Alter, Robert

4516 Background: Ipilimumab/nivolumab (ipi/nivo) is a standard of care first-line treatment (tx) for patients (pts) with mccRCC; however, ideal timing of subsequent immunotherapy txs are not well defined. We performed an analysis of patients initially treated with ipi/nivo and subsequent cohort assignments on PDIGREE (A031704). Methods: The PDIGREE trial treated pts with IMDC intermediate/poor risk mccRCC with first-line ipi/nivo (Step 1) at NCTN sites (categorized as academic (A), academic regional (R), and community (C)). Subsequent management was based on iRECIST responses at 12 weeks: pts with complete response (CR) received 1-year nivo maintenance; pts with progressive disease (PD) received cabozantinib (cabo) monotherapy, pts with non-CR/non-PD were randomized to nivo with or without cabo (for primary endpoint of overall survival [OS], target sample size was 1175). Enrollment was held when the randomized sample target was reached. Pts with unresolved toxicity at week 22 were managed off protocol. Step 1 pt demographics, assignments into Step 2, and adverse event (AE) data are presented. Descriptive statistics were used, and cohorts were compared using a chi-square test. These data were released with DSMB approval and do not inform the primary OS endpoint (1EP). Results: From May 2019 to May 2024, 1111 pts were enrolled and treated with ipi/nivo. Pt characteristics included median age 64.0 years (range 29.0-86.0); 819 (73.7%) males; White (85.1%), Hispanic (10.4%), Black (4.2%), and American Indian/Native Hawaiian (1.3%); 849 (76.8%) intermediate risk/257 (23.2%) poor risk; 458 (41.2%) at Academic, 113 (10.2%) at Regional, and 540 (48.6%) at Community centers; and 603 (54.3%) with de novo metastases. 364 pts (33%) stopped tx in Step 1: 160 (44%) for AEs, 46 (13%) for PD/clinical PD/suspected PD, 42 (12%) withdrawals, 39 (11%) alternative txs, 37 (10%) deaths on the study, 12 (3%) other complicating disease, 8 (2%) MD decision and 19 (5%) other reasons. Of the 37 deaths, 15 (1.4%) grade 5 SAEs were reported, 6 of which were due to PD. Of 747 (67%) pts registered to Step 2 at 3 months, 9 (1.2%) achieved CR, and 141 (18.9%) pts were assigned to the PD cohort. 597 pts (80%) were randomized for the 1EP, notable with fewer pts with poor risk [(21 vs 27%, p = 0.01] and bone metastases [24.5% vs 34.2%, p = 0.0007] compared to Step 1 pts who discontinued tx. Gr 3/4 tx-related AEs in 314/1093 (29%) evaluable pts included diarrhea/colitis (8%), transaminase elevation (3%), rash (2%), adrenal insufficiency (2%), fatigue (2%), and hypophysitis (1%). Conclusions: The PDIGREE trial enrolled a representative US-based population with mccRCC. Step 1 pt characteristics and associated outcomes with induction ipi/nivo reveal new insights into the tolerability and tx response of 1L ipi/nivo. Clinical trial information: NCT03793166 .

Abstract Background: X4P-001 is an orally bioavailable, selective, allosteric inhibitor of the chemokine receptor CXCR4, and has been shown to downregulate hypoxia inducible factor-2α (HIF-2α) and myeloid-derived suppressor cell (MDSC) trafficking in the tumor microenvironment. In multiple RCC xenograft models, the addition of X4P-001 to tyrosine kinase inhibitors (TKIs), including axitinib, has demonstrated increased efficacy and delayed onset of TKI resistance. Methods: This is an ongoing phase 1/2 open-label study of X4P-001 in combination with axitinib in patients (pts) with histologically confirmed clear cell RCC (ccRCC) who have received ≥1 prior systemic therapy. The Ph1 portion of the study evaluates safety, tolerability, PK, PD, and antitumor activity of the combination using a 3+3 dose escalation schema (escalating doses of X4P-001+ axitinib at 5 mg BID). The Ph2 portion is a single-arm expansion cohort evaluating this combination treatment in ~ 45 ccRCC pts. The radiologic assessment is performed every 8 weeks with central review. Results: As of 30 June, 2017, enrollment for the Ph1 portion of the study has been completed. Sixteen (16) pts were enrolled and the median age was 64 years (range 50-76). Pts had received a median of 2 prior lines of therapy (range 1-5). The doses tested were 200 mg BID, 400 and 600 mg QD of X4P-001 + axitinib. There were two dose-limiting toxicities (DLTs) observed at the X4P-001 600 mg QD dose level: one pt had multiple grade (G) 2 adverse events (AEs), including anorexia, cognitive disturbance, fatigue, nausea, vomiting, and somnolence; another pt had G3 dyspnea and fatigue. The MTD/RP2D was determined to be 400 mg QD of X4P-001 + axitinib. Treatment-related AEs (≥ 10%) of any grade were diarrhea, fatigue, hypertension, nausea, headache, anorexia, vomiting, dry eye, dysphonia, abnormal loss of weight, increased lipase, proteinuria, dry mouth, stomatitis, cognitive disorder, dysgeusia, and palmar-plantar erythrodysaesthesia syndrome. Treatment-related G3/4 AEs (≥ 10%) were hypertension. In addition, one pt had SAE due to G2 diarrhea and G2 creatinine elevation. Drug exposures (AUC0-24hr) at steady state (SS) are similar for 200 mg BID and 400 mg QD dose. Mean Cmax and AUC0-24hr at SS increased approximately 1.6- and 1.9-fold, respectively, from 400 mg to 600 mg QD dose. Leukocyte mobilization is a well-established surrogate marker for CXCR4 inhibition. At both 400 mg and 600 mg daily dose levels, X4P-001 demonstrated approximately 2 to 2.5-fold increase of WBC (range: 1.4-4.7 fold) and nearly 4-fold increase of CD34+ progenitor cells (range: 1.8-6.4 fold). The peak elevation of both markers occurred around 2 to 4 hours following dosing. Of the 12 clinically evaluable pts, 3 had confirmed partial response, 8 had stable disease, and 1 had progressive disease. As of 30 June 2017, 9 pts remain on study and median duration on treatment was 27 weeks (range 7.4-60). Conclusions: The combination treatment is well tolerated at a dose of 400 mg QD of X4P-001 + axitinib with preliminary evidence of clinical activity. The doses used in this phase I study were biologically active in inhibiting CXCR4 in peripheral blood as demonstrated by elevating WBC and CD34+ cell counts. The Ph2 portion of the study is ongoing. Citation Format: Michael Atkins, Richard Joseph, Thai Ho, Ulka Vaishampayan, Sarah Ali, Marc Matrana, Robert Alter, Jeff Edenfield, Yan Wang, Sarah Blanchette, Lu Gan, David McDermott. A phase 1 dose-finding study of X4P-001 (an oral CXCR4 inhibitor) and axitinib in patients with advanced renal cell carcinoma (RCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B201.