Clinical Benefit Rate Research Articles

VERITAC-2: A global, randomized phase 3 study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer.

TPS1122 Background: ARV-471 is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. ARV-471 directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of ARV-471 vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Methods: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N~560) are randomized 1:1 to receive 200 mg ARV-471 orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation sub-population. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Clinical trial information: NCT05654623 .

EPIK-B6: A phase 2, open-label, 2-part, multicenter study of alpelisib in combination with fulvestrant for men and postmenopausal women with PIK3CA mutation HR–positive, HER2-negative, advanced breast cancer, which progressed on/after aromatase inhibitor treatment in Japan.

TPS1117 Background: The PIK3CA oncogene mutation, seen in ~40% of patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (aBC), is associated with endocrine treatment resistance and shorter survival. Alpelisib, an α-selective PI3K inhibitor and degrader, was established as standard therapy in combination with fulvestrant for patients with HR+, HER2-, PIK3CA-mutated aBC following progression on/after endocrine-based regimen based on the phase 3 SOLAR-1 study. However, alpelisib is not yet approved in Japan. In the SOLAR-1 study, a high percentage of Japanese patients experienced dose reductions/interruptions (78.5% vs 84.4%), and/or discontinuation (56.3% vs 25.0%) of alpelisib in early stages compared with overall population, due to adverse events such as rash and hyperglycemia. Thus, it is difficult to assess the consistency of the benefit of alpelisib + fulvestrant in Japanese patients as compared to overall population due to the short duration of alpelisib exposure and low-dose intensity. The EPIK-B6 study aims to determine the recommended dose (RD) of alpelisib in Japanese patients as well as assess the efficacy and safety of alpelisib + fulvestrant in Japanese men and postmenopausal women with HR+, HER2-, PIK3CA-mutated aBC, which progressed while on/after aromatase inhibitor treatment, prior/post CDK 4/6i use. Methods: The EPIK-B6 study is designed as a phase 2, open-labelled, 2-part, multicenter study. Part 1 is to determine RD of alpelisib to be used in part 2. Part 2 is designed to assess the efficacy and safety of alpelisib (RD starting on cycle 1 day 1 [C1D1]) + fulvestrant (500 mg on C1D1 and C1D15, and D1 of subsequent cycles) after completion of part 1, in participants with/without prior CDK 4/6i use. Adult Japanese men or postmenopausal women with confirmed HR+, HER2-, PIK3CA-mutated aBC and ≥1 measurable lesion as per RECIST 1.1 criteria are eligible. Patients previously treated with fulvestrant, any PI3K, mTOR or AKT inhibitors are excluded. Use of prophylactic antihistamine is highly recommended for prevention of rash. The primary endpoint for part 2 is overall response rate based on assessments per RECIST 1.1. Secondary endpoints include progression free survival, overall survival, clinical benefit rate, duration of response, time to response, time to deterioration of ECOG performance status, safety, tolerability, and pharmacokinetics. Part 1 has been completed, and recruitment for part 2 is ongoing until August 2023 approximately. As of December 2022, 9 and 8 patients are enrolled in part 1 and 2, respectively. The study will include approximately 50 participants. Primary Analysis is planned in 2024 after at least 6 months follow-up period. Clinical trial information: NCT04524000 .

Alternating 17β-Estradiol and Aromatase Inhibitor Therapies Is Efficacious in Postmenopausal Women with Advanced Endocrine-Resistant ER+ Breast Cancer.

Strategies to implement estrogen therapy for advanced estrogen receptor-positive (ER+) breast cancer are underdeveloped. Preclinical data suggest that cycling treatment with 17β-estradiol followed by estrogen deprivation can control tumor growth long-term. Postmenopausal women with advanced ER+/HER2- breast cancer with recurrence or progression on ≥ 1 antiestrogen or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17β-estradiol (2 mg orally, three times a day) for 8 weeks followed by AI (physician's choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations. Of 19 evaluable patients, clinical benefit rate was 42.1% [95% confidence interval (CI), 23.1%-63.9%] and objective response rate (ORR) was 15.8% (95% CI, 5.7%-37.9%). One patient experienced a grade 3 adverse event related to 17β-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5 of 12 (41.7%) cases. Tumor ER (ESR1) mutations were found by whole-exome profiling in 4 of 7 (57.1%) versus 2 of 9 (22.2%) patients who did versus did not experience clinical benefit from alternating 17β-estradiol/AI therapy. The only two patients to experience objective responses to initial 17β-estradiol had tumor ESR1 mutations. Alternating 17β-estradiol/AI therapy may be a promising treatment for endocrine-refractory ER+ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the antitumor activity of 17β-estradiol differs according to ESR1 mutation status.

Clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials.

3101 Background: The Dutch Drug Rediscovery Protocol (DRUP, NCT02925234) and the Australian Cancer Molecular Screening and Therapeutic (MoST, ACTRN12616000931471) Program are similar non-randomized, multi-drug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic pre-treated cancer patients with tumors harboring Cyclin D-CDK4/6 pathway alterations that were treated with CDK4/6 inhibitors palbociclib or ribociclib as monotherapy. Methods: Eligible adult patients had therapy-refractory solid malignancies with one of the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoints for this combined analysis were clinical benefit, defined as confirmed objective response or stable disease (SD) ≥16 weeks, and safety. Results: Among 139 enrolled patients 33 tumor types were represented, with glioblastoma multiforme (18%), sarcoma (13%), non-small cell lung cancer (9%) and pancreatic cancers (9%) being most common; 116 patients received palbociclib and 23 received ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15% (17 cases of SD ≥16 weeks). Median progression-free survival was 4 months (95% CI 3-5 months) and median overall survival 5 months (95% CI 4-6 months). No unexpected toxicity was observed for either drug. Additional driver alterations were identified in 98% and 77% of patients based on whole genome sequencing (WGS) and sequencing next generation sequencing (NGS) analysis at baseline, respectively (Most common in WGS: TP53 (45%), KRAS (25%), PTEN (15%), SMAD4 (15%). Most common in NGS: TP53 (21%), EGFR (17%), TERT promoter (15%), KRAS (11%). Conclusions: Results show minimal clinical activity of palbociclib and ribociclib monotherapy in patients with pre-treated cancers harboring cyclin D-CDK4/6 pathway alterations. Our findings indicate that single agent use of palbociclib or ribociclib is not recommended. Furthermore, we demonstrate that merging data from similar precision oncology trials is feasible. This finding is especially relevant in the context of precision oncology, with rare molecular subsets and/or cancer histologies. Clinical trial information: NCT02925234 .

Association between baseline radiological tumor burden and outcomes in patients with metastatic breast cancer treated with an immune checkpoint inhibitor.

1103 Background: Lower baseline radiological tumor burden is associated with more favorable outcomes for patients with metastatic non-small cell lung cancer and melanoma treated with immunotherapy. However, minimal data is available for metastatic breast cancer patients. This is despite immunotherapy, in combination with chemotherapy, now being standard-of-care for a subset of metastatic breast cancer patients who have triple-negative disease and are PD-L1 positive. Methods: We reviewed data of 82 patients with metastatic breast cancer consecutively treated at our institution from August 2015 to October 2021, who received > 1 dose of an immune checkpoint inhibitor (anti-PD-1 or -PD-L1) within the context of a clinical trial. Baseline tumour burden was assessed by a single radiologist and calculated as sum of Response Evaluation Criteria in Solid Tumours 1.1 baseline target lesions (baseline tumour size [BTS]) or as sum of all measurable baseline lesions (total tumour burden [TTB]); the impact of both parameters on treatment outcomes was investigated. Treatment outcomes assessed were clinical benefit rate (complete response, partial response or stable disease for 6 months or more [CBR6]), disease free survival (DFS) and overall survival (OS). Multivariate analysis adjusted for ECOG status, line of treatment (first line vs second line or beyond), and whether immunotherapy was given in combination with chemotherapy or as monotherapy. Results: A total of 82 patients were included in the analysis. 43 patients (52%) received combination chemotherapy with immunotherapy, 39 patients (48%) received immune checkpoint inhibitor monotherapy. Median BTS and TTB were 36.5mm (range 0 -204mm) and 43mm (range 0 – 1123mm) respectively. CBR6 was significantly associated with BTS (p=0.004) and TTB (P=0.002) quartiles, with clinical benefit time progressively increasing with decreasing tumor burden quartiles. Both increasing BTS (p<0.001) and TTB (p<0.001) across quartiles were significantly associated with shorter OS. There was a numerical, but not statistically significant, association between both parameters as quartiles (BTS, p=0.25; TTB, p=0.07) and PFS. In the bottom BTS quartile, 32% of patients were progression-free and 95% alive at 12 months, compared with 15% and 40% respectively in the top quartile. Similar results were seen when TTB was used as the baseline measurement: 32% progression-free and 95% alive at 12 months in the bottom quartile compared with 1% and 33% in the top quartile. Multivariate analysis confirmed that both BTS and TTB, considered as continuous variables, are independently associated with OS. Conclusions: Lower baseline radiological tumor burden is associated with better outcomes in patients with metastatic breast cancer treated with immune checkpoint inhibitors.

TROPHY-U-01 Cohort 4 (C4): Sacituzumab govitecan (SG) in combination with cisplatin (cis) as first-line (1L) therapy, followed by maintenance avelumab plus (+) SG or zimberelimab (zim) + SG in patients (pts) with treatment (Tx)-naïve metastatic urothelial cancer (mUC).

TPS4611 Background: SG is a Trop-2–directed antibody-drug conjugate. In the TROPHY-U-01 study, SG monotherapy showed a 27% objective response rate (ORR) and 10.9 months median overall survival (OS) with an overall manageable safety profile in pts with mUC who received platinum (PT)-containing chemotherapy and a checkpoint inhibitor (CPI), resulting in accelerated FDA approval in this population. PT-based chemotherapy followed by avelumab maintenance is standard 1L therapy in pts with Tx-naïve mUC. Zim (anti–PD-1) is a CPI under clinical investigation for antitumor activity. C4 of TROPHY-U-01 will evaluate safety, tolerability, and clinical activity of SG+cis followed by maintenance avelumab+SG or zim+SG in cis-eligible pts with Tx-naïve mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 study. C4 will evaluate 1L SG in combination with cis in pts with cis-eligible mUC or unresectable locally advanced disease. Eligibility requirements include ECOG PS 0-1; no prior anticancer monoclonal antibody within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic and hepatic function. Pts will be treated with cis at 70 mg/m2 on D1 of 21-D cycles (if creatinine clearance [CrCl] ≥60 mL/min) or at an optional split dose of 35 mg/m2 on D1 and D8 of 21-D cycles (if CrCl 50-59 mL/min), followed by SG (5, 7.5, or 10 mg/kg, based on 10-pt safety lead-in of a 3+3 design) on D1 and D8 of 21-D cycles. Granulocyte colony-stimulating factor support is not allowed in the safety lead-in but was permitted during escalation and expansion. SG+cis will continue for up to 6 cycles, followed by maintenance (4 to 8 wk after last induction dose of SG+cis and when RP2D is determined) in the absence of progression. Dose escalation maintenance consists of avelumab 800 mg q2w, then SG 10 mg/kg on D1 and D8 of 21-D cycles. Dose expansion maintenance consists of zim 360 mg (D1 of a 21-D cycle) and SG 10 mg/kg (D1 and D8 of 21-D cycles) and will begin once safety lead-in of 6-8 pts receiving zim+SG of a 21-D cycle in Cohort 5 is deemed safe and completed. Pts will continue Tx until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per RECIST v1.1 by central review. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per central review and investigator assessment. OS and safety will also be evaluated. All statistical analyses will be performed using a two-sided hypothesis test approach at the overall 5% level of significance. Time to event endpoints will be assessed via the Kaplan-Meier method. Enrollment is ongoing; up to 57 pts expected across ~120 sites in North America and Europe. Clinical trial information: NCT03547973 .

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The vulvar cancers.

5517 Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in various rare solid cancers is yet to be established. The efficacy of immunotherapy in vulvar cancer patients has not been explored. This study presents the first results of ipilimumab and nivolumab in vulvar cancers (cohort 35) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) > 6 months, and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years) were analyzed. 14 cases were of squamous cell carcinoma histology and 2 were of poorly differentiated carcinoma. ORR was 18.8% (3/16, 25% when including one unconfirmed PR). There was 1 CR (SCC; PFS of 465 days) and 2 PR (both SCC; one with 57% regression with PFS of 1022 days, another with 53% regression with PFS of 501 days). Of note, there was one SCC patient with unconfirmed PR that showed 69% regression with PFS of 209 days. Overall clinical benefit rate (CBR; no progression > 6months) was 31.3% (5/16). The median PFS was 2.2 months, 6-month PFS 33%, 1-year PFS 20%. The median OS was 7.6 months, 6-month OS 62%, 1-year OS 44%. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3-4 adverse events occurred in 25% of patients (n = 4). There was 1 grade 3-4 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an ORR of 18.8% and CBR of 31.3%, with durable responses seen. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies exploring the role of immunotherapy in vulvar cancers are warranted. Clinical trial information: NCT02834013 .

Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.

4548 Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed to assess the prognostic impact of MAdCAM-1 in ICI-treated mRCC pts. Methods: The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) is a multicentric study that assessed the activity and safety of Nivolumab in pts with clear cell mRCC after anti-angiogenic therapy. We measured serum soluble MAdCAM-1 (sMAdCAM-1) levels (correlating ileal MAdCAM-1 transcripts) using Human Luminex Discovery Assay in the available plasma. Progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) were assessed using sMAdCAM-1 median as a cut off value (high if >median and low if <median). Multivariate Cox analysis adjusted for established risk factors: ATB, gender, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis. Two independent cohorts of metastatic lung and bladder cancer patients validated the data. Results: Overall, 212 pts were included. Median age was 64 years (22-87), and pts were mostly male (82%). ATB users had lower levels of sMadCAM-1. Low sMadCAM-1 pts had diminished OS compared to high sMadCAM-1 pts [HR 2.97 (95%CI 1.99-4.44), p<.0001]: 13.3 (95%CI 9.8-14.9; 72/106) versus 25.3 (95%CI 24.1-NR; 36/106) months. Also, low sMadCAM-1 pts had diminished PFS [HR 1.92 (1.43-2.57), p<.0001]: 2.6 (95%CI 2.4-2.8; 99/106) versus 5.2 (95%CI 4.6-5.7; 86/106) months. Interestingly, sMAdCAM-1 was independently associated with OS [HR 2.40 (1.52-3.80), p=0.0002] and PFS [HR 1.55 (1.13-2.13), p=0.0071] in multivariate analysis. Low sMadCAM-1 pts had lower CBR (37% versus 63%, p=0.0004). Serum sMAdCAM-1 also predicted OS in 381 ICI-treated patients with lung and bladder cancer. Conclusions: Low sMAdCAM-1 is associated with ATB intake, ATB-independent gut dysbiosis and worse outcomes, in ICI-treated pts with metastatic lung, bladder and RCC cancer. ELISA determination of sMAdCAM-1 might guide the selection of patients amenable to microbiota-centered interventions, such as Akkermansia sp., and fecal microbiota transplantation. Clinical trial information: NCT0301335 .

Interim analyses (IA) of the giredestrant (G), G + abemaciclib (A), and G + ribociclib (R) arms in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced/metastatic BC (ER+, HER2– LA/mBC).

1061 Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759 . [Table: see text]

Safety and clinical activity of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma: Results from the low-dose expansion cohort.

11508 Background: TTI-621 is a recombinant fusion protein combining the Fc region of human IgG1 with a fragment of human SIRPα, designed as a decoy receptor for CD47 on tumor cells to interrupt CD47-SIRPα signaling and promote macrophage-mediated phagocytosis of tumor cells as well as activation of NK cells. Preclinical studies suggest TTI-621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as leiomyosarcoma (LMS). A phase 1/2 dose escalation study with high- and low-dose expansion cohorts evaluating TTI-621 + doxorubicin in patients (pts) with advanced LMS is ongoing (NCT04996004); results from the low-dose expansion cohort are presented. Methods: This open-label study enrolled anthracycline-naïve pts aged ≥18 y with evaluable unresectable or metastatic high-grade LMS and ≤1 prior line of therapy for advanced disease. Pts in the low-dose expansion cohort received TTI-621 0.2 mg/kg on Days 1 and 8 in combination with doxorubicin 75 mg/m2 on Day 1 of 21-day cycles for a maximum 6 cycles, followed by TTI-621 monotherapy on Days 1 and 15 of 28-day cycles until objective disease progression. Primary objectives for the expansion phase were evaluation of safety and investigation of clinical activity via assessment of overall response and clinical benefit rates as defined by RECIST v1.1 criteria. Results: At data cut-off (Oct 3, 2022), 23 pts were evaluable for safety and 20 for clinical response. In the safety population, 39% had received prior treatment for advanced disease. Two pts (9%) experienced Grade ≥3 AE assessed as related to TTI-621 treatment: pancreatitis (n = 1, 4%) and platelet count decreased (n = 1, 4%). Seven pts (30%) experienced Grade ≥3 AE related to the combination of TTI-621 and doxorubicin, including two pts (9%) each with platelet count decreased and white blood cell count decreased and three pts (13%) with neutrophil count decreased. Grade ≥3 doxorubicin-related AEs were more common (n = 17, 74%); most frequent were neutrophil count decreased (n = 8; 35%), white blood cell count decreased (n = 7; 30%), and neutropenia (n = 6; 26%). One pt experienced an infusion-related reaction (Grade 1 chills) assessed as related to TTI-621. No pts attained complete response, but one pt had a complete resolution of all target lesions. Five pts (25%) attained partial response for an overall response rate of 25%; 11 pts (55%) attained stable disease for a disease control rate of 80%. Conclusions: Addition of TTI-621 to doxorubicin showed promising clinical activity and a favorable safety profile among pts with advanced LMS, including those with prolonged exposure to TTI-621 ( > 360 d). Clinical trial information: NCT04996004 .

Phase 2 study of weekly polymeric micelle-formulated paclitaxel plus gemcitabine in patients with recurrent and metastatic adenocarcinoma of the pancreas.

e16257 Background: Cremophor EL(CrEL), used to enhance drug solubility, may add paclitaxel’s toxicities such as hypersensitivity reactions or peripheral neuropathy. The rationale for developing an alternative paclitaxel formulation concerns CrEL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. GENEXOL-PM (GPM) is a novel polymeric micelle formulated paclitaxel free of CrEL. This is to report the efficacy and safety of the weekly combined chemotherapy with GPM and gemcitabine in patients with recurrent and metastatic adenocarcinoma of the pancreas conducted in multicenter, Republic of Korea. Methods: This was a multicenter, phase 2 study of weekly GENEXOL-PM plus gemcitabine in subjects with recurrent and metastatic adenocarcinoma of the pancreas. The patients who had met the inclusion/exclusion criteria were enrolled and received GPM (125 mg/m2) and gemcitabine (1000 mg/m2) intravenously on day 1, 8, and 15 in every 4 weeks, unless definite disease progression was confirmed. Tumor evaluation was conducted at the end of every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST). Pre-planned test and adverse reaction evaluation were managed after each cycle of drug administration and before the next cycle. The primary end point of this study was objective response rate, and the secondary end points were toxicity, progression free survival and overall survival. Results: Between January 2016 and February 2022, total 32 patients were enrolled; median age was 65 years; male (n=16) and female (n=16). 26 patients were assessable for efficacy. Overall response rate was 19.2% (5/26 patients) and clinical benefit rate (partial response + stable disease) was 34.6% (9/26 patients). The median progression-free survival and overall survival were 8 months, 22 months, respectively. The median number of cycles administered was 5.0 (range=1-21). Most common grade 3 or higher hematological toxicities were: neutropenia occurred in 9 patients (29.0%), neutrophil count decrease 5 patients (16.1%) and anemia 5 patients (16.1%). The most common grade 3/4 non-hematological toxicities were generalized muscle weakness 3 patients (11.5%), pneumonitis 3 patients (11.5%) and liver abscess 2 patients (4.3%). Conclusions: Treatment of advanced pancreatic cancer with combination of GENEXOL-PM and gemcitabine was generally well tolerated and showed a favorable toxicity profile. In this study, efficacy results of combination regimen were comparable to that observed historically with albumin-bound paclitaxel and gemcitabine combination. This regimen demonstrated chemotherapeutic effects to warrant further development when used as first-line chemotherapy for advanced pancreatic cancer. Future studies directly comparing GENEXOL-PM and albumin-bound paclitaxel are required. Clinical trial information: NCT02739633 .

A phase 2 study of the WEE1 inhibitor AZD1775 in SETD2-deficient advanced solid tumor malignancies.

3104 Background: AZD1775 is an inhibitor of the WEE1 kinase, leading to loss of genome integrity. Pathogenic SETD2 mutations lead to genome-wide loss of histone H3K36 trimethylation (H3K36me3) and hypersensitivity to WEE1 inhibition with a synthetic lethal effect. AZD1775 was studied in 2 cohorts of patients: A) Patients (pts) with locally advanced/metastatic solid tumor malignancy other than clear cell renal cell carcinoma (ccRCC) and B) pts with locally advanced/metastatic ccRCC. Methods: Eligible pts had a locally advanced/metastatic cancer with progression on ≥ 1 prior systemic therapy (including prior tyrosine kinase inhibitor or checkpoint inhibitor for cohort B), and a pathogenic SETD2 mutation by CLIA-certified next generation sequencing panel. Pts received AZD1775 at a starting dose of 300 mg PO daily on days 1-5, 8-12 of each 21-day cycle. The primary objective was to determine the objective response rate (ORR) by RECIST 1.1 criteria in each cohort. Planned sample size was 9 pts in each cohort in stage 1 of a Simon two-stage design. Secondary objectives were to determine the clinical benefit rate (CBR) (defined as partial response or stable disease [SD] > 4 months), duration of response (DOR), and safety. Correlative assays include the evaluation of H3K36me3 mark by immunohistochemistry (IHC) in archival tumor tissue. Results: Between 05/2019 and 10/2021, 18 pts whose tumor harbored a pathogenic mutation in SETD2 were enrolled (9/cohort). The median age was 60 years (range 45 – 74), ECOG PS 0 in 8 (44.4%). One patient remains on treatment; 17 have discontinued (disease progression, n = 9; adverse event, n = 4; patient withdrawal, n = 2; patient death, n = 1). The median duration of treatment was 1.89 months (range 0.75 – 13.5). There were no confirmed objective responses and therefore enrollment was halted following accrual to stage 1. Tumor regression of any magnitude was observed in 5/17 (29%) evaluable pts. Stable disease was the best overall response in 10/17 (59%) evaluable pts, including 3 pts with SD for > 4 months. One patient with RCC remains on treatment with SD for 14+ months duration. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Twelve pts (67%) experienced a Grade ≥ 3 adverse event. Evaluation of H3K36me3 using IHC as an exploratory biomarker is underway. Conclusions: AZD1775 given as monotherapy failed to achieve an objective response in SETD2-altered RCC and other solid tumor malignancies. However, a subset of pts derived clinical benefit as manifested by tumor regressions and/or durable stable disease. Evaluation of AZD1775 in combination with other DNA damage-inducing agents that cause replication stress may be warranted, potentially with the integration of the H3K36me3 mark as a biomarker for patient selection. Clinical trial information: NCT03284385 .

Enhanced Systemic Antitumour Immunity by Hypofractionated Radiotherapy and Anti-PD-L1 Therapy in Dogs with Pulmonary Metastatic Oral Malignant Melanoma.

Although immune checkpoint inhibitors (ICIs), such as the anti-programmed death-ligand 1 (PD-L1) antibody, have been developed for the treatment of canine malignant melanoma, desirable clinical efficacies have not been achieved. Recent studies in humans have suggested that radiation therapy (RT) combined with ICIs induces robust systemic antitumour immunity in patients with cancer. This study retrospectively examined the therapeutic efficacy of combination therapy (hypofractionated RT and anti-PD-L1 antibody [c4G12]) in dogs with pulmonary metastatic oral malignant melanoma. The intrathoracic clinical benefit rate (CBR)/median overall survival (OS) in the no RT (n = 20, free from the effect of RT), previous RT (n = 9, received RT ≤8 weeks prior to the first c4G12 dose), and concurrent RT (n = 10, c4G12 therapy within ±1 week of the first RT fraction) groups were 10%/185 days, 55.6%/283.5 days (p < 0.05 vs. no RT group), and 20%/129 days (p > 0.05 vs. no RT group), respectively. The adverse events were considered to be tolerable in the combination therapy. Thus, hypofractionated RT before the initiation of c4G12 therapy can be an effective approach for enhancing the therapeutic efficacy of immunotherapy, with acceptable safety profiles. Further prospective clinical studies are required to confirm the findings of this study.

Phase 1/2 Study of DF1001, a novel tri-specific, NK cell engager therapy targeting HER2, in patients with advanced solid tumors: Phase 1 DF1001 monotherapy dose-escalation results.

2508 Background: DF1001 is a first in class, Tri-specific, NK cell Engager Therapy (TriNKET), that uses HER2 as an anchor to modulate innate and adaptive immunity. DF1001 redirects both NK and CD8 T cells to reprogram the tumor microenvironment, turning cold tumors hot. DF1001-001 (NCT04143711) is an ongoing phase I/II, first in human study investigating the safety, tolerability, clinical and biologic activity of DF1001. The safety, pharmacokinetic (PK), pharmacodynamic (PD) and efficacy data from the phase 1 monotherapy escalation and safety/PK/PD expansion is presented in this report. Methods: The Phase 1 dose escalation of DF1001-001 evaluated doses ranging from 0.000052-15mg/kg in patients with advanced and/or refractory solid tumors. Safety/PK/PD expansions, mandating paired biopsies, enrolled at doses 0.52-15mg/kg for biomarker assessment in patients with at least HER2 1+ expressing tumors. The primary objective of the Phase 1 study was to evaluate the safety of DF1001. The secondary objective was to assess efficacy. Results: As of 8 Dec 2022, 36 patients were treated in the dose escalation and 68 patients were treated in the safety/PK/PD expansion. 63% of the patients were female with a median age of 61 years. Most common tumor types included breast (38%), urothelial carcinoma (10%), esophageal (8%), non-small cell lung (7%) and colorectal (7%) cancer. Treatment Related Adverse Events (TRAE) were reported in 79% of patients. TRAEs were mostly low grade (86% were Grade 1-2) and rarely led to treatment discontinuation. No Grade 4 or 5 TRAEs were reported. The most common TRAEs were infusion related reactions (26%), asthenia (15%) and fatigue (12%). No dose limiting toxicities were detected, and the MTD has not been reached. Best overall response (BoR) of Partial Response (PR) by RECIST 1.1 was observed in 5 patients, with duration of up to 13 months, and 22 patients experienced stable disease (SD), for a Clinical Benefit Rate (CBR) of 39.7%. Responders included patients with refractory lung and breast cancer, whose tumors expressed HER2 1+ to 3+ by IHC. Biomarker analysis in responders demonstrated increases in inflammatory cytokines and chemokines by gene expression profiling, and consonant increases in NK and CD8 cells in the tumor microenvironment, consistent with TriNKET mechanism of action (MOA). Conclusions: In this dose escalation study, DF1001 is shown to be a safe and well-tolerated novel NK cell engager therapy targeting HER2. DF1001 monotherapy demonstrates promising anti-tumor activity in treatment refractory patients with a spectrum of HER2 expression as well as MOA consistent pharmacodynamic changes in the tumor. This promising data set supports further exploration of DF1001 alone, and in combination with other compounds, as a potential novel therapeutic option for patients with solid tumors. Clinical trial information: NCT04143711 .

Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1–3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d−1) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses. ClinicalTrials.gov registration: NCT04497116.

Clinical benefit (rate) of geriatric assessment in a Veterans Affairs (VA)-based oncology clinic according to the Geriatric 5Ms framework.

e24010 Background: The geriatric assessment (GA) is a validated, multi-system assessment tool that can detect vulnerabilities often not captured with standard oncology assessments in older adult patients with cancer. The Geriatric 5Ms is a novel communication framework used to describe core competencies in geriatrics. Prior studies have shown GA integration in oncology practice can significantly reduce grade 3 or higher chemotherapy-related toxicities, falls, polypharmacy, hospital length of stay (LOS), increase completion of advanced directives, and improve quality of life measures. Despite these benefits, implementation into clinical practice has remained low. This study aimed to utilize telemedicine to integrate GA into a busy VA oncology practice. Methods: In this quality improvement study design, we enrolled adult patients aged 70 years and older with solid tumors or hematologic malignancy, either newly established or receiving active systemic treatment through an urban, academic VA oncology clinic. Patients were assigned to the intervention (GA conducted via telemedicine by a geriatric specialist) if they scored ≤14 on G8, a validated screening tool. Outcomes were compared with a historical control cohort who received usual care (no virtual GA). Reported here are the clinical benefits measured qualitatively according to the geriatric 5Ms framework. Results: Between January 1, 2022 and March 30, 2022, we enrolled 116 patients (n = 57 intervention, 59 control) from a US VA-based population. Patients had a mean age of 76.8 (SD 6.2) between both cohorts and all patients were male (100%). Among patients in the intervention cohort, all patients (100%) derived benefit in at least one element of the 5M’s framework (Mind, Mobility, Medications, Multicomplexity, and Matters Most) from GA. Based on findings from the GA, services were provided in each of the 5M’s categories in the following frequencies: multicomplexity (88%), matters most (71%), medication (58%), mentation (50%), and mobility (46%). Conclusions: Incorporating GA via telemedicine into routine oncologic care was feasible within this VA-based population of older adult patients with cancer. Further, this project led to clinic recognition as an Age Friendly Health System by the Institute for Healthcare Improvement (IHI). When routinely performed, geriatric assessment led to clinical benefit among all patients receiving the intervention according to the 5M’s framework. Future studies will compare the clinical benefits of this intervention to clinical outcomes measures such as hospital length of stay, emergency room utilization, therapy toxicity, and survival among this patient population.

Nivolumab and ipilimumab in advanced non small cell lung cancer previously treated with PD1 axis inhibition.

9121 Background: Nivolumab combined with ipilimumab is currently one of many first line treatment options for patients with advanced non-small cell lung cancer (NSCLC). The benefit of this regimen in patients with NSCLC previously treated with a programmed death 1 (PD1) axis inhibitor is unclear. Methods: We conducted a phase II study (NCT03262779) of nivolumab and ipilimumab in patients with PDL1 unselected advanced NSCLC with either primary resistance (cohort 1) or acquired resistance (cohort 2) to prior PD1 axis inhibitor therapy. Nivolumab 3 mg/kg was administered intravenously every 2 weeks, and ipilimumab 1 mg/kg every 6 weeks, and continued until disease progression or treatment limiting toxicity. If &gt; 1 response or prolonged stability (&gt; 24 weeks) using immune related response criteria were observed in the first 10 patients treated on cohort 1, an additional 30 patients would be accrued (simon 2-stage). A total of 10 patients would be accrued to cohort 2 (exploratory cohort). The primary endpoint was objective response rate (ORR) by RECIST v1.1 in cohort 1. Secondary endpoints included, ORR in cohort 2, progression free survival (PFS) and overall survival (OS) in both cohorts. Results: Among 10 patients with primary resistance to PD1 axis inhibitor therapy, no objective responses were observed (8 patients had progressive disease (PD) and 2 patients had unconfirmed stable disease (SD) as best response). Among 10 patients with acquired resistance to PD-1 axis inhibitor therapy, ORR was 10% (1 patient with confirmed complete response, 5 patients with confirmed SD including 4 patients with SD lasting more than 9 months, 3 patients with unconfirmed SD, and 1 patient with PD). Durable clinical benefit (DCB, response or SD for at least 6 months) rate was 50%. Median duration of benefit in the 5 patients with DCB was 11.9 months. Nine of the 10 patients in cohort 2 developed initial resistance to PD-1 axis inhibitor monotherapy (rather than combination chemo-immunotherapy), all received immunotherapy as part of their last line of therapy. The remaining patient developed resistance while on maintenance chemoimmunotherapy after initial response to chemoimmunotherapy; best response to trial therapy in this patient was unconfirmed SD. Median PFS/ OS in cohort 1 were 1.8 months/ 6.8 months, and in cohort 2, 6.7 months/ 31.8 months. Grade 3 treatment-related adverse events (TRAEs) occurred in 4 patients across both cohorts, including colitis (2 pts), diabetes (1 pt), pneumonia (1 pt) and elevated lipase (1 pt). There were no grade 4/5 TRAEs. Two patients discontinued trial therapy due to toxicity (colitis), both in cohort 2. Conclusions: Combination immunotherapy with nivolumab and ipilimumab does not overcome primary resistance to PD1 axis inhibitor therapy; however, can overcome acquired resistance to PD1 axis inhibitor therapy. Translational studies from tumor and serial peripheral blood collections are ongoing. Clinical trial information: NCT03262779 .

Immunologic constant of rejection as a predictive biomarker of immune checkpoint inhibitors efficacy in non-small cell lung cancer.

e21162 Background: Immune checkpoint inhibitors (ICI) transformed non-small cell lung cancer (NSCLC) prognosis but response rate remains disappointing. Besides PDL1 expression, tumor mutational burden, quantification of tumor infiltrating lymphocytes or methylation profile failed to confirm their predictive role. The ICR (Immunologic Constant of Rejection) signature is defined as an immune phenotype quantifying the expression of 20 genes all involved in cancer immunity. Our first objective was the assessment of ICR signature predictive value and our secondary objectives were to compare ICR signature with other published immune signatures and to assess the prognostic value of ICR signature. Methods: Our series included 77 paraffin-embedded (FFPE) tumors derived from NSCLC patients treated with ICI as a single agent in at least the second line setting. We also collected clinical and biological data from 4 public data sets to expand and confront our local data. Transcriptomic analysis was performed using nCountertechnology Dx analysis by Nanostring based on microscopic imaging counting relative abundance of hundreds of transcripts using the “nCounter PanCancer Immune Profiling Panel” including the 20 ICR genes. Results: We applied the ICR classification to a series of 44 local tumor samples enhanced with 118 samples from public datasets. Hierarchical clustering on both local cohort and public datasets allowed us to distinguish the four ICR classes, from ICR 1 (“cold” tumors) to ICR 4 (“hot” tumors). Among the 5 datasets, we did not observe any significant difference between ICR groups for age, sex and smoking status. We observed a relative homogeneity in Durable Clinical Benefit (DCB) rate among ICR groups 2 to 4 (median DCB above 20%) unlike ICR group 1 (median DCB under 10%) leading us to consider ICR as a binary signature (ICR 1 vs ICR 2-4). ICR signature indeed showed a significant association with DCB among the 5 pooled datasets (OR = 4.40 [95% Confidence Interval 1.44-13.45] p = 0.950) with uniform distribution between them. Then, we conducted a logistic regression univariate analysis of DCB among various previously published immune signatures and ICR signature was the only one to show a significant association with DCB in this analysis ( p = 0.007). Conclusions: We identified a feasible transcriptomic signature with a promising signal of ICI efficacy prediction in the so far disappointing immune biomarkers field. In a near future, predict ICI efficacy will be a major challenge with three pivotal questions. When, balanced with the new data on ICI use in early-stage lung cancer or widely pretreated patients. How, assessing various techniques to develop composite signatures to better consider every driver of immune response. What, considering the amount of potential new therapeutic targets, starting by the 20 genes of ICR signature.

Primary Acetabular Labral Reconstruction In Adolescents, In the Rare Scenario of Irreparable Labral Tears, Resulted In Comparable Improvement, Clinical Benefit, and Revision Surgeries Rate to a Primary Labral Repair Benchmark Group

Primary Acetabular Labral Reconstruction In Adolescents, In the Rare Scenario of Irreparable Labral Tears, Resulted In Comparable Improvement, Clinical Benefit, and Revision Surgeries Rate to a Primary Labral Repair Benchmark Group

Harnessing olaparib, palbociclib, and endocrine therapy: A phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA mutation-associated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HOPE).

TPS1126 Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) in patients (pts) with germline or somatic BRCA1 or BRCA2 (g/s BRCA1/2) mutations has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial showed superiority of fulvestrant (F) with palbociclib (P) compared to F alone. The OlympiAD trial showed the poly-ADP ribose polymerase inhibitor (PARPi) olaparib (O) to be superior to chemotherapy in BRCA1/2-associated MBC. However, treatment resistance inevitably develops; targeting dual therapeutic drivers concurrently may delay or circumvent resistance. O and P have overlapping hematologic toxicity and the safety of combined O, P and F is unknown. The tolerability of O + P is particularly relevant given the emergence of potentially less myelosuppressive PARPi. Methods: HOPE (NCT03685331) is a phase I/II trial to evaluate safety and efficacy of O, P and F in pts with g/s BRCA1/2-associated, HR+ MBC. Eligible pts have an ECOG performance status 0-1, measurable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 lines of chemotherapy for MBC. Prior platinum is allowed for curative intent if completed at least 12 months prior to MBC diagnosis, or for MBC if no progression during therapy. Prior PARPi and CDK4/6i are permitted on phase I, and are permitted during phase II if there was no progression on them. Treatment (28-day cycles) consists of: O orally twice daily continuously; F 500mg intramuscularly on day 1 of each cycle plus load; and P orally once daily on days 1-21. Phase I begins with a 28-day safety run-in of O and F alone. O and P doses are based on dose level (DL): DL 0 (starting level), O 300mg, P 75mg; DL 1, O 300mg, P 100mg; DL 2, O 300mg, P 125mg; DL-1, O 250mg, P 75mg and DL-2, O 200mg, P 75mg. For phase II, O and P will be dosed at MTD. Pts have tissue collection at baseline and peripheral blood cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). Phase I primary endpoint is MTD. A 3+3 dose escalation design is used with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. A minimum of 2 and a maximum of 18 patients will be enrolled on the phase I. Phase II primary endpoint is PFS using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. Phase II will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with O monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment is ongoing. Clinical trial information: NCT03685331 .