LBA612 Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) status to evaluate novel neoadjuvant agents in high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Oral Paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar. Dostarlimab (D) is an intravenous (IV) PD-1 inhibitor. Methods: Women with tumors ≥ 2.5cm and MP high risk cancers (MP1 = MP high; MP2 = MP ultra-high) were treated starting Oct 5, 2020. Treatment included OPE (Oral P 205mg/m2 + encequidar 12.9mg) on days 1-3 weekly x 12 and D 500 mg IV given q 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q 2-3 weeks x 4. Patients with HER2+ disease received IV weekly trastuzumab (T) during the first 12 weeks. The control arm was weekly IV P x 12 with or without trastuzumab followed by AC q 2-3 weeks x 4. OPE + D was eligible to graduate [85% chance of success in a 300-person phase 3 neoadjuvant trial with a pCR endpoint] in any of the pre-defined signatures. Results: 113 (78 HR+HER2-, 17 HR-HER2- and 18 HER2+ patients) received OPE + D +/- T. The control arm included 388 historical controls (201 HR+Her2-, 156 HR-HER2-, 31 HER2+). 77 patients (70 HR+ and 7 HR-) were MP1 and 36 patients (24 HR+ and 12 HR-) were MP2. Safety events of note for OPE + D versus IV P include increased rates of nausea (85% vs. 72%) diarrhea (77% vs. 41%). There was no significant difference in rates of neutropenia (23% vs.17%). Peripheral neuropathy (37% vs. 64%) and alopecia (59% vs. 66%) were significantly decreased. Immune related adverse events (irAEs) were lower than expected. Conclusions: Although both OPE and D have both been shown to have efficacy in other settings, combination therapy with OPE + D did not graduate in any of the predefined subtypes. In the HR+ signature where we would not expect a benefit of D, we see equal response to OPE with decreased rates of peripheral neuropathy and alopecia, which suggest this oral agent may be an attractive alternative to IV P in this subgroup and is under consideration in ISPY 2.2. We did not observe the expected improvement in pCR rates seen with PD-1 inhibitors in the HR- or MP2 subtypes (over P alone historic control). In addition, the irAEs were less than expected. Together these findings suggest interference of OPE with D. A potential mechanism of interference could be change in microbiome with the use of OPE vs. IV P, as the microbiome is known to influence the efficacy of immunotherapy. The source of interference is being investigated. Clinical trial information: NCT01042379 . [Table: see text]
Abstract Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with ATM mutation (mut) or deletion (del) treated with O are reported. Methods: Eligible pts had solid tumors, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received O tablets (300mg) or capsules (400mg) orally twice daily until disease progression. Low accruing histology-specific cohorts with the same genomic alteration were collapsed into one histology-pooled cohort for this analysis. Primary endpoint was disease control (DC) (complete (CR) or partial (PR) response or stable disease at 16+ wks (SD16+)) (RECIST v1.1). For histology-specific cohorts a Simon 2-stage design with a null DC rate of 15% vs. 35% (power = 0.85; α = 0.10) requires 28 pts with futility stopping after 10 pts. For histology-pooled cohorts with sample size > 28, if the lower limit of a one-sided 90% CI is >15%, the null hypothesis of a DC rate of 15% is rejected. 2-sided 95% CIs were used for other efficacy endpoint estimates. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 39 pts with solid tumors (17 histologies) with ATM mut (n=36) or del (n=3) were enrolled from 6/2016 to 1/2019. 3 pts were unevaluable for efficacy. Table 1 shows demographics and outcomes. 1 CR (prostate), 2 PR (unknown primary) and 6 SD16+ were observed in pts with ATM mut for a DC rate of 25% (90% CI: 16%, 100%) and an OR rate of 8% (95% CI: 2%, 23%). The null DC rate was rejected. 9 pts had ≥1 Grade 3 tx-related adverse or serious adverse event related to O. Conclusions: Monotherapy O showed evidence of anti-tumor activity in pts with various solid tumors with ATM mut. Table 1. Demographics and Baseline Characteristics (N=39); Efficacy Outcomes (N=36); Toxicity Outcomes (N=39) Median (Med) age, years (range) 65 (35, 77) Female, % 46 ECOG PS, % 0 33 1 59 2 8 Prior systemic regimens, % 0 3 1 8 2 15 ≥3 74 DC rate, % (OR or SD 16+) (1-sided 90% CI) 25 (16, 100) OR rate, % (95% CI) 8 (2, 23) Med PFS, wks (95% CI) 8.4 (8.0, 15.9) Med OS, wks (95% CI) 40.4 (30.3, 50.7) Med duration OR (range), wks 18.9 (4.3, 24.4) Med duration SD16+ (range), wks 27.3 (19.4, 31.0) Number of pts1 with treatment-related adverse or serious adverse events (all Grade 3) AE2 9 SAE3 4 1Patients may have experienced one or more events2anemia, anorexia, dehydration, fatigue, hypokalemia, nausea 3colitis, dizziness, lung infection, proteinuria, urinary tract infection/obstruction Citation Format: Kathryn F. Mileham, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Eddy S. Yang, Olatunji B. Alese, Angela Jain, Herbert L. Duvivier, Phillip Palmbos, Eugene R. Ahn, Jeanny B. Aragon-Ching, Kathleen W. Beekman, Deepti Behl, Funda Meric-Bernstam, Rodolfo Gutierrez, Amy Sanford, Ramya Thota, Michael Zakem, Song Zhao, Raegan O'Lone, Gina N. Grantham, Susan Halabi, Richard L. Schilsky. Olaparib (O) in patients (pts) with solid tumors with ATM mutation or deletion: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT110.
573 Background: Immunotherapy has shown great efficacy in hepatocellular carcinoma (HCC). No clear consensus exists on when to stop the immune checkpoint inhibitor (ICI) after complete response (CR), and clinical course after stopping ICI remains unknown. Methods: We identified 138 HCC patients who received ICI at Cedars-Sinai Medical Center and Mayo Clinic Rochester from 2016-2023. Modified Response Evaluation Criteria In Solid Tumors (mRECIST) was used to assess treatment response. We further described the clinical course of patients who achieved CR after ICI discontinuation, including cancer recurrence, subsequent treatment, liver transplantation (LT) listing and outcomes. Results: The median age at ICI initiation was 68 years; 79% were male; 55.9% were white; 51.5% were BCLC stage C. 9.4% CRs, 25.4% partial responses, 39.9% stable diseases, and 25.4% progressive disease. Hepatitis C etiology was associated with higher likelihood of CR (P=0.005). Among 13 patients who achieved CR, 10 stopped ICI (60% for LT evaluation, 40% for toxicity). After stopping ICI, 40% had recurrence (Table). 3 patients underwent local therapy for recurrent HCC within Milan criteria and 1 patient restarted ICI for recurrence beyond Milan criteria. Among CR patients, 9 patients underwent LT evaluation after stopping ICI and 7 patients were waitlisted. After listing, 3 dropouts were observed, due to recurrent HCC beyond Milan criteria, sepsis leading to death, and personal preference. 4 patients underwent LT. 2 patients underwent local therapy before LT for recurrent HCC (Table). All transplanted patients had the last dose of ICI more than 1 year before LT (12, 21, 24, and 29 months). On explanted livers, 2 patients had no residual viable tumor and 2 patients had residual HCC within Milan criteria. 1 patient developed acute cellular rejection and was treated with immunosuppressants and maintained stable graft function. None had graft loss or evidence of HCC recurrence in the follow-up period at 8, 20, 28, and 51 months. Conclusions: Immunotherapy demonstrated excellent effects on a subset of HCC patients, including 9.4% who achieved CR. After stopping ICI, 40% had cancer recurrence but 3 out of 4 were within Milan criteria. 4 underwent successful LTs (2.9%) with excellent post LT outcome. Larger prospective data is needed to establish a protocol for ICI use, especially to determine the optimal timing for ICI discontinuation after CR. BCLC at ICI initiation ICI cycles before stopping, ICI Recurrence after last ICI (days) Within Milan at recurrence Treatment(s) received after recurrence and outcomes OS (days) Patient 1 B 7, Nivolumab 730 No Nivolumab. Died from GI bleeding 1065 Patient 2 B 64, Atezo/Bev 149 Yes TACE with CR, followed by LT without recurrence. 1203 Patient 3 A 8, Nivolumab 1393 Yes Y90 with CR. No recurrence. 1984 Patient 4 C NA, Pembrolizumab 407 Yes TACE and MWA with CR, followed by LT without recurrence. 1722
LBA501 Background: I-SPY2.2 is a multicenter phase 2 platform sequential multiple assignment randomized trial (SMART) in the neoadjuvant breast cancer setting that evaluates novel experimental regimens as first in a sequence (Block A) followed by standard chemo/targeted therapies (Blocks B/C) if indicated. The goal is to achieve a pCR after novel targeted agents alone or in sequence with standard therapies, with the optimal therapy assigned based on the tumor response predictive subtype (RPS). RPS incorporates expression-based immune, DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to subset patients into 6 subtypes: S1: HR+HER2-Immune-DRD-; S2: HR-HER2-Immune-DRD-; S3: HER2-Immune+; S4: HER2-Immune-DRD+; S5: HER2+/non-Luminal; S6: HER2+/Luminal. Methods: RPS S1, S2, S3, and S4 were eligible for assignment to Dato+Durva in Block A. Patients were followed by MRI during treatment (at 3, 6, and 12 weeks after start of Blocks A and B). Predicted responders by MRI and biopsy at the end of Block A or B have the option of going to surgery early; otherwise, they proceed to next treatment Block (B +/- C). Randomization to Block B includes a taxane-based regimen specific to the RPS, and options include S1: paclitaxel; S2 and S3: paclitaxel + carboplatin + pembrolizumab; S4: paclitaxel + carboplatin vs. paclitaxel + carboplatin + pembrolizumab. Patients who did not go to surgery after Block B proceeded to Block C (AC or AC + Pembrolizumab if HR-HER2-). The primary endpoint is pCR. Efficacy is evaluated within each RPS and HR+HER2- and HR-HER2- signatures. To estimate the arm's efficacy as a stand-alone therapy, we use a Bayesian covariate-adjusted model to estimate the pCR rate and compare the posterior distribution to a subtype-specific fixed threshold. This model uses pCR data when available and MRI data when pCR is not. To estimate pCR rate in the context of a multi-decision treatment regimen, we use a Bayesian model based on if and when a pCR occurred in the trial. The posterior is compared to a subtype-specific dynamic control generated from historical I-SPY data. Results: 106 patients were randomly assigned to the Dato+Durva arm between September 2022 and August 2023. The results for Dato+Durva as a stand-alone therapy are summarized in Table. After completion of Block A, 36 patients proceeded to surgery without completing Blocks B/C. Conclusions: Dato+Durva meets threshold for graduation within the RPS S3 subtype based on estimated pCR rate of 72% and warrants further investigation in a larger randomized controlled trial. Clinical trial information: NCT01042379 . [Table: see text]
