Unconfirmed Partial Response Research Articles

Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study.

Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines. In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed. Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest. Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.

Ramucirumab in combination with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma: a single-centre, phase 1/2 trial

VEGF, a key mediator of angiogenesis and resistance to immunotherapy, is overexpressed in head and neck squamous cell carcinoma (HNSCC). We aimed to determine the recommended phase 2 dose of ramucirumab, a selective VEGFR2 inhibitor, given with pembrolizumab and the objective response rate of this combination as first-line treatment for recurrent or metastatic HNSCC. In this single-centre, phase 1/2 trial, which was done at Washington University (St Louis, MO, USA), eligible patients were aged 18 years or older with incurable recurrent or metastatic HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. Patients in phase 2 were required to have had no previous systemic therapy for recurrent or metastatic disease. In a dose de-escalation phase 1 design, patients received ramucirumab (starting dose 10 mg/kg given intravenously) and pembrolizumab (200 mg intravenously) on day 1 of each 21-day cycle. The recommended phase 2 dose of ramucirumab was defined as the highest dose at which one or fewer of three patients had dose-limiting toxicity during cycle one (primary endpoint of phase 1). In a Simon's two-stage phase 2 design, patients received the recommended phase 2 dose of ramucirumab and pembrolizumab. Tumour response (primary endpoint of phase 2) was assessed by Response Evaluation Criteria in Solid Tumours (version 1.1). We hypothesised that there would be an objective response rate of 32% or higher (null ≤13%). Eight or more responses among 33 evaluable patients (those with at least one response assessment) was evidence for activity (80% power; one-sided α=0·05). Analyses were done per protocol. The trial is registered with ClinicalTrials.gov, NCT03650764, and is closed to enrolment. Between June 18, 2019, and Feb 11, 2021, three patients enrolled and were treated in phase 1 and 37 patients in phase 2. Median age of all patients was 64 years (IQR 59-72). 36 (90%) of 40 patients were men and four (10%) were women, and 36 (90%) patients were White, three (8%) were Black or African American, and one (3%) was Asian. In phase 1, no dose-limiting toxicity event occurred. The recommended phase 2 dose of ramucirumab was 10 mg/kg. Median follow-up for patients on phase 2 was 14·8 months (IQR 4·9-31·0). In phase 2, 18 (55%; 95% CI 38-70) of 33 evaluable patients had an objective response, including confirmed complete response in 11 patients, confirmed partial response in six patients, and unconfirmed partial response in one patient. The most common grade 3 or worse adverse events were dysphagia (14 [38%] of 37 patients), lung infection (11 [30%]), lymphocyte count decrease (ten [27%]), hypophosphataemia (nine [24%]), and hypertension (eight [22%]). No treatment-related deaths were recorded. Ramucirumab and pembrolizumab were safe to administer to patients with recurrent or metastatic HNSCC, and the objective response rate with this combination as first-line treatment for recurrent or metastatic HNSCC was favourable. Further studies of ramucirumab and pembrolizumab in patients with recurrent or metastatic HNSCC are warranted. Lilly and the Joseph Sanchez Foundation.

Lung-MAP S1800D: A phase II/III study of N-803 (ALT-803) plus pembrolizumab versus standard of care in participants with stage IV or recurrent non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy.

2619 Background: IL-15 is a member of the IL-2 common gamma chain family of cytokines. N-803 is IL-15 administered in complex with IL-15 receptor alpha. Lung cancer, despite advances in targeted therapies and immunotherapy, remains the leading cause of cancer related death in the United States. Strategies to improve the performance of immunotherapy in advanced NSCLC is a clinical unmet need. Methods: Lung-MAP S1800D was a randomized study comparing N-803 plus pembrolizumab (NP) to investigators’ choice standard-of-care chemotherapy (SoC) for previously treated advanced NSCLC. Patients were enrolled into an Acquired Resistance Cohort (ARC) if disease progression on prior anti-PD-(L)1 occurred > 84 days from start of treatment and otherwise into a Primary Resistance Cohort (PRC). The ARC was a phase II/III study with a sample size goal of 334 patients. The PRC was a phase II with sample size of 134 patients. The first interim analysis (IA1) in the ARC evaluated futility among the first 25 patients treated with NP which required ≥1 response and ≥50% with disease control at 12 weeks to continue accrual. The primary endpoint in both cohorts was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response, and toxicity. Results: Accrual in the ARC and PRC were closed at the IA1 in the ARC with 74 pts in the ARC and 8 in the PRC. Of the 74 ARC patients, 71 met eligibility (36 SoC, 35 NP), and 32 pts on each arm received treatment. With 44 events, OS was not significantly different between the two arms (HR (95%CI: 0.73(0.40-1.36), p=0.32) with a 12-month OS rate of 25% with SoC and 44% with NP. With 61 events, PFS was not significantly different but numerically worse (HR (95% CI): 1.29 (0.78-2.13, 95% CI), p=0.33). There were 3 unconfirmed partial responses and 1 confirmed complete response with NP and 3 unconfirmed partial responses and 2 confirmed partial responses with SoC. On the NP arm, there were 10 Grade 3 (1 hematologic) and 1 Grade 5 treatment-related adverse events reported as Disease Progression (34% Grade 3+ TRAE). The Grade 3+ TRAE rate on the SoC arm was 53% with 10 Grade 3+ hematologic toxicities. Conclusions: While the study failed to continue accrual past IA1, there is an indication of a subgroup that might benefit from NP with a potential OS difference at 12 months. NP was safe when compared to SoC, and responses were seen in both treatment arms, including partial and complete responses in the NP group. Evaluation of tumor and patient characteristics will be critical to define if there are those who may benefit from N-803 plus pembrolizumab. Clinical trial information: NCT05096663 .

Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

3091 Background: RYZ101 (225Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improved therapeutic index. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Herein, we report updated results from the phase Ib portion of the trial. Methods: The phase Ib portion of the trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level –1 90 kBq/kg; Level –2 60 kBq/kg. DLT was assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions/safety data were overseen by a Data Review Committee. Tumor response was assessed locally by RECIST v1.1. Results: 17 patients have received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 30 June 2023, the most frequent TEAEs were nausea (58.8%) and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (none were treatment related); grade ≥3 AEs occurred in 9 patients (5 were treatment related). No AEs led to treatment discontinuation. 4 patients had TEAEs leading to dose modification, dose hold, and/or delays. The confirmed objective response rate was 29.4% (n=5; all partial responses); 1 patient had an unconfirmed partial response. 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of response and progression-free survival, will be presented. Conclusions: RYZ101 was well tolerated and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Longer-term safety and efficacy data will be presented. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 .

A phase I study of ATR inhibitor BAY1895344 (elimusertib) plus topotecan (ETCTN 10402): Results of dose escalation.

3076 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA abnormalities in various cancers. The topoisomerase-I (Top1) inhibitor topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in small cell lung cancer and gastrointestinal cancer xenografts when combined with Top1 inhibitors . Methods: This is phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. The study combination was assessed starting at Topotecan 1 mg/m2 IV (D1-D5) plus elimusertib 20 mg BID (D2, D5) (Cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination. Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity of the combinations. Results: Eight patients were treated in dose escalation. Participants were a median of 63 years old and had received 2 median lines of previous therapy. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities with one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg Daily) and no DLTs were observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized in Table. Disease control rate was 43% among evaluation patient including one unconfirmed partial response. Median progression-free survival in the RP2D cohort was 3.45 months. PK studies are in process and results will be presented at time of meeting. Conclusions: RP2D and MTD was established for elimusertib in combination with Topotecan: Topotecan 1 mg/m2 IV [D1-D5] plus elimusertib 20 mg Daily [D2, D5] every 3 weeks. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts but the concept of ATR + topo I inhibition remains relevant. Clinical trial information: NCT04514497 . [Table: see text]

Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 study.

6014 Background: EGFR is a known oncogenic driver in HNSCC, and the leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a receptor expressed on cancer stem cells, including in HNSCC. Petosemtamab is a human, common light chain, IgG1 bispecific antibody with ADCC-enhanced activity, targeting EGFR and LGR5. In the dose escalation part of a phase 1/2 study, the recommended phase 2 dose (RP2D) was determined to be 1500 mg every 2 weeks (Q2W). Interim data of petosemtamab monotherapy at the RP2D in 2L/3L HNSCC led to a 37.2% overall response rate (ORR; per investigator) with 6.0 months (mo) median duration of response (DOR) [Cohen, Cancer Research 2023]. Petosemtamab (RP2D) with pembrolizumab (400 mg Q6W) is being investigated in an expansion cohort of the ongoing phase 2 study (NCT03526835) in 1L HNSCC. Methods: Primary endpoints are safety and investigator-assessed ORR (RECIST v1.1). Secondary endpoints include DOR, progression-free survival (per investigator), and overall survival. Key eligibility criteria were r/m HNSCC with no prior systemic therapy, PD-L1 combined positive score ≥1, ECOG PS 0–1, measurable disease, and primary tumor location in oropharynx (regardless of p16 status), oral cavity, hypopharynx, or larynx. Results: No dose-limiting toxicities were observed in the safety run-in. As of a November 6, 2023 data cutoff, 26 pts were treated (24 continuing therapy at the data cutoff) and median follow-up was 1.35 mo. Median age was 62.5 years (range 23–80), ECOG PS 0/1 in 10/16 pts, and 65.4% were male. The most frequent primary tumor locations were oropharynx (34.6%), oral cavity (19.2%), and hypopharynx (19.2%). A median of 2 cycles (range 1–8) were administered. The combination was well tolerated and no significant overlapping toxicities were observed. Treatment-emergent adverse events (AEs) were reported in 26 pts, and most were Grade (G) 1 or 2 in severity (no G4–5 were observed). The most frequent AEs (all Gs/G3) were acneiform dermatitis (30.8%/0%), asthenia (26.9%/0%), and rash (26.9%/0%). Infusion-related reactions (composite term) were reported in 26.9% (all Gs) and 3.8% (G3) of pts, all occurred during the first infusion and resolved. Among 10 pts evaluable for efficacy (≥2 cycles and ≥1 post-baseline scan, or early progressive disease), there were 1 confirmed complete response, 2 confirmed and 3 unconfirmed partial responses (2 confirmed after data cutoff), 3 stable disease, and 1 progressive disease; with all 6 responders on treatment at data cutoff. Enrollment has been completed and updated data will be presented. Conclusions: Petosemtamab, a first-in-class EGFR x LGR5 bispecific antibody, in combination with pembrolizumab demonstrates a well-tolerated safety profile and promising preliminary clinical efficacy as 1L treatment for pts with r/m HNSCC. Clinical trial information: NCT03526835 .

Abstract PS12-06: A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy as treatment for hormone receptor-positive metastatic breast cancer. Preclinical studies suggest CDK4/6 inhibitor monotherapy might also be effective in a subset of triple-negative breast cancers (TNBCs), including those that express a functional retinoblastoma (RB) protein and/or those of the Luminal Androgen Receptor (LAR) subtype. Currently, the clinical activity of CDK4/6 inhibitor therapy in TNBC has not been reported. Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with locally advanced or metastatic TNBC. Key eligibility criteria included: (i) Measurable disease by RECIST 1.1; (ii) Between 1-3 prior lines of systemic therapy for advanced TNBC; (iii) RB-positive tumor (defined as ≥ 50% of tumor cells staining positive for RB by immunohistochemistry [archival or fresh sample] on central testing); (iv) ECOG PS 0/1. Patients were treated with abemaciclib 200 mg orally (28-day cycles) twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or death. Tumor biopsies were mandatory at baseline and C2D1 if tumor tissue was safely accessible. The primary outcome was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR: CR + PR + SD ≥ 24 weeks), and safety and tolerability. The study had a two-stage design. Thirteen patients were enrolled in the first stage, with the plan to enrol a further 25 patients if at least one objective response was observed. Results: One unconfirmed partial response was observed in stage 1, and a total of 27 patients were enrolled before the trial was closed early due to slow accrual. The median age was 61 years and patients had received a median of 2 prior lines of systemic therapy for metastatic disease. Twelve patients had received prior immunotherapy. After a median follow-up of 28.5 months, the confirmed ORR was 0% and the CBR was 15%, with 4 of 27 patients experiencing stable disease for ≥ 24 weeks. The median PFS was 1.94 months (95% CI: 1.8 – 11.5 months), and the median OS was 8.44 months (95% CI: 4.6 – 15.6 months). There was no significant difference in PFS or OS between patients with PD-L1-positive versus PD-L1-negative disease, or Androgen Receptor (AR) positive versus negative tumors by immunohistochemistry. The most common adverse events of grade 2 or higher were diarrhea (41%), neutropenia (41%), anemia (30%), and nausea (30%). RNA-sequencing of baseline biopsies has been performed to identify biomarkers associated with clinical benefit, and results will be presented at the meeting. Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with Rb+ metastatic TNBC. This finding suggests that future trials of CDK4/6 inhibition as monotherapy in TNBC are not warranted. Citation Format: Shom Goel, Bojana Jovanović, Xiangying Chu, Melissa Hughes, Ayesha Mohammed-Abreu, Julie Kasparian, Timothy Erick, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nabihah Tayob, Stuart Schnitt, Nancy Lin, Sara Tolaney. A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-06.

Abstract PO5-05-03: Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer

Abstract Background Zotatifin (eFT226) is a first-in-class, potent and sequence selective inhibitor of RNA helicase eIF4A that promotes a stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs present within the 5’-UTR of select transcripts, thereby blocking production of the encoded proteins. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes including CDK4, ERα, ERBB2, KRAS, and CCND1. Previous clinical research has demonstrated the activity of zotatifin in combination with other agents in ER+ metastatic breast cancer (MBC). Methods Part 1 is a 3+3 dose escalation portion of the protocol followed by Part 2 as a Simon’s two-stage design in patients with ER+ MBC enrolled at the recommended phase 2 dose (RP2D) of zotatifin (0.07 mg/kg IV two weeks on/one week off) in combination with fulvestrant (ful) and abemaciclib (abema) (Z+F+A). Part 1a and Part 1b are 3+3 dose escalation portions evaluating zotatifin in combination with ful (Z+F) at QW IV and Q2W IV dosing schedules, respectively. Key eligibility criteria included at least one line of therapy for advanced/metastatic disease, progression on hormone therapy, and in addition, the Z+F cohorts required prior CDK 4/6 inhibitor (CDKi). Primary endpoint of Part 1a/1b was determination of RP2D and primary endpoint of part 2 was objective response rate (ORR) per RECIST v1.1. Additional endpoints included safety, progression-free survival (PFS) and other efficacy analyses, and characterization of pharmacodynamic (PD) markers and pharmacokinetics. Results As of a data cut-off of July 6, 2023, 20 pts were enrolled in the Z+F+A cohort and had a median of four prior metastatic lines of therapy. In 19 evaluable pts in Z+F+A cohort, there were four confirmed partial responses (PR), one unconfirmed PR, and 10 pts with best overall response (OR) of stable disease (SD). All pts with PR/unconfirmed PR received prior CDKI, ful, and chemotherapy for MBC. Confirmed PRs were observed in patients with and without mutations in ESR1 and PIK3CA. mPFS, while not yet mature, exceeds 20 weeks. In Z+F+A the most common adverse events (AEs) were diarrhea (80%, all grades (Gr)) and nausea (75%, all Gr 1/2) and the most common Gr 3/4 AE was diarrhea (15%). In Z+F cohorts of 0.07 mg/kg QW (n=3), 0.1 mg/kg Q2W (n=3), and 0.14 Q2W (n= 2) there were no dose-limiting toxicities or Gr 5 adverse events (AEs). There was one confirmed PR and one SD in 0.1 and 0.14 mg/kg Q2W cohorts, respectively, and no PR or SD in the 0.07 mg/kg QW cohort. In Z+F+A, 9 pts had paired pre- and on-treatment ctDNA analyzed by Guardant assay. Of the remaining 11 pts, 4 came off study prior to scheduled collection of the on-treatment sample and 5 had unavailable samples. Of the 9 patients with paired samples, 8 had ctDNA decreases of >50%, all of whom had SD or PR. In the Z+F Q2W cohort, 2 of 3 patients had ctDNA decreases >50%, one of whom had a PR. Reduction below the limit of detection was seen for mutant alleles in ESR1, PIK3CA and other genes with potential to confer resistance to endocrine therapy. Conclusion Z+F+A showed encouraging efficacy in heavily pretreated ER+ MBC patients, with results that compare favorably to other treatment options available after progression on CDKi plus endocrine treatment. Efficacy was seen independent of ESR1 or PIK3CA mutations, suggesting the potential to treat a broad, unrestricted patient population. Initial results with Z+F Q2W dosing are encouraging and support continued dose escalation of this regimen. Citation Format: Ezra Y. Rosen, Manish Sharma, David Berz, Jennifer Caswell-Jin, Georgina Fulgar, Mark Densel, Gary Chiang, Samuel Sperry, Douglas Warner, Funda Meric-Bernstam. Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-03.

Feasibility of implementation of the early tumor shrinkage as a potential predictive marker to daily clinical practice in patients with RAS wild type metastatic colorectal cancer, treated with cetuximab - a non-interventional observational study.

With the aim to show the feasibility of early tumor shrinkage (ETS) concept implementation into daily clinical practice in the Czech Republic, a non-interventional, multicentric, single arm, prospective study in real world set-up was performed. The study objectives were to explore the time interval from the treatment starting date to the date of the first radiographic control (TFRC) and evaluate the proportion of patients who achieved ≥ 20% tumor regression within the first 8 weeks of first-line therapy, in the real-world settings. The medians of TFRC in all individual participating centers were > 12 weeks (range 14.0-36.4 weeks). TFRC ≤ 8 weeks was reported for only 3% of patients in the cohort with first-line therapy, and there were only 3 patients (1%) who achieved tumor regression of ≥ 20% by day 60 (8.6 weeks). These findings indicate that the basic time parameter of ETS could not realistically be employed in routine oncology care of patients with metastatic colorectal cancer (mCRC) in the Czech Republic, unless there would be a strict request to perform TRFC by week 8 since the initiation of the therapy. In addition, the frequency of objective tumor response to first-line therapy with cetuximab + chemotherapy was evaluated. Based on the relative regression in the sum of diameters of measurable metastatic lesions, unconfirmed partial responses were achieved in 42.4 % and unconfirmed complete response in 8.6% of patients, altogether corresponding to the overall response rate of 51% with first-line therapy. The frequency of responses was higher among patients with left than right sided primary tumors. It seems that the regimen of cetuximab/FOLFOX might be more active in frontline therapy of right sided RAS wild type mCRC than cetuximab/FOLFIRI.

Phase II Clinical Trial of Trametinib and Low-Dose Dabrafenib in Advanced, Previously Treated BRAFV600/NRASQ61 Wild-Type Melanoma (TraMel-WT).

Patients with BRAFV600/NRASQ61 wild-type melanoma who progress after immune checkpoint inhibitors (ICIs) have a poor prognosis. MEK inhibition has shown activity in this patient population but is associated with treatment-limiting skin toxicity. Combining a BRAF inhibitor with a MEK inhibitor is associated with less skin toxicity. This phase II trial investigated trametinib (2 mg once daily) in patients with advanced BRAFV600/NRASQ61 wild-type, ICI-refractory melanoma. In case of treatment-limiting skin toxicity, low-dose dabrafenib (50 mg twice daily) was added to trametinib. After a trial amendment, both drugs were combined up-front. The confirmed objective response rate (cORR) served as the primary end point. Twenty-four patients were included (50% male; median age 57 years; 92% Eastern Cooperative Oncology Group Performance Status 0-2; 75% stage IV-M1c/stage IV-M1d; median number of prior therapies: two [range, 1-5]). Three patients were enrolled before and 21 patients after the amendment, respectively. Seven confirmed and one unconfirmed partial responses (PRs) were observed (cORR, 29.2%). The median duration of response was 16.6 weeks (95% CI, 5.5 to 27.7). Stable disease (SD) was the best response in an additional five patients. Among the responding patients, genetic alterations causing mitogen-activated protein kinase (MAPK) pathway activation were documented in six patients. The disease control rate in patients with MAPK pathway-activating alterations was 64.3% (five confirmed PR, one unconfirmed PR, and three SD). The median progression-free survival was 13.3 weeks (95% CI, 3.5 to 23.1), and the median overall survival was 54.3 weeks (95% CI, 37.9 to 70.6). Adding low-dose dabrafenib to trametinib effectively mitigated or prevented treatment-limiting trametinib-related skin toxicity. The combination of trametinib plus low-dose dabrafenib demonstrated encouraging efficacy and effective mitigation of skin toxicity in patients with advanced, ICI-pretreated BRAFV600/NRASQ61 wild-type melanoma patients. MAPK pathway-activating alterations hold promise as a predictive biomarker.

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.

Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150mg twice daily with dose escalation of oral uprosertib starting at 50mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5mg daily and oral uprosertib starting at 25mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56days of treatment. Radiographic responses were assessed at 8-week intervals. Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N=7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150mg twice daily and trametinib 2mg daily plus uprosertib 75mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.

Phase II study of GEN-001 in combination with avelumab in patients with PD-L1–positive locally advanced, or metastatic gastric cancer (GC) or gastroesophageal junction cancer (GEJC) who have progressed after second-line (2L) and beyond (GEN001-201 study).

368 Background: The relationship between gut microbiota and the response to immune checkpoint inhibitors is likely due to cross-reactivity between microbial and tumor antigens, enhancing dendritic cell (DC) activation, antigen presentation, and inflammatory cytokine production. GEN-001 is a live biotherapeutic product (LBP) consisting of a lyophilized formulation of a strain of Lactococcus lactis. This study is designed to investigate the safety and efficacy of GEN-001 in combination with avelumab (the PD-L1 inhibitor) for patients with PD-L1 positive advanced GC/GEJC. Methods: This is an open-label, single arm, phase II clinical trial for PD-L1 positive (CPS ≥1) patients with unresectable, locally advanced, or metastatic GC/GEJC who have progressed after second-line and beyond. All patients were treated with GEN-001 (9x1011 CFU, administered as oral once daily) in combination with avelumab (800 mg, administered as an intravenous infusion every two weeks) until progressive disease, unacceptable toxicity, death, or withdrawal. Tumor response was assessed every 8 weeks for 6 months and every 12 weeks thereafter. The primary endpoint was objective response (OR); secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Results: As of August 31, 2023, a total of 42 patients were enrolled. 37 patients have been assessed for response. The confirmed partial response (PR) and unconfirmed PR were achieved by 5 patients and 1 patient respectively, 8 patients have experienced as stable disease (SD). Median PFS and median OS were 1.73 months (95% confidence interval [CI]: 1.67-2.37 months) and 7.9 months (95% [CI]: 6.07-NE months). Treatment-related adverse events (TRAEs) of any grade occurred in 12 patients (28.6%) and Grade ≥3 TRAEs occurred in 2 patients (4.8%) out of 42 patients. Conclusions: Treatment of patients with GC/GEJC with GEN-001 in combination with avelumab in the ≥ 3L setting showed promising antitumor activities with an overall manageable safety profile. The results from this trial will be updated about its effects on clinical outcome, including survival, safety, and biomarker findings. Clinical trial information: NCT05419362 .

An Open-Label Phase I Study of Metformin and Nelfinavir in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma

BackgroundIn preclinical models, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor shows synergistic therapeutic potential against multiple myeloma (MM). Thus, this study evaluated the safety and tolerability of repurposing metformin, a complex I inhibitor, and nelfinavir, a GLUT4 inhibitor, in combination with bortezomib for the treatment of relapsed/refractory MM that had progressed on all standard of care therapies. Materials and MethodsThis trial utilized a 3 + 3 dose escalation design with 3 dose levels planned for up to a maximum of 6 (21-day) cycles. Metformin and nelfinavir were administered for 14 of 21 days, and subQ bortezomib was administered to a portion of patients on days 1, 8, and 15. The primary objective was to determine the maximal tolerated dose, and the secondary objective was to evaluate the safety and overall response rate (ORR) of this combination. ResultsNine patients were accrued with a median age of 65 (range: 42-81) and received a median of 7 prior lines of therapy (Range: 5-12). The first 3 patients received only metformin (500 mg BID) and nelfinavir (1250 mg BID) at the first dose level, with 1 patient experiencing an unconfirmed minimal response (MR) in the first cycle, 1 experiencing progressive disease after 1 cycle of treatment and 1 patient going off treatment prior to assessing response but with signs of progressive disease. Given the limited therapeutic activity, the upfront addition of bortezomib (1.3 mg/m2) was utilized for the subsequent 6 patients accrued. Three of these 6 patients went off study due to progressive disease, 1 patient achieved an unconfirmed partial response after 1 cycle of treatment but reported progressive disease in the subsequent cycle, 1 patient went off study to enter hospice, and the remaining patient experienced stable disease (SD) after receiving 6 cycles of clinical trial treatment. The study was closed before accrual to the next dose level was started. ConclusionThis is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of relapsed and refractory MM. This was an overall negative study with no ORR observed. Fortunately, 1 patient experienced an SD response, allowing this combination to stabilize their disease until another novel therapy on a clinical trial was available.

Abstract B037: A pharmacodynamic pilot study of DS8201a in patients with HER2 expressing advanced solid tumors

Abstract Background: DS-8201a (Trastuzumab (T) deruxtecan(D)) is an antibody-drug conjugate consisting of the HER2-targeting antibody T covalently bound via a lysosomal protease-cleavable linker to the novel topoisomerase 1 (Top1) inhibitor D with activity in tumors with low HER2 IHC scores of 1+ or 2+. The primary purpose of this study is to investigate the pharmacodynamic (PD) mechanisms underlying the activity of DS-8201a in advanced solid tumors, including those with low HER2 expression. Methods: This multicenter pilot study enrolled patients (pts) with advanced solid tumors expressing HER2 as defined by CLIA-certified labs i.e., a HER2 IHC score of 1+ or greater or ERBB2 amplifications (amp) or mutations (mut). DS-8201a was administered at 5.4 mg/kg intravenously once every 3 weeks, in 21-day cycles (C). PD biomarkers of Top1 target engagement by D payload, consequent DNA damage and repair (DDR), and immune microenvironment changes were analyzed in mandatory tumor biopsies collected at baseline, post-dose C1 and pre-dose C3. Blood samples for biomarker analyses were taken at several time points. Safety and overall response were also evaluated. Results: As of June 16, 2023, a total of 48 pts have been enrolled with diverse HER2 status distribution: 11 IHC 1+, 20 IHC 2+, 6 IHC 3+, 7 ERBB2 amp, 3 ERBB2 mut, and 1 with both IHC 1+ and ERBB2 amp. Median number of prior lines of systemic therapy was 3.5 (range 1-13) and 11 pts received prior Top1 inhibitor therapy. Grade (Gr) 3 or higher treatment-related adverse events (trAEs) were reported in 12 pts (25%). The most common Gr3/4 trAEs were myelosuppression. There were 7 pts (15%) with Gr2 and 1 pt (2%) with Gr3 pneumonitis. One pt with Gr2 pneumonitis was retreated after trAE resolution with steroid therapy and continued for another 9 Cs prior to progression. Of the evaluable patients, 1 pt (2%) had complete response (cervical, HER2 2+), 6 pts (13%) had confirmed partial response (PR) (uterine, 2+; ovarian, 2+; bladder, ERBB2 mut; uterine carcinosarcoma, 2+; 2 head and neck cancers, 1+ and 2+), 4 pts (8%) had unconfirmed PR (breast, 1+; extramammary Paget’s disease, 2+; pancreas, ERBB2 amp; uterine, 2+), and 17 pts (35%) had stable disease as their best response. Median progression free survival was 3.4 months (range 0.5-17.2). Top1 target engagement and induction of nuclear biomarkers of DDR (RAD51, pNBS1) were observed in more than half of the paired biopsies tested to date. DDR biomarker response was associated with both HER2 1+ and 2+ status. PD analyses are currently ongoing. Conclusion: DS-8201a demonstrated responses in various tumor types outside of breast cancer with HER2 low/ERBB2 alteration status. Preliminary PD data demonstrated expected Top1 target engagement and DDR induction, the extent of which is possibly independent of the degree of HER 2 staining. Analyses are currently underway to further define the effect of DS-8201a in advanced solid tumors. Citation Format: Sarah J Shin, Geraldine O'Sullivan-Coyne, Elizabeth K Lee, Arjun Mittra, Cora N Sternberg, Mary Jane Ong, Deborah Wilsker, Katherine Ferry-Galow, Jared Foster, Lamin Juwara, Naoko Takebe, Cheryl A Pickett, Ralph Parchment, James Doroshow, Alice Chen. A pharmacodynamic pilot study of DS8201a in patients with HER2 expressing advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B037.

Abstract C022: Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results

Abstract Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in non-small cell lung cancer (NSCLC) and glioblastoma (r/rGBM). For NSCLC, EGFR tyrosine kinase activity can be driven by classical driver (L858R, Ex19del), intrinsic (atypical) driver (L718Q, L861Q, S768I), and acquired resistance mutation (C797X). BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4th generation tyrosine kinase inhibitor that targets all 3 classes of EGFR mutations. Preliminary results from the Phase 1 dose escalation study (NCT05256290) are presented. Methods: BDTX-1535-101 is a first-in-human study enrolling patients with locally advanced or metastatic NSCLC harboring EGFR mutations, with or without CNS disease, following standard of care EGFR inhibitor therapy, or patients with r/rGBM expressing EGFR alterations. The primary objective is to determine the BDTX-1535 recommended Phase 2 dose (RP2D) based on the overall safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Using an adaptive Bayesian optimal interval design, eligible patients are enrolled and dosed daily for 21-day cycles until treatment discontinuation. Results: As of 20 May 2023, 51 patients (24 NSCLC, 27 r/rGBM) were enrolled and treated across 7 dose cohorts (15mg – 400mg QD). For NSCLC, mean age was 65 years (range 47-81), patients had a median of 2 prior lines of treatment (1-9), and 79% received prior osimertinib. For r/rGBM, the mean age was 58 years (41-85) with a median of 2 prior lines of treatment (range 1-4). The most common all-grade treatment-related AEs (TRAE) were rash (76%), diarrhea (51%), stomatitis (29%), paronychia (20%) and nausea (20%), vast majority Gr 1 to Gr 2. Gr 3 TRAEs greater than or equal 10% were diarrhea (12%) and rash (10%). Plasma exposure of BDTX-1535 increased dose proportionally with a half-life of ~15h supporting once daily dosing. The maximum tolerated dose is 300mg QD. Circulating tumor DNA (ctDNA) assessment in NSCLC patients with classical and intrinsic drivers as well as acquired resistance mutations revealed significant ctDNA reductions across all EGFR mutation types. Five of 12 patients with either intrinsic driver (eg, L718Q) or acquired resistance (C797S) mutations in a subgroup of NSCLC efficacy evaluable patients at doses at or above 100mg had a confirmed partial response (PR) by RECIST1.1; 1 patient had unconfirmed PR, while the remaining 6 patients had stable disease. Additional GBM data will be shared separately.Conclusions:BDTX-1535 was well-tolerated at a daily dose up to 300mg and promising preliminary clinical activity was observed in NSCLC patients harboring either intrinsic driver or acquired resistance EGFR mutations post-progression with an EGFR inhibitor. A preliminary RP2D dose is being explored in NSCLC patients in dose expansion cohorts. : Citation Format: Helena Yu, Melissa Johnson, Jason T. Henry, Alex Spira, Ji-Youn Han, Minal Barve, James Battiste, Iyad Alnahhas, DoHyun Nam, Jeffrey Edenfield, Balazs Halmos, Shinkyo Yoon, Tae Min Kim, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Manmeet Ahluwalia, Patrick Wen. Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C022.

Abstract LB_A12: Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor

Abstract Background PARP-1 has a well-established role in DNA repair. PARP-1 selective inhibitors are a new subclass of PARPi that offer potential for improved tolerability. NMS-03305293 (NMS-293) is an oral, brain-penetrant PARP-1 selective inhibitor with strong antitumor activity in BRCA mutated preclinical models. Furthermore, NMS-293 is synergistic with temozolomide (TMZ) in glioblastoma mouse models. Methods Two phase I/I-II dose-escalation/expansion studies assessed safety, tolerability, and preliminary antitumor activity of NMS-293. Both are actively recruiting. In PARPA-293-001 (NCT04182516), NMS-293 was administered orally, ranging from 20 mg (QD) to 160 mg (BID) for 21 or 28 days on 28-day cycle in adult patients with advanced/metastatic, relapsed/refractory solid tumors who have exhausted standard treatment options. In PARPA-293-002 (NCT04910022), NMS-293 was administered in a range of doses orally, QD or BID on days 1-7 plus TMZ 150mg/m2 QD on days 1-5 in repeated 28-day cycle in adult patients with recurrent diffuse gliomas. Tumor responses were measured by investigator-assessed RANO criteria. Results The unpooled safety database at the data-cut-off (02-AUG-23), includes 45 patients in PARPA-001 and 21 patients in PARPA-002. PARPA-001 showed an MTD of 100 mg BID for 28 days on a 28-day cycle, a dose with meaningful PK relative to preclinical activity. PARPA-002 dose finding is ongoing with no DLTs as of cutoff date. The most frequent (≥10%) any-grade treatment related adverse events (TRAEs) in PARPA-001 were reversible QTcF prolongation, nausea, asthenia, decreased appetite and vomiting, mainly mild/moderate. In PARPA-002, with discontinuous NMS-293 plus TMZ, no G≥3 TRAEs were reported. The most frequent (≥10%) any-grade TRAEs were: nausea, fatigue, vomiting, decreased appetite, and platelet count decreased, mainly G1 adverse events. Overall, no dose-dependent trends of myelosuppression have been observed. 14 recurrent glioma patients across dose levels in PARPA-002 were evaluable for tumor response. A patient with glioblastoma had confirmed partial response (PR) with duration 7.6+ weeks, remaining on treatment at cutoff date. A patient with grade 3 IDH-mutant astrocytoma had unconfirmed PR with ongoing tumor shrinkage at 16.1+ weeks. A patient with glioblastoma had complete radiological disappearance of enhancing non-target lesions, remaining on treatment at cutoff date. NMS-293 PK profiles showed an increase in exposure with the dose with approximately 5 to 13 hours half-life. Conclusion NMS-293, a PARP-1 selective, brain penetrant inhibitor was well tolerated in phase I clinical trials with no dose dependent trends of myelosuppression. Furthermore, NMS-293 showed encouraging clinical activity in combination with TMZ in difficult-to-treat recurrent glioma patients. Citation Format: Marjolein Geurts, Dorothee Gramatzki, Sara Merler, Matteo Duca, Fabio Girardi, Ugur T. Sener, Domenico Roberti, Grazia Saturno, Patrizia Crivori, Alessia Montagnoli, Lisa Mahnke, Siqing Fu, Paola Gaviani, Kurt A. Jaeckle, Jian Zhang, Yehui Shi, Valentina Guarneri, Michael Weller, Sani H. Kizilbash, Martin J. van den Bent, Michele Milella, Silvia Damian. Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A12.

A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better

BackgroundStimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma.MethodsWe employed a Simon’s two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects.ResultsThirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses.ConclusionsHigher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options.Trial registrationClinicalTrials.gov Identifier: NCT03502330.

Deciphering the tumor microenvironment (TME) dynamics in advanced colorectal (CRC) and pancreatic cancers (PDAC) treated with durvalumab (D) with olaparib (O) or cediranib (C): Results from a phase 2 randomized trial.

63 Background: There is limited efficacy for immunotherapy (IO) in mismatch repair proficient CRC (pMMR-CRC) or PDAC. The mechanisms driving their intrinsic IO resistance are largely unknown. DAPPER (NCT03851614) is a phase 2 study randomizing patients (pts) with pMMR-CRC or PDAC to D+O or D+C. Methods: PDAC or pMMR-CRC pts with ECOG 0-1 were randomized to either D+O (arm A), or D+C (arm B). In a 28 day-cycle, D 1500mg every 4 weeks (w) IV was given with either O 300mg orally twice daily or C 20mg orally once daily 5d/week. Primary endpoint included pharmacodynamic immune changes in the TME. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples (baseline and cycle 2 (C2)) were analyzed by multiplexed immunohistochemistry (CD3, CD8, CD20, CD68 and FOXP3) and RNA-sequencing. A total of 48 publicly available gene expression signatures (GES) were associated with treatment outcomes and investigated with predictIO software (Bareche Y et al. Ann Oncol, 2022). Results: Thirty-one pMMR-CRC pts were randomized to arm A (n=16) or B (n=15). Median age was 59y (range 34-77y), M:F 19:12. In 28 evaluable pts, 3 pts had stable disease (SD) (2 pts on D+O and 1 pt on D+C) while 25 had progressive disease (PD). The median PFS of arm A and B were 2.6 (95% CI 2.5-2.6) and 2.4 (95% CI 1.5-2.7) months (m) respectively. Among 19 pts with PDAC, 9 and 10 pts were randomized to arm A and arm B respectively. Median age was 60y (range 48-76y), M:F 9:10.In 18 evaluable pts, 1 pt had an unconfirmed partial response with D+C, 1 pt had SD with D+O while 16 had PD. The median PFS of arm A and B were 1.3 (95% CI 0.8-NA) and 2.1 (95% CI 1.3-NA) m respectively. Increased CD8+ tumor-infiltrating lymphocytes (TILs) at baseline (p=0.04) and at C2 (p=0.023) and low baseline CD68+ cells (p=0.018) were associated with longer OS. Different GES at baseline were associated with OS and PFS (see table). None of these GES were associated with OS or PFS in CRC or PDAC pts in the TCGA database, suggesting specificity to IO. Conclusions: In pts with pMMR-CRC or PDAC, D+O and D+C showed limited anti-tumor activity. Although increased CD8+ TILs infiltration was observed in a subset of pMMR-CRC or PDAC pts and associated with longer OS, immune infiltration of the TME did not result in radiographic response or durable disease control. Clinical trial information: NCT03851614 . [Table: see text]

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 .

Phase 1/2 study of XTX101, a masked, tumor-selective Fc-modified anti-CTLA4, in patients with advanced solid tumors.

e14685 Background: XTX101 is a tumor-selective, anti-CTLA-4 monoclonal antibody (mAb) engineered with covalently linked peptides that mask CTLA-4 antigen-binding regions. The masking peptides are cleaved by matrix metalloproteases that are more active in the tumor microenvironment (TME) compared with healthy tissues. XTX101 is designed with 2 Fc domain mutations (S239D and I332E) which enhance binding to Fcγ receptors and are intended to improve effector function, resulting in depletion of regulatory T-cells in the TME. In a murine model, XTX101 at 0.3 mg/kg achieved similar tumor growth inhibition as 3 mg/kg of an ipilimumab analog, suggesting higher relative potency of XTX101 over ipilimumab (Powderly SITC 2021). Methods: Interim results of first-in-human, Phase 1 portion of study XTX101-01/02-001 (NCT04896697) are reported here. Part 1A examines XTX101 monotherapy in 3+3 dose escalation. Part 1B is evaluating pharmacodynamic (PD) biomarkers. Results: As of January 27, 2023, 22 patients (pts) with advanced solid tumors were enrolled including colorectal (n = 3), pancreatic (n = 3), non-small cell lung (n = 3), squamous cell skin (n = 2), breast (n = 2), uterine (n = 2), cervical, prostate, Fallopian tube cancer, leiomyosarcoma and Merkel cell carcinoma in Part 1A, and melanoma and colorectal cancer in Part 1B. Pts had a median of 3 prior lines of therapy (1-10). Dose levels (DL) of 7, 20 and 60 mg every 3 weeks (Q3W) were cleared (1 dose limiting toxicity (DLT) of colitis among 8 patients treated at 60 mg Q3W), while 2 DLTs of colitis were reported among 6 pts at 180 mg Q3W. An alternative dosing schedule of 150 mg every 6 weeks (Q6W) was implemented based on clinical and pharmacokinetic (PK) data, and no DLTs were reported among 5 pts at this alternative schedule. There were no grade (G) 4 or 5 treatment-related (TR) adverse events (AEs) on the study. G3 TRAEs included colitis (n = 4), infusion reaction (IR, n = 3) and lymphopenia (n = 2). There were no skin, endocrine or liver-related TRAEs of any grade. One patient with squamous cell lung cancer treated at 150 mg Q6W dose had an unconfirmed partial response and continues on treatment. PK exposure with 150 mg Q6W schedule were comparable to 2 cycles of 60 mg Q3W. Among 8 pts treated at 60 mg Q3W and 5 treated at 150 mg Q6W, 2 out of 13 patients (15%) experienced G3 colitis, 1 pt G2 colitis and 1 pt G2 diarrhea. All colitis AEs improved with immunosuppression and resolved. There were 2 IRs at 60 mg Q3W, while no IR occurred with the Q6W schedule. Based on the totality of clinical and PK data, 150 mg Q6W is the recommended Phase 2 dose (RP2D), and enrollment in part 1B is ongoing at this dose. Conclusions: XTX101 is a Fc-engineered, masked, tumor-activated, anti-CTLA-4 mAb in development for advanced solid tumors. At RP2D, the preliminary safety profile is differentiated from systemically active anti-CTLA4 mAb. Updated clinical data, PK, immunogenicity and PD data from the study will be presented. Clinical trial information: NCT04896697 .