebo with gemcitabine（QW × 3, 1 week off） maintenance therapy. Treatment will continue until disease progression or intolerable toxicity, withdrawal of consent, loss to follow-up or death, end of study, whichever occurs first. The primary endpoint is overall survival (OS). Key secondary endpoints are ORR and progression free survival (PFS). PFS and ORR will be assessed independently per RECIST v1.1 at screening, every 8 weeks for 1 year and then every 12 weeks until disease progression. Tumor and blood samples will be collected at baseline and during study treatment for pharmacokinetic, immunogenicity and biomarker assessment. The first patient was enrolled in early February 2022. Clinical trial information: NCT05149326.

Abstract P5-16-11: Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC)

Abstract Background: Ipat is a potent oral AKT inhibitor that has been studied in multiple clinical trials, primarily in breast and prostate cancers. Combining fulv and AKT inhibition demonstrated efficacy in pts with HR+ aBC regardless of PI3K/AKT pathway alterations [Jones, Lancet Oncol 2020]. IPATunity150 (NCT04060862) was designed as a phase III trial with an open-label phase Ib portion adding ipat to palbo plus fulv in biomarker-unselected HR+ HER2-negative aBC. The biological rationale was to prevent or delay resistance to CDK4/6 inhibition plus endocrine therapy (ET). AKT1 alterations and PTEN loss have been implicated in resistance to CDK4/6 inhibitors [Wander, Cancer Discov 2020; Costa, Cancer Discov 2020]. We report results from the open-label phase Ib portion. Patients and Methods: The primary objective was to assess safety and pharmacokinetics (PK) of ipat in combination with palbo and fulv; several efficacy parameters were also analyzed. Pts with measurable disease who had not previously received a CDK4/6 inhibitor and had experienced relapse during adjuvant ET were treated with ipat at a dose of 300 mg/d, d1-21 q28d, plus standard-of-care doses of palbo (125 mg/d, d1-21 q28d) plus fulv (500 mg q28d with a loading dose in cycle 1). The selected ipat dose was lower than the 400 mg typically used in other studies because of the anticipated drug-drug interaction (DDI) when combining ipat (a sensitive CYP3A4 substrate and mild-to-moderate CYP3A inhibitor) with palbo (a weak time-dependent CYP3A4 inhibitor and CYP3A substrate). Results: Of the 20 pts treated, 20% were Asian, 65% had primary endocrine resistance (relapse ≤2 years after starting adjuvant ET), 80% had received prior (neo)adjuvant chemotherapy, and 60% had liver and/or lung metastases. At the data cutoff (19 Mar 2021; median follow-up 6.1 months), median treatment duration was 5.1, 5.9, and 5.3 months for ipat, palbo, and fulv, respectively. Treatment was ongoing in 13 pts. Grade 3/4 adverse events (AEs) occurred in 80% of pts (no grade 5). The most common AEs were diarrhea (80% any grade, 10% grade 3, no grade 4) and neutropenia (75% any grade, 45% grade 3, 20% grade 4). Other notable grade ≥3 AEs were grade 3 liver function test elevations in 10%. There were no cases of febrile neutropenia and only 1 case of pneumonitis (grade 1). AEs led to at least one dose reduction of ipat in 6 pts (30%; diarrhea n=3 [with vomiting in 1 pt], neutropenia n=3 [with fatigue in 1 pt]) and of palbo in 9 pts (45%; all for neutropenia). One pt (5%) discontinued ipat and palbo permanently due to ongoing neutropenia after protocol-defined dose reductions. As expected, a DDI led to increased ipat exposure (AUC0-24,ss ~60% and Cmax ~40%) when ipat and palbo were combined. Based on population PK analysis, palbo AUC0-24,ss was ~30% higher than reported from the PALOMA 1 and 2 trials, which was expected and consistent with previously reported physiologically based PK modeling of palbo exposure when administered with moderate CYP3A inhibitors [Yu, J Clin Pharmacol 2017]. All 20 pts had at least one post-baseline tumor assessment. Best overall response rate was 45% (95% CI: 23-68%), including confirmed responses in 7 pts (35%; 5% complete response, 30% partial response) at the clinical cutoff date. Median duration of response was 9.6 months (95% CI: 7.1-not estimable). An additional 10 pts (50%) had stable disease. Progression-free survival results were immature (events in 7 pts). There was no obvious association between efficacy and mutations in PIK3CA/AKT1 as tested in ctDNA. Conclusion: The triplet combination of ipat, fulv, and palbo had an acceptable safety profile generally consistent with that of the individual study drugs; ipat exposure was increased through a predicted DDI. Updated results will be presented. Citation Format: Mafalda Oliveira, Aditya Bardia, Sung-Bae Kim, Naoki Niikura, Cristina Hernando, Gustavo Werutsky, Yoland Antill, Pedro Liedke, Catherine Oakman, Eriko Tokunaga, Seth Wander, Vanessa Krause, Toshinari Yamashita, Frauke Schimmoller, Jacob Rotmensch, Heidi Savage, Rucha Sane, Nicholas Turner. Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-11.

Abstract P5-16-02: Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC)

Abstract Background: Eganelisib is a first-in-class, oral, immuno-oncology macrophage reprogramming agent. The IMpassion130 randomized trial in 1L advanced TNBC has demonstrated improved efficacy with the addition of atezo to nab-pac in patients with PD-L1+ tumors. Adding eganelisib to the approved doublet of atezo and nab-pac is expected to improve patient benefit regardless of PD-L1 status. Methods: Eligible patients (pts) had measurable unresectable locally advanced or metastatic TNBC and no prior systemic therapy for advanced disease. A safety run-in assessed the safety of the triplet of oral eganelisib 30 mg daily in combination with IV nab-pac 100 mg/m2 given on days 1, 8, &amp; 15, and IV atezo 840 mg given on days 1 &amp; 15 of a 28 day cycle. After establishing tolerability and confirmation of the 30 mg dose in the safety run-in (n=6), the expansion phase of the phase II study was initiated to enroll approximately 60 pts (30 PD-L1+ and 30 PD-L1-). Cycles are repeated until loss of clinical benefit, unacceptable toxicity or consent withdrawal. The primary efficacy endpoint is confirmed complete response (CR) rate per RECIST v1.1. Secondary endpoints include the overall response rate (ORR), progression free survival and safety assessment. Results: As of 6/26/2021, data from the safety run-in and the expansion cohorts are reported for 43 pts evaluable for safety and 38 evaluable for efficacy defined as having at least one post-baseline tumor assessment. 2 CRs (2/38), 19 PRs (19/38), and 11 SDs (11/38) were observed with an ORR of 55.3% (21/38) and a disease control rate (DCR) of 84.2% (32/38). Responses were seen irrespective of PD-L1 status; in PD-L1+ pts, ORR is 66.7% (8/12) and DCR is 91.7% (11/12), and in PD-L1- pts, ORR is 47.8% (11/23) and DCR is 78.3% (18/23). The most common all-grade adverse events were nausea (51.2%), fatigue (48.8%), alopecia (32.6%), diarrhea (32.6%), rash maculo-papular (30.2%), ALT increased (27.9%), and AST increased (25.6%). The most common grade ≥3 adverse events were ALT increased (18.6%), AST increased (14.0%), neutrophil count decreased (9.3%) and rash maculo-papular (9.3%). The safety profile is acceptable and in line with expectations of component drugs with no additive or new safety signals. Translational data from paired biopsies show a shift in tumor associated macrophages towards an immune activated state as well as an increase in cytotoxic T cells. In addition, a subset of tumors with baseline PD-L1 negative status show conversion to PD-L1 positive status post treatment. Consistent with immune activation, increased interferon gamma signature, increased proinflammatory cytokines and T cell invigoration were observed in peripheral blood cells. Conclusions: The novel triplet regimen of eganelisib, atezo, and nab-pac shows promising anti-tumor activity (ORR 55.3% and DCR 84.2%) irrespective of PD-L1 status and has manageable toxicity. . Translational data from paired biopsies and peripheral blood show evidence of immune activation regardless of PD-L1 status as well as conversion from PD-L1 negative to PD-L1 positive subtype within a subset of patients treated with the triplet regimen. The expansion phase of the phase II study is currently enrolling. At the time of presentation, we will have updated efficacy, safety and translational data. Citation Format: Soliman Hatem, Jeffrey Hargis, Anthony Elias, Arielle Lee, Rachel Swart, Shaker Dahkil, Alexandra Drakaki, Vu Phan, Frederic Kass, Melody Cobleigh, Sanil Babu, Katherine Tkaczuk, Brenda O'Connell, Jennifer Roberts, Nora Zizlsperger, Erika Hamilton. Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-02.

Efficacy of derazantinib in intrahepatic cholangiocarcinoma patients with FGFR2 mutations or amplifications: Interim results from the phase 2 study FIDES-01.

427 Background: Derazantinib, a potent anti- FGFR1-3 oral kinase inhibitor, has shown clinically meaningful anti-tumor activity (21%), durable responses (median, 6.4 months), and progression-free survival (median, 8.0 months) in patients (pts) with FGFR2 fusion (FGFR2F)-positive intrahepatic cholangiocarcinoma (iCCA), and with a manageable toxicity profile. Herein, we report an interim analysis of the clinical efficacy data of derazantinib for pts with iCCA harboring FGFR2 mutations or amplifications (FGFR2M/A), a potential therapeutic option currently not addressed by FGFR inhibitors. Methods: Study FIDES-01 enrolls in a dedicated cohort pts with FGFR2M/A+ advanced iCCA who received previous chemotherapy. Pts receive 300 mg derazantinib daily until disease progression, death or intolerance. The primary endpoint is the proportion of pts alive and free of disease progression at 3 months (PFS3; RECIST 1.1, central imaging review) using a Simon’s two-stage sample-size minimizing statistical design. The interim analysis population comprises 23 pts dosed (intention to treat) who had at least one post-baseline tumor assessment (or clinical progression, or died) by June 3, 2021, using investigator assessments based on RECIST 1.1. Results: To date, 28 pts have been enrolled and dosed. FGFR2M/A observed in these pts included missense point mutations (78%), other short variants (11%) and amplifications (11%). Transition from stage 1 to stage 2 of the study was achieved earlier than planned after 8 (67%) of 12 pts were assessed as PFS3 based on central imaging review. In 23 pts included in this interim analysis for efficacy, the best overall response (investigator assessment) was confirmed partial response in two (8.7%) and stable disease in additional 15 pts (65.2%), resulting in a disease control rate of 73.9% (95% CI, 51.6–89.8). Using Kaplan-Meier analyses, the median PFS was 7.3 months (95%CI, 3.5–16.7) and the probability of being progression-free at 3 months and at 6 months were 76.3% (95%CI, 51.9–89.4) and 50.3% (95%CI, 21.7–73.4), respectively. Clinically meaningful anti-tumor efficacy was observed across all types of genetic aberrations. The safety profile of derazantinib in FGFR2M/A+ iCCA pts was consistent with that previously reported for FGFR2F+ iCCA pts. Conclusions: This interim data in study FIDES-01 suggest that derazantinib treatment provides clinical benefit to pts with advanced iCCA harboring FGFR2M/A who progressed after at least one line of standard chemotherapy. To our knowledge, this is the first report of clinically meaningful anti-tumor efficacy in a prospectively planned cohort of iCCA pts harboring FGFR2M/A. The study is ongoing to accrue 43 patients, assessing derazantinib as a therapeutic option for FGFR2M/A+ iCCA pts after disease progression on first-line treatment. Clinical trial information: NCT03230318.

Phase 1/1b trial of fruquintinib in patients with advanced solid tumors: Preliminary results of the dose expansion cohorts in refractory metastatic colorectal cancer.

93 Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P &lt; 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R]) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.

Intracranial Activity of Tepotinib in Patients (pts) With MET exon 14 (METex14) Skipping NSCLC Enrolled in VISION

<h3>Purpose/Objective(s)</h3> Brain metastases (BMs), reported in 20–40% of pts with <i>MET</i>ex14 skipping NSCLC, present a high unmet need with a poor prognosis. Preclinical data from tepotinib, a highly selective MET inhibitor, demonstrated intracranial activity in MET-driven lung cancer orthotopic BM models. In VISION Cohort A (N=152), tepotinib had robust and durable clinical activity in pts with <i>MET</i>ex14 skipping NSCLC, with an objective response rate (ORR) of 45% and a median duration of response (mDOR) of 11.1 months. Here, we report the intracranial activity of tepotinib. <h3>Materials/Methods</h3> In VISION, pts with <i>MET</i>ex14 skipping NSCLC received oral tepotinib 500 mg QD (450 mg active moiety). Pts with BM (neurologically stable on symptomatic therapy with stable steroids, and pts with asymptomatic BM) were eligible. Primary endpoint was systemic ORR per RECIST v1.1; a subgroup analysis in pts with BM (determined by RECIST v1.1) was predefined. An ad-hoc retrospective analysis of brain lesions determined by CT/MRI was conducted by an independent review committee using RANO-BM criteria, which accounts for pts' clinical status and steroid use. Responses were determined in pts with ≥1 evaluable post-baseline tumor assessment. For those with non-measurable lesions per RANO-BM (enhancing and non-enhancing non-target lesions [NTLs]), disease control in the brain was defined as non-complete response (CR)/non-progressive disease (PD). Data cut-off was July 1, 2020. <h3>Results</h3> Per RECIST v1.1, 23 pts in Cohort A had BM at baseline. Systemic efficacy was consistent with the overall population (ORR 47.8% [95% CI: 26.8, 69.4], mDOR 9.5 months [95% CI: 5.5, not estimable]). 15 pts were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before tepotinib initiation [range 2.6–44]). Systemic best objective responses (BORs) were partial response (PR; n=9), stable disease (SD; n=3), and PD (n=3). Seven pts had measurable CNS disease per RANO-BM (all with prior radiotherapy); intracranial BORs were PR (n=5; including three with complete disappearance of target lesions), SD (n=1) and PD (n=1). Of eight pts with NTL only, seven achieved intracranial disease control and one had PD. Of the seven with disease control, three had a CR of the enhancing NTL. <h3>Conclusion</h3> Tepotinib demonstrated robust systemic activity in pts with <i>MET</i>ex14 skipping NSCLC with BM, complemented by intracranial activity in an ad-hoc analysis using RANO-BM. Small pt numbers, a large proportion of pts with prior radiotherapy for BM, and the retrospective nature of the analysis should be considered. A prospective evaluation of intracranial activity data from VISION Cohort C is ongoing. ©2021 American Society of Clinical Oncology, Inc. Reused with permission. Accepted and presented at ASCO 2021. All rights reserved.

Abstract P185: Preliminary antitumor activity of MCLA-158, an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma

Abstract In the expansion part of an ongoing phase 1 study, MCLA-158 is being investigated at the recommended phase 2 dose (RP2D) in patients (pts) with advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) and WNT signaling are known oncogenic and mitogenic drivers in several cancers, including HNSCC. MCLA-158 is a human common light chain IgG1 bispecific antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. It targets EGFR and the leucine-rich, repeat-containing, G-protein coupled receptor 5 (LGR5), a transmembrane receptor associated with tumor initiating cells, particularly cancer stem cells. Potent antitumor activity was seen with MCLA-158 in pt-derived HNSCC xenograft models. The RP2D of MCLA-158 was determined to be 1500 mg every 2 weeks (q2w), with 4-week cycles, during the dose escalation part of the study, based on safety, PK and receptor occupancy prediction. A maximum tolerated dose was not reached. The primary objective of the expansion part is to characterize the safety and tolerability of single-agent MCLA-158 and confirm the RP2D. Secondary objectives include assessment of antitumor activity (investigator-assessed overall response rate [ORR] per RECIST 1.1 and duration of response). Key eligibility criteria include prior exposure to standard therapy, ECOG performance status (PS) 0-1, measurable disease (RECIST 1.1), and availability of a baseline tumor biopsy. At the interim data cutoff date of 15 June 2021, 7 pts with advanced recurrent/metastatic HNSCC were enrolled and treated in the expansion phase. Median age was 63 years (range 50-74), ECOG PS 0/1: 2/5. Primary tumor locations were oropharynx (2 pts), hypopharynx (1 pts), larynx (3 pts), and unknown primary (1 pt). All pts had a histology of squamous cell carcinoma. Prior treatment included platinum-based chemotherapy in all pts, and anti-PD-1/PD-L1 in 6 pts. No pts received prior cetuximab. A median of 3 treatment cycles (range 1-8) were administered to the 7 pts, 4 of whom were continuing with therapy at the cutoff. Of the 5 pts who had a postbaseline assessment, 2 had confirmed partial responses (5+ and 8 cycles initiated), and 2 pts had stable disease (reduction in the sum of target lesions of 7% and 17%; 4+ and 5 cycles initiated, respectively). Scheduled first postbaseline tumor assessments for 2 pts occurred after the data cutoff date. Among 26 pts who were treated at the RP2D in the dose escalation and expansion cohorts, the most frequent adverse events regardless of causality (all grades/grade 3) were infusion-related reactions (73%/8%), rash (39%/0%), asthenia (35%/4%), decreased appetite (27%/4%), nausea (27%/4%), and acneiform dermatitis (23%/4%). There were no treatment-related grade 4 or 5 adverse events. In conclusion, MCLA-158 shows promising signs of antitumor activity in pretreated HNSCC, and a well-tolerated and favorable safety profile. Citation Format: Antoine Hollebecque, Irene Brana, Lara Iglesias, Caroline Even, Kato Shumei, Marc Díez García, Mateo Bover, Patricia Martin-Romano, Rocio Garcia-Carbonero, Guillen Argilés, Josep Tabernero, Rajan Khanna, Viktoriya Stalbovskaya, Jeroen Lammerts van Bueren, Kees Bol, Mohamed Bekradda, Andrew Joe, Ernesto Wasserman, Ezra E.W. Cohen. Preliminary antitumor activity of MCLA-158, an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P185.