Fort Wayne Medical Institute

Adavosertib is a highly selective, small molecule Wee1 inhibitor that sensitizes tumor cells to cytotoxic agents. We report results from the lead-in cohorts of two phase II studies: carboplatin/pemetrexed plus adavosertib versus carboplatin/pemetrexed in first-line metastatic non-squamous non-small-cell lung cancer (NSCLC) (NCT02087241); and docetaxel plus adavosertib versus docetaxel in recurrent NSCLC (NCT02087176). Both lead-in cohorts assessed early safety and efficacy (objective response rate [ORR]). First-line metastatic treatment was carboplatin (area under the curve to 6 h [AUC6]) plus pemetrexed 500mg/m2 intravenously on day 1, every 21 days; recurrent treatment was docetaxel 75mg/m2 intravenously on day 1 plus prophylactic granulocyte-colony stimulating factor 6mg subcutaneously on day 4 every 21 days. All patients received adavosertib 225mg twice daily orally on days 1-3 (five doses). After a planned safety analysis of the first-line trial, dose and schedule were modified to reduce toxicity. First-line: 14 patients were enrolled in four treatment cohorts. Median time on trial was 17.3 weeks, with an ORR of 29%. The most common adverse events were diarrhea (50%), nausea (50%), vomiting (50%), anemia (43%), neutropenia (43%), decreased appetite (43%), and dehydration (43%). Recurrent: 32 patients were enrolled. The ORR was 9%. The most common adverse events were diarrhea (66%), anemia (50%), nausea (47%), fatigue (47%), vomiting (44%),and thrombocytopenia (41%). Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care. ClinicalTrials.gov, NCT02087241 and NCT02087176.

105 Background: SEZ6 is a potential neuroendocrine lineage marker that is expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine neoplasms (NENs). NENs have a significant unmet need for novel effective targeted therapies. ABBV-706, a unique antibody-drug conjugate comprising a SEZ6-directed antibody conjugated to a potent topoisomerase 1 inhibitor payload, is being evaluated in a phase 1 study (NCT05599984) in patients (pts) with advanced solid tumors. Preliminary results from ABBV-706 monotherapy dose escalation showed a manageable safety profile with promising efficacy in SCLC and NENs ( J Clin Oncol 2024;42[suppl 16]: abs 3001). Herein, updated safety and efficacy of ABBV-706 monotherapy in NENs are presented. Methods: Pts (≥18 yr) with relapsed/refractory high-grade NENs (well-differentiated grade [G] 3 neuroendocrine tumors [G3 NETs] and poorly differentiated neuroendocrine carcinomas [NECs]), atypical lung carcinoid, and medullary thyroid cancer (MTC) were enrolled in dose-escalation and -expansion cohorts of a phase 1, open-label study. Pts received ABBV-706 monotherapy IV at 1.3–3.5 mg/kg once every 3 weeks. Primary study objectives are assessment of safety, PK, and efficacy. SEZ6 expression is evaluated retrospectively. Results: As of Aug 27, 2024, 191 pts were enrolled overall, including 64 with NENs. In the NEN cohort, median age was 63 yr (range 33–86) and pts had received a median of 3 (range 1–8) prior therapies. NEN histologies were large cell NEC (LCNEC; 22%, n=14), gastro-enteropancreatic NEC (GEPNEC; 19%, n=12), MTC (9%, n=6), neuroendocrine prostate carcinoma (NEPC; 8%, n=5), G3 NETs (8%, n=5), and other NECs (34%, n=22). The safety profile for ABBV-706 was similar across NEN subtypes and aligned with the entire study population. For the overall study population, TEAEs occurred in 184 (96%) pts and G≥3 in 134 (70%). Most frequent hematologic TEAEs were anemia (58%; G≥3: 45%), neutropenia (44%; G≥3: 33%), and thrombocytopenia (35%; G≥3: 21%). Most frequent nonhematologic TEAEs were fatigue (45%; G≥3: 3%) and nausea (38%; G≥3: 2%). Unadjudicated pneumonitis/interstitial lung disease rate was 4% (G≥3 in 2 pts). For the entire NEN cohort, the objective response rate (ORR) was 31.3% (20/64) and the clinical benefit rate was 92.2% (59/64). ORR by NEN type was: LCNEC, 28.6% (4/14); GEPNEC, 16.7% (2/12); NEPC, 60.0% (3/5); G3 NET, 60% (3/5); MTC, 16.7% (1/6); other NEC, 31.8% (7/22). The median duration of response was 5.59 mo (95% CI: 4.24, not estimable) and median progression-free survival was 6.80 mo (95% CI: 5.45, 7.75). Correlation analysis of efficacy with SEZ6 expression is ongoing. Conclusions: ABBV-706 showed preliminary efficacy in several high-grade NENs with a high unmet need, supporting its further development in specific subtypes. Clinical trial information: NCT05599984 .

Introduction: Ropeginterferon alfa-2b-njft (ropeg) was approved and recommended as a preferred cytoreductive treatment for polycythemia vera (PV). The approved regimen requires an initial dose of 100 μg or 50 μg if transitioning from hydroxyurea (HU) and up-titrations of 50 μg every 2 weeks to 500 μg maximumly. The time to achieve the plateau dose takes approximately 20 weeks. This study compares the approved regimen with a higher initial dose and accelerated dose titration (HIDAT) regimen. Methods: ECLIPSE-PV is a randomized, open-label, multicenter trial in patients with PV in the USA and Canada. Patients received ropeg either per the approved dosing schema or HIDAT regimen, i.e., 250 μg on day 0, 350 μg at week 2, and 500 μg from week 4 thereafter if tolerable. The primary endpoint is complete hematologic response (CHR) rate at week 24. CHR is defined as hematocrit <45%, white blood cells <10 × 109/L, platelets ≤400 × 109/L without phlebotomy in the previous 12 weeks. Secondary endpoints include molecular response, safety, tolerability, and quality of life. Conclusion: A total of 111 patients were randomized and the last patient was enrolled on June 21, 2024. As of November 12, 2024, the discontinuation rate was 14.4%, and 16 patients (14.4%) completed the study. The study is expected to be completed in the summer of 2025. This is the first prospective trial comparing two dosing regimens of ropeg. The results will inform the optimal treatment strategy for patients with PV.

Abstract Background: In patients (pts) with ER+/HER2− metastatic breast cancer (MBC) following progression on prior endocrine and CDK4/6i therapy, the EMERALD trial demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile for elacestrant versus standard of care endocrine therapy (SoC). Benefit was observed in all pts and in pts with ESR1 mutant MBC (ESR1-mut). EMERALD is the only oral SERD monotherapy pivotal trial where all pts were pretreated with CDK4/6 inhibitor (CDK 4/6i). Here, we examine the impact of duration of prior CDK4/6i on PFS. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled pts with ER+/HER2- MBC who previously had 1-2 lines of endocrine therapy, mandatory CDK4/6i, and ≤1 chemotherapy; prior treatment with fulvestrant was allowed. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SoC (investigator’s choice of aromatase inhibitor or fulvestrant). If randomized to the control arm, patients who received prior fulvestrant were to receive an aromatase inhibitor, and vice versa. If two CDK4/6i were used in the metastatic setting (n=40), the cumulative duration was calculated. Results: A total of 478 pts were randomized (228 with ESR1-mut) between Feb 2019 – Oct 2020 (n=239, elacestrant; n=239, SoC). Overall survival was not yet mature, as of September 2nd 2022. Updated PFS results show statistically significant results in favor of elacestrant, both in all pts and in pts with ESR1-mut. The duration of prior CDK4/6i in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6i in the metastatic setting (n=465), the longer the PFS on elacestrant versus SoC (Table 1). Updated safety data were consistent with previously reported results. Most of the adverse events (AEs), including nausea, were grade 1 and 2, and only 3.4% and 0.9% of the pts discontinued trial therapy because of an AE on elacestrant and SoC, respectively. A low percentage of pts received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia. Conclusions: EMERALD is the first phase 3 trial to demonstrate a significant PFS improvement versus SoC in all pts and in the subgroup with ESR1 mutations in pts with ER-positive/HER2-negative MBC with 1-2 prior lines of endocrine treatment ± one line of chemotherapy. Elacestrant demonstrated longer PFS versus SOC that was positively associated with the duration of prior treatment with CDK4/6i, which was more pronounced in pts with ESR1-mut MBC. In this 2nd and 3rd line setting, elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for pts with ER+/HER2- MBC. Table 1: PFS estimates in the elacestrant and SoC arms based on different cut-off points for the duration of prior CDK4/6i. Citation Format: Aditya Bardia, Francois-Clement Bidard, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frederic Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Donatienne Taylor, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, Jose Angel García-Sáenz, Emilio Bria, Marina Elena Cazzaniga, Philippe Aftimos, Javier Cortés, Giulia Tonini, Tarek Sahmoud, Nassir Habboubi, Krzysztof Grzegorzewski, Virginia Kaklamani. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-01.

TPS278 Background: The standard of care (SoC) for first-line management of non-microsatellite instability-high/deficient mismatch repair (non-MSI-H/dMMR; also referred to as microsatellite-stable/proficient MMR) mCRC includes systemic chemotherapy and targeted agents that improve overall survival (OS). However, in patients (pts) with later-line disease, current SoC treatments (including regorafenib and TAS-102) are associated with poor responses (objective response rates [ORR] &lt; 2%) that are not durable, limited OS (6.4-7.1 months) and substantial toxicity. Immunotherapies targeting programmed death (PD)-1 show promising efficacy in pts with MSI-H mCRC; however, single-agent immunotherapy does not provide benefit for pts with non-MSI-H/dMMR mCRC. Therefore, additional treatment options with an improved benefit-risk profile in pts with later-line non-MSI-H/dMMR mCRC are needed. Emerging data suggest that dual inhibition of LAG-3 and PD-1 has the potential to boost immune surveillance and elicit durable responses in non-MSI-H/dMMR mCRC. RELA is a human immunoglobulin G4 lymphocyte-activation gene 3 (LAG-3)-blocking antibody that enhances the antitumor immune response. Here we describe the RELATIVITY-123 study investigating NIVO + RELA FDC in later-line mCRC. Methods: RELATIVITY-123 (NCT05328908) is a phase 3, randomized (1:1), open-label study to assess NIVO + RELA FDC versus regorafenib or TAS-102 in adult pts with later lines of non-MSI-H/dMMR mCRC. Inclusion criteria include metastatic or recurrent unresectable CRC, recent progression following 1–4 prior lines of treatment (or documented intolerance of prior systemic chemotherapy regimens), ECOG performance status ≤ 1, and measurable disease per RECIST version (v) 1.1. Exclusion criteria include confirmed MSI-H/deficient mismatch repair, prior treatment with an immunotherapy, regorafenib, or TAS-102 and history of significant cardiovascular disease, interstitial lung disease/pneumonitis, or autoimmune disease. Dual primary endpoints are OS in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. Secondary endpoints include ORR, progression-free survival, and duration of response by blinded independent central review and investigator per RECIST v1.1, safety, and time until definitive deterioration-physical function and -quality of life in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. The study initiated in April 2022 and is enrolling globally. Clinical trial information: NCT05328908 .

Purpose:To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt.Patients and Methods:We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1–28) + azacitidine (75 mg/m2 days 1–7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.Results:Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18).For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt.For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively.For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients.Conclusions:In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients.See related commentary by Green and Zeidner, p. 5235

Purpose:To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone.Patients and Methods:In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences.Results:Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03).Conclusions:Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.