Clinical Benefit Rate Research Articles

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART SWOG 1609) in patients with refractory gallbladder cancer (cohort 48).

e16330 Background: Immune checkpoint blockade has improved outcomes in multiple tumor types, however little is known about the efficacy of these agents in rare tumors. We report the results of the gallbladder cohort of SWOG S1609 Dual Anti–CTLA-4 and anti–PD-1 blockade in Rare Tumors (DART). Methods: We performed a prospective, open label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the gallbladder cohort reported here. Eligible patients had progressed following at least one line of standard systemic therapy, and did not have an approved or standard therapy available that had been shown to prolong survival. All participants received nivolumab 240 mg i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks on a continuous schedule. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity Results: Nineteen patients (79% female) with a median age of 60 years were enrolled and received treatment. The median prior lines of therapy was 2 (range 1-6). The confirmed overall response rate was 16% [complete response, n=1 (5%); partial response, n=2 (11%)] (duration = 35+, 16, 13 mo). The unconfirmed overall response rate and clinical benefit rate were both 32% [complete response, n=1 (5%); partial response, n=5 (26%); stable disease > 6 months, n=0 (0%)]. The 6-month progression-free survival was 26% (95% CI 12-55%); median overall survival was 7.0 months (95% CI, 3.9-19.1 months). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was one death from hepatic failure possibly related to treatment in the setting of progressive liver metastasis and biliary infection. Conclusions: Ipilimumab plus nivolumab demonstrated a 16% ORR in patients with gallbladder cancer including a complete response lasting 35+ months; The unconfirmed overall response rate was 32%. Clinical trial information: NCT02834013 . [Table: see text]

A phase 1b/2 dose escalation and expansion study of OP-1250 in combination with ribociclib or alpelisib in patients with advanced and/or metastatic estrogen receptor–positive (ER+)/HER2-negative (HER2-) breast cancer.

TPS1127 Background: Therapies targeting the estrogen receptor (ER) are standard of care in the management of ER+/HER2- metastatic breast cancer (MBC) and when administered concurrently with cyclin-dependent kinase (CDK) inhibitors are the most effective first-line therapy. CDK 4/6 inhibitors plus endocrine therapy improve progression-free survival and, for some agents, overall survival for patients with MBC. However, most patients will acquire resistance, highlighting an unmet need for more effective endocrine options in ER+ disease. OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity. OP-1250 potently inactivates both wild-type and mutant forms of ER, the latter of which confers ligand independent activity as a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with CDK4/6 inhibitors demonstrated synergistic activity in models of both wild-type ER and those with ESR1 (the gene that encodes ER) activating mutations, and in brain metastasis. OP-1250 is orally bioavailable with a favorable pharmacokinetic (PK) profile supportive of once-daily dosing, and a low probability of drug:drug interactions, making it an attractive agent for patients with ER+/HER2- MBC. Methods: The study (NCT05508906) is an open-label, multicenter, 2-part study of OP-1250 in combination with either the CDK4/6 inhibitor ribociclib or the PI3K inhibitor alpelisib for patients with MBC. Eligibility includes adults with evaluable (measurable or non-measurable) ER+/HER2- recurrent, locally advanced or MBC confirmed by histology/cytology, ≤2 prior hormonal regimens (prior CDK4/6 inhibitors allowed) and ≤ 1 prior line of chemotherapy. Patients in the alpelisib arm must have a PIK3CA mutation. A total of 30 patients will be enrolled in each arm. The dose escalation cohorts will evaluate the safety and PK of varied OP-1250 doses (30mg, 60mg, or 120mg) administered orally (PO) every day (QD) in combination with approved dosages of either ribociclib 600 mg PO QD or alpelisib 300 mg PO QD to identify the recommended phase 2 doses (RP2D). The dose expansion cohorts will assess additional safety and PK parameters and further explore the anti-tumor activity of OP-1250 in combination with ribociclib or alpelisib. Tolerability, safety and PK of OP-1250 in combination with ribociclib or alpelisib constitute the primary endpoints. Overall response rate, clinical benefit rate and duration of response are key secondary endpoints. Enrollment at approximately 20 sites in the United States and Australia is ongoing. Clinical trial information: NCT05508906 .

Meta-analysis of efficacy outcome measures across immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) in melanoma to guide future clinical trial design.

e21520 Background: Systemic treatments (Tx) for unresectable or metastatic melanoma include TTs and ICIs, with TT+ICI combinations under exploration. Heterogeneity in clinical trial sample size and subject characteristics pose obstacles for treatment class comparisons. We applied meta-analysis to elucidate Tx and covariate effects on efficacy outcomes in melanoma. Methods: A PICOS-guided literature search was conducted from 2000-2022 for TT or ICI given as monotherapy or in combination for unresectable or metastatic melanoma. Median progression-free survival (mPFS), median overall survival (mOS), and overall response rate (ORR) were recorded. Random-effects models were fit to endpoints with study arms weighted by variance. Covariate inclusion was based on likelihood-ratio tests (P < 0.05). For simulation, parameter distributions from weighted linear regression (wi ~ nstudy) of mPFS to ORR were sampled (N = 5000) with residual error scaled by mean Phase 3 arm size. ORR uncertainty was modeled by normal approximation. Results: From 134 publications, 100 (mPFS), 73 (mOS), and 111 (ORR) outcomes were retained, from 53, 44, and 63 studies, respectively, and classified by treatment. For all endpoints, Tx classification was an outcome predictor (P< 0.001). BRAFi+MEKi+PD-1 combination therapy had the greatest predicted duration of mPFS (16.7 months [11.8, 23.6]) and ORR (62.8% [53.7%, 71.1%]). mPFS and mOS outcomes were reduced by prior Tx failure and evidence of brain metastases, with mOS also impacted by elevated lactate dehydrogenase. I2 statistics for the final models were 89.0% (mPFS), 73.9% (mOS), and 51.8% (ORR). A robust correlation between ORR and mPFS (R2= 0.77, P < 0.001) was observed across all treatment classes. The predictive power of this relationship was demonstrated by simulating the probability of achieving target Phase 3 mPFS outcomes from ORR derived from as few as 20 patients. Conclusions: This meta-analysis characterizes the shifting space of Tx in unresectable or metastatic melanoma and provides a model-based framework for simulation of efficacy endpoints and trial designs for TT+ICI combinations. ORR-based predictions of trial success illustrate the value of utilizing early endpoints to inform decisions in drug development, across all Tx options in melanoma. Further investigation will include longitudinal PFS and OS modeling and refinement of PFS predictions from tumor growth metrics and clinical benefit rate.

Real-world efficacy of nivolumab in Peruvian patients with advanced melanoma.

e18849 Background: Malignant melanoma in Latin American (LATAM) population has aggressive features as higher rates of Acral lentiginous (ALM) subtype and shorter survival. Immunotherapy has improved prognosis among patients with cutaneous melanoma; however, there is scarce reports of the effectiveness in LATAM population. We describe our experience with management and survival of Peruvian patients with advanced melanoma treated whit nivolumab. Methods: A retrospective study based on cases review evaluated the efficacy of nivolumab. Eligible patients were metastatic, recurrent or unresectable malignant melanoma undergoing treatment with nivolumab as first-line for at least 3 consecutive months between 2020 and February 2021 in two institutions (Instituto Nacional de Enfermedades Neoplasicas, Oncosalud). Clinical pathologic features and immune inflammatory blood markers (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and prognostic nutritional index (PNI)) were evaluated. Efficacy was measured as progression-free survival (PFS), objective response rate (ORR), Clinical benefit rate (CBR) and overall survival (OS). A p < 0.05 value (SPSS) will be considered for a significant difference. Results: 57 patients were analyzed; median age was 63 yo (range 34-83); 59.6% were female. 77.2% had a Zubrod 0-1. Regarding histology, 37% (n = 21) had acral subtype, 38% (n = 22) non-acral, 17% (n = 10) mucosal and 8% (n = 4) unknown primary (UP). 81.1% had negative BRAF mutation status, and the median lactate dehydrogenase (LDH) level was 257 U/L (130-1281). 63.2% had visceral metastasis, the most common site being lung (42%) and liver (9%). Central nervous system (CNS) metastases was reported in 5%. After a median follow-up was 25 months, the median OS reported was 51.43 months (95% CI, 14.23-88.62). Median OS was 28.93 for acral melanoma (95% CI, 14.66-43.19) and not reached for other subtypes. Median PFS was 7.93 months (95% CI, 2.49-13.36); 4.93, 14.73 and 5.26 months in patients with acral, non-acral and mucosal melanoma, respectively. A significant difference was founded in OS (p = 0.024) and PFS (p = 0.001) between acral and non-acral melanoma. ORR was reached in 28.1% of patients; 19%, 31.8% and 20% in acral, non-acral and mucosal subtype, respectively. However, global CBR was 64.9%, with the higher and lower rate for non-acral (81.82%) and mucosal melanoma (50%). The overall incidence of immune related adverse effects (irAEs) was 69.5%, the most common were skin reactions (14%), followed by asthenia (12%); not grade 3-4 AEs were reported. Regarding immune inflammatory blood markers, no association between PFS with NLR (p = 0.49), PLR (p = 0.3) and PNI (p = 0.71) were founded. Conclusions: Nivolumab showed efficacy in improving OS for patients with advanced melanoma, however ALM had shorter OS and PFS. No prognostic immune blood markers were reported. New biomarkers are necessary, especially in acral melanoma.

Tumor agnostic efficacy and safety of erdafitinib (erda) in patients (pts) with advanced solid tumors with prespecified FGFR alterations (FGFRalt): RAGNAR primary analysis.

3121 Background: FGFRalt are present across malignancies at various frequencies and may act as oncogenic drivers across tissue histology. Erda is an oral selective pan-FGFR tyrosine kinase inhibitor with activity and safety in pts with prespecified FGFR-altered locally advanced or metastatic urothelial carcinoma (UC) and cholangiocarcinoma . RAGNAR (NCT04083976) is an ongoing phase 2 open-label, single-arm tumor agnostic trial of erda in pretreated adult and pediatric pts with FGFRalt advanced solid tumors. Interim results showed erda clinical benefit, with an objective response rate (ORR) of 29.2%. Here we report results of the primary analysis. Methods: Pts aged ≥12 y with advanced or metastatic (non-UC) tumors of any histology with predefined FGFR1-4alt (mutations/fusions per local/central test), disease progression on ≥1 prior line of systemic therapy (tx), and no alternative standard tx received oral erda until disease progression or intolerable toxicity. The primary end point was ORR by independent review committee (IRC). Secondary end points included duration of response (DOR), disease control rate (DCR [CR + PR + SD]), clinical benefit rate (CBR [CR + PR + SD >4 mo]), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Results: At data cutoff, 217 pts were treated, median age was 57.0 y (range, 12-79), median prior systemic tx was 2 (46%; ≥3 lines of tx) with an ORR to last line prior to study entry of 10.1%. ORR to erda tx by IRC was 29.5% (95% CI, 23.5-36.0) with 6 CRs (2.8%) and 58 PRs (26.7%) in 16 distinct tumor types, including advanced CNS, thoracic, gastrointestinal, gynecologic, and rare tumors. ORR was comparable across FGFR1-3 mutations (25.3% [95% CI, 16.0-36.7]) and fusions (32.6% [95% CI, 25.1-40.9]). Median DOR, PFS, and OS were 6.9 mo (95% CI, 4.4-7.1), 4.2 mo (95% CI, 4.1-5.5), and 10.7 mo (95% CI, 8.7-12.1), respectively; DCR was 73.7% and CBR was 45.6%. 99.5% of pts experienced TEAEs, including 70.0% with grade ≥3. Treatment-related serious AEs occurred in 8.3% of pts with no treatment-related deaths. Conclusions: Primary analysis results from RAGNAR, the largest tumor agnostic trial of targeted tx to date, confirm efficacy of erda in heavily pretreated pts with FGFRalt advanced solid tumors. Erda activity was observed in adults and adolescents across tumor types, and across FGFR1-3 gene mutations and fusions. Erda tolerability was consistent with its known safety profile. Clinical trial information: NCT04083976 . [Table: see text]

An exploratory trial of a novel R-ISV-RO technique in the treatment of advanced solid tumors.

e14666 Background: The immunotherapy of bone and soft tissue sarcomas remains a challenge. Our pre-clinical trial confirmed that the combination of Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and OX-40 agonist had prominent synergistic effects. Immunoradiotherapy, especially Stereotactic Body Radiotherapy (SBRT) could further activate specific immune response. We hypothesized that intratumoral injection of “RO” (R837+αOX40) combined with SBRT will realize tumor control and reduce adverse reactions. Meanwhile, the synergetic application of PD-1 mAb systematically will improve the effectiveness of immunotherapy. Methods: This is a single-arm, single-center, open-label, exploratory trial that explore intratumoral injection of an emulsion of “RO” in combination with SBRT as “in situ vaccination” for advanced solid tumor (Ethics number: 2021-133-02). The inclusion criteria included: 1) advanced solid tumors which progress after standard therapies, 2) presence of one or more injectable lesions. SBRT to injected lesions was at a dose of 5-8Gy per fraction at a total dose of 20-32Gy. Imiquimod (0.75mg/ml) and αOX40 (2.5mg/ml) were prepared as emulsion and intratumoral injected into the target lesion for 4 times. Patients were also systematically administrated with PD-1 mAb (serplulimab). The primary endpoint was objective response rate (ORR) of target lesions. The secondary endpoint mainly included disease control rate (DCR) of target lesions, progression free survival (PFS), overall survival (OS), and clinical benefit rate (CBR), etc. Results: From May 2021 to October 2022, 30 patients were eligible for this trial (60% were sarcomas). 46.7% and 33.3% had received radiotherapy or PD-1/PD-L1 mAb respectively before. The ORR, DCR and CBR of target lesions were 29.2%, 91.7% and 41.7%, while these of systemic efficacy were 21.7%, 82.6% and 17.4%, respectively. In sarcomas, the ORR, DCR and CBR of target lesions were 25.0%, 93.8% and 50.0%, while these of systemic efficacy were 20.0%, 93.3% and 26.7%, respectively. Systemic median PFS were 3.67 months. The median event-free survival (EFS) of target lesions and median OS were not reached. Among the evaluable target lesions, 6-month EFS was 85.7% in sarcomas (6/7) and 76.9% in all patients (10/13). The most common TRAEs were leukopenia (50%), hypoproteinemia (30%) and anemia (20%), demonstrating that treatment is tolerable. Grade≥3 treatment-related adverse events (TRAE) occurred in 3 patients, including myocarditis (6.7%) and thyroiditis (3.3%). Conclusions: In situ vaccination with “RO” emulsion, along with SBRT was tolerable and induced anti-tumor immunity, which would also trigger systemic response when synergized with PD-1 mAb. This in situ vaccination has been proved to be a promising option for advanced solid tumors especially for sarcomas. Clinical trial information: ChiCTR2100053870 .

A phase I study of nanoparticle albumin-bound sirolimus (NAB-S) combined with pazopanib (PAZO) in patients with advanced soft tissue sarcoma (STS).

11521 Background: NAB-S (ABI-009, nab-rapamycin) is approved for treatment of adults with unresectable or metastatic perivascular epithelioid cell tumors. Albumin binding improves sirolimus solubility and may target it to tumoral cells. mTOR inhibition may enhance PAZO activity directly and by overcoming resistance. We assess feasibility and safety of the combination. Methods: Eligible patients (≥18y) had: advanced, unresectable, non-adipocytic STS progressing after 1-5 prior therapies; adequate end-organ function; ECOG performance status 0-1; measurable target lesions (RECIST v1.1); and no prior mTOR or angiogenesis inhibitor treatment. The study was conducted according to a 3+3 design. Initial cohorts received 800 or 400 mg PAZO daily and 60, 45 or 30 mg/m2 of NAB-S on days 1 and 8 on a 21-day cycle. Subsequently, NAB-S was administered only on day 1 based on preliminary analysis of adverse events (AEs) and pharmacokinetics (PK). Primary endpoint was determination of maximally tolerated dose (MTD). Dose-limiting toxicities (DLT) were grade 3-5 adverse events (AE) during the first cycle not due to PAZO. Secondary endpoints included AE characterization (CTCAE v5.0), descriptive evaluation of responses and their duration, and correlative/PK studies. Results: 19 patients were treated; initially, 13 received NAB-S on days 1 and 8. DLT included thrombocytopenia (TCP, n = 7), decreased WBC/neutrophils (n = 2), increased lipase (n = 1), and proteinuria (n = 1). Due to overlapping AEs or possible NAB-S/PAZO interaction, further cohorts received 400 mg PAZO daily and either 30 or 45 mg/m2 NAB-S (n = 6). There were no DLTs in the 30 mg/m2 cohort (n = 3). In the 45 mg/m2 cohort, 2 out of 3 patients had TCP meeting DLT definition. Grade 3-4 AEs in more than 10% included: TCP (58%), neutropenia (11%), leukopenia (11%), lymphopenia (11%), and diarrhea (11%). Any grade AEs in > 50% included: TCP (74%), mucositis (63%), fatigue (58%), and acneiform rash (53%). There was no grade 5 AEs. Of 19 treated, 11 (58%) discontinued due to disease progression, 3 (16%) due to AE (TCP-2, transaminitis-1), and 1 (5%) due to death from disease. Four (21%) remain on study as of 2/2023. 18 were evaluable for best response: 3 partial responses (PR; leiomyosarcoma, solitary fibrous tumor, spindle cell sarcoma), 13 stable disease (SD), 2 progressive disease. Clinical Benefit Rates (CBR = PR+SD) at 3 and 6 months were 72% (13/18) and 59% (10/17). Among the leiomyosarcoma subset, CBR at 3 and 6 months were 90% (9/10) and 80% (8/10). Correlative and pharmacokinetic results will be presented. Conclusions: Thrombocytopenia was the most prominent DLT when studying the NAB-S/PAZO combination. 3 patients out of 19 discontinued therapy due to AEs; the remainder continued therapy after adjustment. MTD and RP2D is NAB-S 30 mg/m2 day 1 and PAZO 400 mg days 1-21. Preliminary evidence of activity of the combination was observed. Clinical trial information: NCT03660930 .

Outcomes with first-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs physician’s choice combination chemotherapy (combo CT) by age in pre/perimenopausal patients (pts) with aggressive HR+/HER2− advanced breast cancer (ABC): A subgroup analysis of the RIGHT Choice trial.

1063 Background: The progression-free survival (PFS; primary endpoint) results from the Phase II RIGHT Choice trial demonstrated a statistically significant median PFS (mPFS) benefit of ≈1 y with RIB + ET over combo CT (mPFS, 24.0 vs 12.3 mo; hazard ratio [HR], 0.54; 95% CI, 0.36-0.79; P = .0007) in pts with aggressive HR+/HER2− ABC. Younger pts with aggressive ABC have a worse prognosis, which impacts treatment (tx) decisions. Hence, a subgroup analysis of key efficacy endpoints from RIGHT Choice by age (< 40 vs ≥ 40 y) was undertaken. Methods: Pre/perimenopausal pts (aged 18-59 y) with HR+/HER2− ABC and no prior systemic therapy for ABC were randomized 1:1 to either RIB with letrozole/anastrozole + goserelin or investigator’s choice of combo CT (docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine). Pts in the trial had ABC not amenable to curative therapy and for which combo CT was clinically indicated by physician’s judgment (ie, symptomatic visceral metastases, rapid progression of disease or impending visceral compromise, or markedly symptomatic non-visceral disease). Results: In total, 70 pts were aged < 40 y and 152 were aged ≥ 40 y. In the combo CT arm, pts aged < 40 y fared worse and had a shorter mPFS, shorter median time to tx failure (mTTF), and higher 3-month tx failure rate (TFR) than pts aged ≥ 40 y. Pts aged < 40 y showed a significant PFS benefit with RIB + ET vs combo CT (mPFS, not reached [NR] vs 10.2 mo; HR, 0.38). This PFS benefit with RIB + ET over combo CT was also observed in pts aged ≥ 40 y (21.2 vs 16.0 mo; HR, 0.71). Regardless of age, the mTTF was longer and the 3-month TFR was lower in the RIB + ET arm than the combo CT arm. The median time to response (mTTR), overall response rate (ORR), and clinical benefit rate (CBR) were similar between the two tx arms in both age groups. Conclusions: This analysis demonstrated a clinically meaningful PFS benefit and improved secondary outcomes with 1L RIB + ET over combo CT along with similar treatment responses in both tx arms in pts aged < 40 y as well as in those ≥ 40 y with aggressive HR+/HER2− ABC. This analysis supports RIB + ET as a preferred tx option in this pt population, including younger pts aged < 40 y. Clinical trial information: NCT03839823 . [Table: see text]

A phase 2 study of alrizomadlin, a novel MDM2/p53 inhibitor, in combination with pembrolizumab for treatment of patients with malignant peripheral nerve sheath tumor (MPNST).

e14627 Background: MPNST is a rare and aggressive soft tissue malignancy accounting for 10% of all soft tissue sarcomas. This disease is characterized by high risk of local recurrence and distant metastasis, and there is no current effective standard of care treatment option for patients with MPNST, with the only curative option of complete resection. Therefore, further treatment options are warranted. Investigational mouse double minute 2 (MDM2) inhibitor alrizomadlin restores TP53 function, activating p53-mediated apoptosis in tumor cells. Alrizomadlin also functions as a host immunomodulator and may restore antitumor activity in patients with MPNST that progressed on PD-1/PD-L1 inhibitors. Methods: This US/Australian multicenter trial evaluated alrizomadlin combined with PD-1 inhibitor pembrolizumab in patients with MPNST that progressed on available therapy or in those for whom therapy was unavailable. ECOG performance status was between 0-2 for eligible patients. Alrizomadlin 150 mg was administered orally every other day for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg intravenously for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 12, 2022, preliminary clinical results are reported for 24 patients with MPNST, of whom 16 were male, with a median (range) age of 35 (14-73) years. Treatment (alrizomadlin or pembrolizumab)-related adverse events of any grade (>10%) were reported in 18 patients. They included nausea (41.7%), vomiting and anemia (37.5% each), fatigue and diarrhea (33.3% each), thrombocytopenia (25.0%), and decreased leukocyte and lymphocyte counts (12.5% each). A total of 12.5% of patients reported treatment-related serious adverse events, including colitis, abdominal pain, diarrhea, and pericardial effusion. Among17 efficacy evaluable patients, the clinical benefit rate, as defined by the combination of overall response rate and stable disease for ≥ 4 cycles, was 53% per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1) and iRECIST. The median (range) treatment duration was 10 (4-20) cycles. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates meaningful clinical benefit in patients with MPNST for whom standard of care therapy is unavailable. Internal study identifiers: APG-115-US-002. Clinical trial information: NCT03611868 .

NOTOS: A pivotal study of navtemadlin, a first-in-class mouse double minute 2 inhibitor (MDM2i), in patients (pts) with TP53 wild-type (TP53WT) Merkel cell carcinoma (MCC) for whom anti PD-1/L1 therapy has failed.

TPS9600 Background: There are no approved therapies for pts with MCC for whom an anti PD-1/L1 agent has failed. The high rate of non-responsive disease after anti PD-1/L1 therapy together with high mortality rate and the absence of a standard of care in this setting highlight the urgent unmet need for effective novel therapies. Approximately 80% of MCC tumors carry the oncogenic Merkel cell polyoma virus (MCPyV) and most cases are TP53WT. Oncoproteins from MCPyV inhibit p53 tumor suppressor functions by activating MDM2. Navtemadlin, a potent, selective, orally available MDM2i, overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT MCC tumors. Navtemadlin is the first targeted therapy to show single-agent activity in pts with metastatic MCC for whom anti-PD-1/L1 has failed (Wong ASCO 2022). In the dose finding study, evaluable pts (n=8) receiving the recommended phase 2 dose of navtemadlin (180 mg QD on Day 1-5/28-day cycle) demonstrated a 25% confirmed objective response rate (ORR), 38% unconfirmed + confirmed ORR, and 63% disease control rate. The median duration of response was not reached (range, 6-16.2+ months [mos]) and median time to treatment response was 4.1 mos (range, 1.2-7). Responses to navtemadlin were highest in those pts with no prior chemotherapy (chemo; Wong ASCO oral 2022). In pts receiving navtemadlin at doses of ≥180 mg, an ORR of 40% was reported with no prior chemo (n=15) versus 14% in those who received prior chemo (n=14, Wong ASCO oral 2022). Navtemadlin demonstrated an acceptable safety profile with the most common treatment emergent adverse events (TEAEs) cytopenias, nausea, vomiting, diarrhea, and fatigue. Grade 3/4 TEAEs were 32% anemia, 32% lymphopenia, and 19% thrombocytopenia (Wong 2022). Based on this encouraging data, the NOTOS study (navtemadlin induces p53-driven apoptosis in Merkel cell carcinoma) will evaluate the safety and efficacy of navtemadlin in two post PD-1/L1 treated cohorts: chemo-naive pts and chemo treated pts. Methods: Adults with MCC for whom anti PD-1/L1 therapy has failed, who have ≥1 measurable lesion per RECIST v1.1, ECOG PS 0-1 and TP53WT MCC by central testing will receive 180 mg QD on days 1-5 of a 28-day cycle until disease progression, unacceptable toxicity, death or withdrawal of consent. The primary endpoint is ORR per RECIST v1.1 by blinded independent review. Secondary endpoints include ORR per investigator, duration of response, progression-free survival, overall survival, clinical benefit rate (including stable disease for ≥10 wk, partial response or complete response), and safety. The NOTOS trial is currently enrolling (NCT03787602). Clinical trial information: NCT03787602 .

Dose expansion results of the bifunctional EGFR/TGFβ inhibitor BCA101 with pembrolizumab in patients with recurrent, metastatic head and neck squamous cell carcinoma.

6005 Background: Pembrolizumab (P) is approved to treat patients (pts) with recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). BCA101 is a first-in-class bifunctional EGFR antibody fused to a TGFβ immune modulating payload which is well tolerated and has clinical activity as monotherapy and in combination with pembrolizumab in advanced solid tumors (ESMO 2022 731MO). Here we report the results from the interim analysis of an expansion cohort combining BCA101+P as first line therapy in R/M HNSCC. Methods: This ongoing single-arm, open-label multicenter dose expansion cohort enrolled pts with R/M HNSCC with a tumor PD-L1 CPS≥1 with no prior systemic therapy for R/M disease, ECOG 0-1, and measurable disease (RECIST v1.1). Pts received BCA101 (1500 mg IV on days 1, 8, 15) with P (200 mg IV on day 1) every 21-days. Primary endpoint: safety; secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS). Exploratory: molecular and immunologic predictors of response. A Simon optimal two-stage design was employed: among 18 evaluable pts in stage 1, >3 pts in response triggered continuation to stage 2 enrolling 21 additional pts targeting an ORR>35%. Results: From 2/2022 to 1/2023, 20 pts enrolled while 18 were evaluable (had first restaging scans) in stage 1. Pts were more often men (n=13, 65%) with a median age of 66 (range: 31-77). Oropharynx (10, 50%) [7/10 (70%) were HPV/p16-pos] and oral cavity (7, 35%) were the most common primary subsites (larynx/hypopharynx: 3). Fifteen (75%) had distant metastatic disease. The ORR in stage 1 was 44% (8 PRs, 4 SD) with a clinical benefit rate (CBR=PR+SD) of 67%; 7/12 (58%) HPV-neg pts achieved a response. Median DOR not reached, but median time on-treatment was 6.7 months (range: 2.7-11.0+) among responders. Ten pts discontinued therapy; all but 1 for PD (n=1 for toxicity). Grade 3+ treatment-related adverse events (TRAEs) were observed in 4 pts (20%, most common: anemia). No treatment-related deaths were observed. Acneiform rash was the most common TRAE of any grade (15, 75%). PFS and OS estimates are forthcoming. Eight (44%) had baseline PD-L1 CPS scores of 0-19, while ten (56%) were ≥20. Stage 2 is actively enrolling with completion of accrual expected by the meeting. Conclusions: Stage 1 of this dose expansion cohort of BCA101+P shows encouraging anti-tumor activity with additive potential, particularly among HPV-neg pts; and the combination is well tolerated among this R/M HNSCC population. Further investigation is warranted. Study funded by Bicara Therapeutics and conducted in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. USA (NCT04429542). Clinical trial information: NCT04429542 . [Table: see text]

A phase II study of tinostamustine in patients (pts) with advanced solid tumours.

3021 Background: The novel multi-action alkylating deacetylase inhibitor tinostamustine improves drug access to DNA strands within cancer cells, breaks them and counteracts damage repair. Tinostamustine was well tolerated with signals of efficacy during dose escalation in pts with advanced solid tumours (Mita et al. Cancer Res 2019;79[13 Suppl]:CT023). Methods: This was an open-label Phase I/II trial of single agent tinostamustine in pts with advanced solid tumours (NCT03345485). The Phase II primary endpoint was objective response rate (ORR: complete response + partial response [PR]) and the rate of stable disease ≥4 mo duration following the recommended Phase II dose (RP2D; 80 mg/m2 over 1 h on Day 1 & 15 of each 4-wk treatment cycle). Secondary endpoints included progression-free (PFS) and overall survival (OS), and duration of response. Eligible pts were ≥18 y with life expectancy ≥3 mo, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, histologically confirmed diagnosis of advanced/metastatic soft tissue sarcoma (STS), small-cell lung (SCLC), triple-negative breast (TNBC), ovarian (OvCa) or endometrial cancer, progression following ≥1 prior line of therapy, with no other standard therapy with proven clinical benefit available or recommended. Results: 36 pts were enrolled and evaluable for response; mean ± SD age 59.6 ± 11.2 y, 83.3% female, 80.6% Caucasian, all ECOG PS ≤1, median of 3 (range 1–9) lines of prior therapy. At data cut-off (30 November 2022) pts had received a median of 2 (range 1–8) cycles of tinostamustine. 19 pts (52.8%) discontinued treatment due to progressive disease. One pt with synovial sarcoma (STS cohort; n=10) and one pt with OvCa (n=12) achieved a PR. Overall, 14 pts (38.9%) had stable disease ≥4 mo (0/4 SCLC; 3/10 STS; 3/4 TNBC; 5/12 OvCa; 3/6 endometrial cancer); Clinical Benefit Rate, 44.4% (95% CI: 27.9%, 61.9%). Median PFS and OS for all treated pts were 2.2 mo (95% CI 1.8, 3.3 mo) and 5.5 mo (95% CI 4.1, 15.0 mo), respectively. All pts experienced ≥1 treatment-emergent adverse event (TEAE), with 56.7% of events considered related to tinostamustine. Serious tinostamustine-related AEs were reported in 30.6% of pts (13 haematological events); 10 (27.8%) pts discontinued treatment due to TEAEs (platelet count decreased: 5 events in 3 pts, including 2 Grade 3 and 1 Grade 4; all other events n=1). Two pts experienced fatal TEAEs; n=1 each of intra-abdominal haemorrhage (considered related to study drug), hypoxia/dyspnoea (not study drug related). Conclusions: Tinostamustine demonstrated modest signals of efficacy, with 2 pts achieving a PR, and manageable tolerability in pts with advanced solid tumours for whom no other standard therapy with proven clinical benefit was available or recommended. Further studies are needed to fully explore the benefits of tinostamustine in solid tumours. Clinical trial information: NCT03345485 .

Phase 1 dose-expansion study of oral TP-1287, a cyclin-dependent kinase 9 (CDK9) inhibitor, in patients with Ewing sarcoma (EWS).

TPS11589 Background: Cyclin-dependent kinase 9 (CDK9) blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as myeloid cell leukemia-1 (MCL-1) and c-MYC. CDK9 overexpression has been observed in sarcoma patients (pts), and CDK9 has emerged as a potential therapeutic target in pts with sarcoma. TP-1287 is an investigational orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. In preclinical studies, TP-1287 has been shown to decrease MCL-1 expression and phosphorylation of RNA polymerase II (RPB1), and inhibit tumor growth in an Ewing sarcoma (EWS) mouse model. Phase 1 dose-escalation in solid tumors has completed and TP-1287 is being investigated in a dose expansion cohort in pts with EWS (NCT03604783). The design of the expansion part of the trial in pts with EWS is herein described. Methods: Up to thirty pts with EWS will be enrolled in this dose expansion cohort. Key eligibility criteria are age ≥18 years (≥12 years, if weight ≥40 kg); histologically confirmed locally advanced or metastatic unresectable EWS; received 1 to 5 prior lines of treatment including an anthracycline; one or more measurable tumors per the RECIST v1.1; ECOG performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status; no treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives. Eligible pts will be treated with oral TP-1287 monotherapy RP2D established from the dose escalation part (11 mg BID, continuous dosing in a 28-day treatment cycle) and will continue treatment until treatment-related adverse event or disease progression. Assessments will be performed on Day 1 and Day 15 of each cycle. Tumor response assessment will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objectives are objective response rate (ORR) and clinical benefit rate (CBR) ; secondary objectives are median progression-free survival (PFS), PFS rate at 16-weeks and 24-weeks and safety; and exploratory objectives include evaluation of systemic exposure and pharmacodynamics. Safety data will be reviewed on an ongoing basis and a Bayesian approach will be used to assess the efficacy data. Statistical analysis for safety and efficacy parameters will be primarily descriptive in nature. EWS dose expansion cohort is currently recruiting in the United States. Clinical trial information: NCT03604783 .

Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)–resistant succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST).

11540 Background: Treatment of pts with GIST has been transformed by TKIs. However, treatment resistance is a challenge in managing locally advanced or metastatic disease. Pts with SDH-deficient GIST typically present with multifocal and multinodular disease that is insensitive to most TKIs. Olverembatinib is an investigational novel, potent, orally active third-generation TKI with promising activity against GIST in multiple preclinical models. Methods: The aim of this study was to evaluate the safety and efficacy (per RECIST v1.1) of olverembatinib in pts with TKI-resistant metastatic SDH-deficient GISTs (confirmed by immunohistochemistry). Olverembatinib was administered orally once every other day (QOD) in 28-day cycles. Results: As of January 15, 2023, 20 pts with SDH-deficient GIST had received ≥ 1 dose of olverembatinib (median age, 30 [14-56] years), and 19 had received 1 to TKIs (50% of pts ≥ 3; Table). The dose range of olverembatinib was 20 to 50 mg (50 mg cohort [n = 6]; 40 mg [n = 8]; 30 mg [n = 6]). The median (range) treatment duration was 7.8 (1.81-42.3) months. A total of 5 of 20 pts experienced partial response (PR) as the best response. Of 16 evaluable pts treated with > 4 cycles of olverembatinib, the clinical benefit rate (CBR; complete response + PR + stable disease > 4 cycles) was 93.8% (15/16); the longest treatment duration was 42 months. All pts experienced treatment-emergent adverse events (AEs; most, grade 1 or 2); 2 pts experienced grade 3 AEs; the only hematologic AE with an incidence rate ≥ 20% was anemia (55%). A total of 15 (75%) pts experienced treatment-related AEs (grade 3 neutropenia [n = 1]). No treatment-related serious AEs were reported. Conclusions: Olverembatinib was well tolerated up to 50 mg QOD and showed antitumor activity in pts with TKI-resistant, SDH-deficient GIST. A total of 5 PRs were reported among 20 evaluable pts and 15 SDs among 16 pts treated for ≥ 4 cycles (98.3% CBR). These promising findings warrant further investigation. Internal study identifier: HQP1351SJ003. Clinical trial registration: NCT03594422 . [Table: see text]

EvERA Breast Cancer (BC): Phase III study of giredestrant + everolimus vs exemestane + everolimus in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC (ER+, HER2– LA/mBC).

TPS1119 Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in pts with ER+, HER2– mBC in the first-line setting. Fulvestrant ± a CDK4/6i, and everolimus + exemestane are the current approved second-line regimens. However, therapeutic resistance to some ETs, such as aromatase inhibitors, can arise from ESR1 mutations (m) driving estrogen-independent transcription and proliferation. Current post-CDK4/6i treatment options are suboptimal. New therapy options are therefore needed to reduce this risk and to improve outcomes, tolerability, quality of life, and adherence to treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy and is active regardless of ESR1-mut status. While Phase I SERD combination data in the post-CDK4/6i setting are encouraging, there are no randomized combination data. Combining giredestrant and everolimus may improve outcomes after CDK4/6is and in pts with ESR1m tumors. Methods: evERA BC (NCT05306340), a Phase III, global, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant + everolimus vs. exemestane + everolimus in pts with ER+, HER2– LA/mBC who had previous treatment with a CDK4/6i and ET in the LA/mBC or adjuvant setting. Pts will be randomized to either giredestrant (30 mg) + everolimus (10 mg) by mouth (PO) every day (QD), or exemestane (25 mg) + everolimus (10 mg) PO QD. Pts will receive treatment until disease progression or unacceptable toxicity. Pts will use a dexamethasone mouth rinse 4 times QD for 8 weeks concurrently with study treatment. Eligibility: Female/male pts ≥ 18 years with ER+, HER2– LA/mBC and disease progression ≥ 6 months (mo) after initiating ET + CDK4/6i in the LA/mBC setting (and ≥ 4 mo on most recent ET, if ET + CDK4/6i was not the most recent therapy received), or relapsed either while taking or within 12 mo of exposure to combination adjuvant ET (≥ 12 mo) + CDK4/6i (≥ 6 mo), and available blood sample for circulating tumor DNA central testing for ESR1m status. Men and pre-/perimenopausal women will receive a LHRH. Co-primary endpoints: Investigator-assessed progression-free survival (per RECIST v1.1) in the intent-to-treat and ESR1m populations. Secondary endpoints: Overall survival; objective response rate; duration of response; clinical benefit rate; pt-reported outcomes; safety; pharmacokinetics. Co-primary endpoint analyses will use a two-sided stratified log-rank test at an overall 0.05 significance level. An independent data monitoring committee will be in place for safety. Target enrollment is 320 pts, and this study is currently recruiting. Encore from SABCS 2022 (OT2-01-07). Clinical trial information: NCT05306340 .

Efficacy and safety of tenalisib, a PI3K δ/γ and SIK3 inhibitor, in patients with locally advanced or metastatic breast cancer: Updated results from an on-going phase II study.

1064 Background: Several studies have shown that the upregulation of the PI3K–AKT–mTOR pathway interacts with the Estrogen Receptor pathway and confers endocrine resistance. Elevated Salt Inducible Kinase-3 (SIK3) expression, which often is overexpressed breast cancer, is shown to contribute to tumorigenesis. Tenalisib (RP6530), a highly selective, PI3Kδ/γ and SIK3 inhibitor, has shown promising efficacy in T-cell lymphoma with a distinct safety profile. Tenalisib’s major metabolite, IN0385 is a SIK3 inhibitor. Breast cancer cell line studies have demonstrated that tenalisib potentiated the activity of paclitaxel and doxorubicin. The aim of this phase II study was to investigate the efficacy and safety of single-agent tenalisib in patients (pts) with HR+ HER2- locally advanced or metastatic Breast cancer. Methods: This randomized, open-label study was designed to evaluate two doses (800 mg BID and 1200 mg BID) of Tenalisib in MBC pts (including TNBC) whose disease had progressed following at least one line of therapy. Tenalisib was administered orally daily for every 28 days cycles until the disease progression. The study would enroll forty pts (20 at each dosage level), with the primary outcome being the proportion of patients who did not have disease progression at the end of six months. Other outcomes were investigator-assessed ORR, PFS, DCR (DCR=CR+PR+SD) and Clinical Benefit Rate (CBR= CR+PR+SD≥24 weeks) as per RECIST v1.1 criteria. Results: The trial enrolled 40 pts. Pts had a median of 3 (range 1-7) prior therapies of which, 87% pts had prior endocrine therapy, which included 40% pts treated with an aromatase inhibitor and 30% of pts treated with fulvestrant as their last therapy respectively. Prior chemotherapy in any setting included taxane (60%), and anthracycline (47.5%). The median age was 63.8(31-71) years, 77.5% pts had visceral disease, and 95.0% had 2 or more metastatic lesions. As of 06-Feb-2023, of the 40 pts, 5 pts (12.5%) showed PR and 22 (55%) had SD. The CBR was 57.5% while the DCR was 67.5%. The median duration of response in PR pts and median duration of clinical benefit were 9.36 and 7.46 months respectively. The progression free survival (PFS) was 5.6 months (range: 0.93 to 15.26+ months). Drug related AEs were manageable. The most common AEs (≥10%) of any grade were transaminitis, GGT elevation, and rash. Grade 3/ 4 events were limited to GGT elevation (12.5%), and transaminitis (12.5%). Discontinuations due to related AEs were infrequent (<5%) and limited to two events (one event each of rash and GGT elevation). Conclusions: Based on the data from the ongoing study, tenalisib shows encouraging efficacy as a single agent in pts with relapsed/refractory HR+ HER2- difficult to treat MBC patients. Updated efficacy and tolerability data will be provided at the time of presentation. Clinical trial information: NCT05021900 .

Racial differences in outcomes of patients with relapsed/refractory multiple myeloma treated with selinexor.

e20016 Background: Multiple Myeloma (MM) is the 2nd most common hematologic malignancy in the US, though survival in patients with MM has improved over the past decade. Survival improvements in African Americans (AAs) have been smaller, which may be due to disparity in access to therapies. There are also key differences in MM biology between races, including higher rates of IgA disease and genetics. Given underrepresentation of minorities in clinical trials, we analyzed whether outcomes were similar between AAs and other races in the phase 2 STORM trial (NCT02336815) of selinexor. Selinexor, an oral, first-in-class selective inhibitor of nuclear export via exportin 1, has proven efficacy for refractory MM. To our knowledge, this is the first race subgroup analysis of selinexor in any clinical trial. Methods: Pts from STORM who received study drug (N = 202) were included. Pts with heavily pretreated MM, including triple-class and penta- refractory MM refractory to the last line of therapy were given selinexor (80mg) + dexamethasone (20mg) twice weekly. We conducted a retrospective racial subgroup analysis. Cox proportional modeling was used to determine the hazard ratio (HR) for MM relapse between races controlling for covariates. Results: AAs represented 17% of pts (35 AAs, 148 White, 2 Asian, 11 other and 6 missing). AAs were younger compared to other races (median age 60.7 vs 65.3) with more females (74.3% vs 40.7%). Cytogenetic abnormalities and R-ISS staging were similar between races. AAs had a median progression free survival (PFS) of 6.5 mos (95% CI 4.7, NR) compared with 3.7 mos (95% CI 2.8, 4.6; p = 0.035) for other races. Overall response rate (ORR) was 25.7% (95% CI 12.5, 43.3) in AA pts vs 23.4% [17.2, 30.5] in other races), clinical benefit rate (37.1% [21.5, 55.1] vs 35.9% [28.7, 43.7]), median duration of response (5.6 mos [2.1, NR] vs 5.3 [3.6, NR]), median duration of treatment (9 wks [IQR 3-22 wks] vs 8 wks [4-16 wks]), and mean dose intensity (117.9 mg/wks [STD 35.1] vs 117.1 [34.7]) were similar between grps. Rates of Adverse Events (AEs) ≥ grade 3 (94.3% vs 95.8%), and AE-related dose reductions (45.7% vs 54.5%), discontinuations (22.9% vs 30.5%), and deaths (5.7% vs 10.8%) were also similar. The adjusted HR for MM relapse in AAs was 0.45 (95% CI 0.22, 0.92; p = 0.028) after controlling for gender, age and prior therapy. Conclusions: This subgroup analysis showed that compared with other races, AAs pts were younger and included a greater percentage of women. Although ORRs were similar, AAs had a longer PFS compared with other races after adjusting for covariates. Despite small sample size, the differences were statistically significant. It is unclear if the better PFS reflects a different biology, pharmacology of selinexor or both. Dose adjustments and tolerability were relatively comparable. These results could assist in the placement of selinexor in the treatment sequence of relapsed refractory MM for AAs.

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The desmoid tumors (cohort 27).

11516 Background: Dual inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors is efficacious in many malignancies, but their potential role in numerous rare solid cancers is yet to be established. Desmoid tumors (DT; fibromatosis) are rare tumors of the soft tissue, and the mainstay of treatment is surgery (Richard Riedel, 2022). The utility of immunotherapy in this group of patients has not been explored. This study presents the first results of ipilimumab and nivolumab used in the DT cohort (#27) 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 includes objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)). Secondary endpoints include progression-free survival (PFS), overall survival (OS), stable disease (SD) > 6 months, and toxicity. Results: Sixteen evaluable patients (median age 37) with desmoid tumors were analyzed. Location of the tumors are: 8, abdomen; 3, lower limb: 2, upper limb; 2, pelvis; and 1, neck. ORR was 18.8% with 3 patients attaining PR: 40% regression with ongoing duration of response (DoR) at over 30+ months; 83% regression (PFS 16 months); and 71% regression (PFS of 8.4 months). Of note, 3 patients had SD (3/16, 18.8%) with some shrinkage of the tumors and a durable response; 23% regression with PFS of 1820+ days; 6% regression with PFS of 902 days; 1% regression with PFS of 1147+ days. Overall clinical benefit rate (CBR; no progression > 6 months) was 62.5%. The median PFS was 17.9 months, 6-month PFS 69%, 1-year PFS 62%. All patients were alive at 1 years; median OS was not assessable as 14 patients are showing ongoing survival. The most common adverse events were fatigue (43.8%, n = 7), nausea (37.5%, n = 6), hypothyroidism (31.3%, n = 5), diarrhea, hyperthyroidism, headache, and adrenal insufficiency (25%, n = 4 each). There were 8 incidents (50%) of grade 3-4 adverse events. 7 adverse events led to discontinuation. There were no grade 5 adverse events. Conclusions: Ipilimumab plus nivolumab in treatment of desmoid tumors resulted in an ORR of 18.8% and CBR of 62.5% with durable responses seen. This is the first prospective study demonstrating efficacy of the combination in this rare disease. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in desmoid tumors are needed. Clinical trial information: NCT02834013 .

Olaparib (O) in advanced triple negative breast cancer (aTNBC) patients (pts) with BRCA1/2 promoter methylation: GEICAM/2015-06 study (COMETA-Breast).

1093 Background: Epigenetic silencing by aberrant BRCA1/2 promoters’ methylation ( BRCA-meth) can be responsible for a dysfunctional BRCA protein. BRCA-meth occurs in 15-57% of TNBC pts. BRCA-meth breast cancer (BC) display pathologic features and genetic profiles like germline BRCA1/2-mutated (g BRCA1/2m) carriers. O is a PARP inhibitor approved for treating g BRCAm HER2-negative advanced BC (aBC) pts. These are the results of a phase II study assessing the O efficacy in aTNBC pts with BRCA1/2-meth (NCT03205761). Methods: We included aTNBC pretreated pts (≥1 line) with centrally confirmed somatic BRCA1/2-meth (in most recent lesion(s) available) and no g BRCA1/2m. O 300mg b.i.d. was administered. BRCA1/2 CpG island was considered methylated if value was ≥25%. Overall response rate (ORR) (complete response [CR] + partial response [PR]) according to RECIST 1.1) was the primary objective. Thirty-one evaluable pts were required based on an optimal 2-stage Simon’s design (α error=0.05, 1-β error=80%), estimating an ORR increase of 24%, with a null hypothesis of 30%. Whole exome/transcriptome and 105-genes NGS assays (Tempus xE & xF) were performed on pretreatment tumor and sequential ctDNA of a long-term responder. Results: Eleven pts received ≥1 cycle of O (ITT population). Median age was 51 years (37-64), and 8 pts were postmenopausal. All M0 pts at diagnosis had neo-/adjuvant chemotherapy (CT). Median O exposure duration was 8 (1-88) weeks and relative dose-intensity was 97% (76-100), with any dose modifications in 6 pts. ORR was 9% (1 PR/11; 95% CI, 0.2-41). Clinical benefit rate (CR + PR + stable disease of any duration) was 36% (4/11; 95% CI, 11-69). Most pts (n=9) discontinued O due to BC progression. Median PFS was 2 months (95% CI, 1-4), and median OS was 9 months (95% CI, 1-14). One pt with confirmed PR was on O for >20 months. AEs were reported in 3 pts in line with O safety profile. No AE led to O discontinuation and no SAEs were reported. The statistical assumptions for the 1st Simon’s model stage were not met (≥ 4/12 pts with CR or PR), so the recruitment did not proceed onto the 2nd stage. Preliminary NGS analysis on the long-term responder identified alterations on tumor (TP53, BCL11A, MYC) and on-treatment ctDNA (PMS2). Conclusions: In this proof-of-concept study, O did not show clinically nor statistically significant antitumor activity in pretreated aTNBC pts with BRCA1/2-meth . Clinical trial information: NCT03205761 . [Table: see text]

TACTIVE-U: Phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer.

TPS1121 Background: ARV-471, an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in a phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. The CDK4/6 inhibitors abemaciclib and ribociclib are approved in combination with endocrine therapy as first- and second-line treatment for ER+/HER2- advanced or metastatic breast cancer; abemaciclib is also approved as monotherapy and in combination with other agents in additional breast cancer settings. ARV-471 combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Here we describe the first sub-studies of the open-label, phase 1b/2 TACTIVE-U umbrella study, which evaluate the safety and clinical activity of ARV-471 plus abemaciclib (sub-study A; NCT05548127) and ribociclib (sub-study B; NCT05573555) in patients with ER+/HER2- advanced or metastatic breast cancer. Future combination sub-studies will be included in TACTIVE-U. Methods: Patients eligible for sub-studies A and B are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection with ≥1 measurable lesion by RECIST 1.1, and have received ≤2 lines of prior therapy for advanced or metastatic disease and 1 line of any CDK4/6 inhibitor–based regimen in any setting. In sub-studies A and B, patients will receive ARV-471 orally once daily (QD) continuously in a dose escalation/de-escalation approach. In sub-study A, abemaciclib will be given orally twice daily continuously, and in sub-study B, ribociclib will be given orally QD for 21 days followed by 7 days off treatment. For both sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of ARV-471 in combination with abemaciclib or ribociclib. Secondary endpoints of phase 1b are antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), progression free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. Phase 2 further evaluates the antitumor activity of the combinations; the primary endpoint is ORR and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Clinical trial information: NCT05548127 , NCT05573555 .