Prior Immune Checkpoint Inhibitor Therapy Research Articles

Prior immune checkpoint inhibitors may enhance severe hypersensitivity related to selpercatinib in RET fusion gene-positive lung cancer

Selpercatinib, a tyrosine kinase inhibitor approved for RET-fusion gene-positive lung cancer, can induce hypersensitivity, potentially exacerbated by prior immune checkpoint inhibitor (ICI) therapy. We present a case of severe toxicity following selpercatinib treatment in a 58-year-old female with lung adenocarcinoma, refractory to previous treatments including pembrolizumab. Symptoms included fever, rash, and multiorgan failure indicative of grade 4 hypersensitivity. Treatment involved platelet transfusion, heparin therapy, and prednisolone, leading to improvement upon selpercatinib cessation. This case highlights the importance of monitoring for hypersensitivity reactions in patients treated with selpercatinib, especially following prior ICI therapy.

Abstract CT008: A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer

Abstract Background & Objectives: Folate receptor-alpha (FRα) expression is associated with poor prognosis in endometrial cancer (EC). Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the tubulin-disrupting maytansinoid DM4, showed tolerability and single agent activity in a Phase 1 dose expansion study in FRα-positive advanced/recurrent EC (NCT01609556). In addition to target-mediated cytotoxicity, MIRV activates monocytes and promotes phagocytosis of tumor cells through Fc-FcγR interactions. We therefore hypothesized that MIRV would improve the low response to immune checkpoint inhibitors (ICI) in MSS/pMMR EC and conducted this two-stage, phase 2, single cohort study evaluating the activity of MIRV in combination with pembrolizumab in patients with recurrent/persistent EC (NCT03835819). Methods: Patients with advanced or recurrent MSS/pMMR, FRα positive (defined as ≥50% of tumor cells with ≥2+ staining on IHC by Ventana, Inc.) serous EC received MIRV 6 mg/kg AIBW and pembrolizumab 200 mg every 21 days until disease progression or unacceptable toxicity. Patients could have received 1-3 prior lines of therapy; prior ICI therapy was allowed. The co-primary endpoints were objective response rate (ORR) as measured by RECIST 1.1 and frequency of patients surviving progression-free for 6 months (PFS6). In the first stage of the study, 16 patients were enrolled; if there were ≥2 objective responses or ≥2 PFS6 responses, an additional 19 patients would be enrolled in Stage 2. If a total of 4 objective responses or 8 PFS6 events were achieved, the combination would be considered worthy of further study. Data: Among 130 patient tumors prescreened for FRα expression, the median FRα (% of tumor cells with ≥2+ staining) was 30% (IQR: 5-55) and 43 (33.1%) were FRα positive (PS 2+ ≥50%). As of data-cutoff in November 2023, a total of 16 patients had received study treatment with median follow-up of 4.7 months (IQR 2.9, 17.3). Of 16 treated patients, 6 patients (37.5%, 95% CI: 15.2-64.6%) achieved an objective response, including 1 patient achieving a confirmed CR and 5 patients achieving a PR [3 confirmed PR (18.8%) and 2 unconfirmed PR (12.5%)] (Fig. 1). An additional 31.3% (5/16) had stable disease and two patients were alive and progression free at 6 months. The most common TRAEs included AST elevation (50%), blurred vision (44%), fatigue (44%) and diarrhea (43%); grade 3 TRAEs occurred in 2 patients (12.5%). Ocular toxicities of any grade were reported in 56.3% of patients. Updated efficacy and safety data as well as ongoing correlative studies will be reported at the time of the meeting. Conclusions: In this investigator-initiated study, the combination of MIRV and pembrolizumab met the co-primary endpoint to be considered worthy of further study in FRα-positive recurrent MSS/pMMR serous EC. Investigations into subpopulations most likely to derive clinical benefit from this combination are ongoing. Citation Format: Rebecca L. Porter, Niya Xiong, Nabihah Tayob, Madeline Polak, Hannah Sawyer, Martin Hayes, Jeanette Gardner, Susana Campos, Neil Horowitz, Carolyn Krasner, Elizabeth K. Lee, Joyce F. Liu, Elizabeth H. Stover, Jennifer Veneris, Alexi A. Wright, Ursula A. Matulonis, Panagiotis Konstantinopoulos. A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT008.

Abstract 5260: Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice

Abstract Eribulin (ERI) has been reported a microtubule dynamics inhibitor with unique tumor microenvironment modulations such as vascular remodeling activity. In the previous meeting (AACR2022, 2023), we reported that ERI and liposomal formulation of ERI (ERI-LF) also have immunomodulatory activity that induces CD8+ T cells via its vascular remodeling activity and ERI-LF showed more potent immune modulation and combination activities with anti-PD-1 antibody (PD-1 Ab) than ERI in syngeneic mice models and humanized mice models. Although immune-checkpoint inhibitors (ICI) are using as a key drug for various types of cancers in clinical setting, several clinical questions regarding suitable therapies after ICI therapy and efficacy of ICI rechallenge are remaining. In this study, we evaluated anti-tumor activities of combination of ERI-LF and PD-1 Ab in two syngeneic transplantation models using mouse non-small lung cancer cells, P-glycoprotein-knockout (Pgp-KO) KLN205 cells and Pgp-KO LL2 cells. As a result, combination of 1mg/kg ERI-LF (Q7D×2) with PD-1 Ab (200 ug/head, twice a week ×2 weeks) showed significant stronger antitumor activity compared with each monotherapy in only Pgp-KO KLN205 model, in which ERI-LF increased intratumoral microvascular density as a vascular remodeling activity, not in Pgp-KO LL2 model. We next conducted continuous treatment of PD-1 Ab in Pgp-KO KLN205 model to investigate tumor regrowth during treatment of PD-1 Ab. In this model, tumor growth was inhibited by PD-1 Ab until about two weeks after initiation of the treatment and then this inhibitory activity disappeared after two weeks even by continuous treatment of PD-1 Ab. We performed flow cytometry analysis (FCM) for tumor-infiltrating immune cells and RNAseq analysis using regrowing tumors compared with non-treatment tumors. Expressions of mRNA of several immune inhibitory receptors were upregulated in tumors with regrowth, although CD4+ cells and CD8+ cells were also increased in FCM using tumor samples. Furthermore, we investigated anti-tumor activity of combination of ERI-LF and PD-1 Ab against tumors which changed from inhibitory phase to regrowth phase during PD-1 Ab treatment in Pgp-KO KLN205 model. The combination of ERI-LF at 1mg/kg (Q7D×3) and PD-1 Ab (200 ug/head, twice a week ×3 weeks) also showed potent anti-tumor activity against tumors with regrowth by prior PD-1 Ab treatment as well as PD-1 Ab-naïve tumor, suggesting that this combination therapy might be effective after prior ICI therapy. Currently, Phase 1b/2 clinical trial of ERI-LF plus nivolumab in patients with selected solid cancers (NCT04078295) is underway. Patients with or without prior ICI therapy were enrolled in a small cell lung cancer cohort of this clinical study. Our preclinical results might provide a scientific rationale for a uniqueness of ERI-LF as a post ICI therapy. Citation Format: Moe Tamura, Yuki Niwa, Taro Semba. Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5260.

Safety and efficacy of immune checkpoint inhibitor cancer therapy in patients with preexisting type 1 diabetes mellitus.

Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM. This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class. Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2-3.56), p = 0.81, and OR 1.69 (0.31-9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy. These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.

Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): Primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study.

LBA4500 Background: ICI-based regimens are the standard of care for first-line (1L) treatment of metastatic clear cell (cc) RCC. Treatment options following disease progression during or after ICI therapy are limited but can include single-agent TKIs, such as cabozantinib (cabo). CONTACT-03 evaluated anti–PD-L1 atezolizumab (atezo) + cabo vs cabo alone in patients (pts) with metastatic RCC that progressed during or after prior ICI treatment and is the first phase 3 randomized trial to test the benefit of ICI rechallenge by direct addition to a control arm. Methods: CONTACT-03 enrolled pts with histologically confirmed, inoperable, locally advanced or metastatic cc or non-cc RCC, regardless of PD-L1 status, that progressed on or after ICI treatment. Randomization was 1:1 to atezo (1200 mg IV q3w) plus cabo (60 mg oral qd) or cabo alone. Stratification factors were IMDC risk factors (0 vs 1-2 vs ≥3); most recent line of prior ICI therapy (adjuvant vs 1L vs 2L); and histology (dominant cc without sarcomatoid vs dominant non-cc [papillary or unclassified] without sarcomatoid vs cc or non-cc with any sarcomatoid component). The multiple primary efficacy endpoints were centrally reviewed RECIST 1.1 PFS and OS. Key secondary endpoints were investigator (INV)-assessed PFS, centrally reviewed RECIST 1.1 ORR and DOR and safety. Results: Of 522 pts randomized to atezo + cabo (n=263) or cabo (n=259), 55% and 51% had most recent ICI in the 1L setting and 10% and 11% had sarcomatoid RCC, respectively. At the data cutoff (Jan 3, 2023), median follow-up was 15.2 mo. No PFS or OS benefit was observed with atezo + cabo vs cabo. ORR was 41% in both arms; DOR was 12.7 (95% CI: 10.5, 17.4) mo with atezo + cabo and 14.8 (95% CI: 11.3, 20.0) mo with cabo. All-cause Grade 3/4 adverse events (AEs) occurred in 68% (177/262) and 62% (158/256) of safety-evaluable pts receiving atezo + cabo or cabo, respectively; all-cause Grade 5 AEs occurred in 6% and 4%. AEs leading to treatment withdrawal occurred in 16% of pts on atezo + cabo and 4% on cabo. Conclusions: The addition of atezo to cabo did not improve clinical outcomes and led to increased toxicity in patients with RCC that progressed on or after prior ICI treatment. CONTACT-03 is the first randomized, phase III oncology trial to test the benefit of PD-(L)1 inhibitor continuation by direct addition to a standard control arm; the results prompt caution with this approach in other cancers. Clinical trial information: NCT04338269 . [Table: see text]

Baseline autoantibody profiling in patients with NSCLC with pre-existing autoimmune diseases or who had received prior anti-PD-1 therapy before enrolling in the TAIL study.

2512 Background: Patients (pts) with pre-existing autoimmune diseases (AID) and prior immune checkpoint inhibitor (ICI) experience were historically excluded from studies with ICIs. Moreover, about 50% pts with pre-existing autoimmunity have a flare up when given ICI therapies (1). In this post-hoc exploratory analysis, we characterized the baseline autoantibody (AAb) profiles and evaluated its correlation with efficacy and safety outcomes in NSCLC pts with either pre-existing AID or who had prior ICI therapy and received atezolizumab in the TAIL study (2). Methods: Plasma samples were obtained from 57 NSCLC pts prior to receiving atezolizumab (TAIL study, NCT03285763). AAb testing was performed using tailored immuno-oncology bead-based antigen arrays comprising 1,340 tumor, AID and immune pathway antigens (3, 4). The cohort includes 39 pts with prior ICI therapy or prior AID (experimental group) and 18 pts without prior ICI therapy or AID (control group). Differences in IgG AAbs were compared between the experimental and control group in pts with or w/o irAE and overall survival (OS) longer or shorter than 11.1 months (median OS in overall population in TAIL). Furthermore, the AAb profiles of a subgroup of pts with therapeutic benefit (OS ≥ 11.1 months) and no or low grade irAEs (standard toxicity grade ≤ 2) were analyzed. Statistical analysis included 2-way permutation-based ANOVA (factors: outcome, study group) and Significance Analysis of Microarrays (SAM). Results: While pre-treatment AAbs were detected in the overall cohort, significant differences in AAb were observed between the experimental and control group at baseline, which were associated with OS and irAEs. In experimental group pts, pre-existing AAbs to AQP4 and NCOA1 predicted the development of irAEs. Differences were also observed in AAbs predicting longer OS. AAbs to CENPT were specifically identified in pts in the experimental group with longer OS, whereas AAbs to SOX5 were elevated in pts of the control group with longer OS. In the subgroup of pts with therapeutic benefit and no or low risk of irAE, AAbs to IL6, CENPT and the cancer testis antigens NY-ESO-2 and MAGEB2 were elevated in the experimental group. Conclusions: This AAb analysis provides important preliminary data in helping to understand the drivers of clinical outcomes with ICIs in pts with pre-existing AID and prior ICI therapy. The findings seem biologically plausible as some of the identified antigens refer to the breach of tolerance to classical AAb targets e.g. CENPT, AQP4 and to an immune response to classic tumor antigens e.g. NY-ESO-2 and MAGEB2. Further validation of the AAb profiling approach is warranted to shed insights on potential therapeutically actionable antigens and generate data orthogonal to efforts to identify biomarkers that are predictive of efficacy and safety outcomes with ICI therapies.

First in human phase Ⅰ study of BMS-986299 as monotherapy and combined with nivolumab and ipilimumab in advanced solid tumors.

e14584 Background: Immune checkpoint inhibitors (ICIs) face hurdles in overcoming the immunosuppressive tumor microenvironment. BMS-986299 is first-in-class, NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasome agonist enhancing adaptive immune and T cell memory responses. In-vivo studies demonstrated BMS-986299 synergy with ICIs and induction of durable immunological memory. Methods: This multicenter, open-label, phase I [NCT03444753] study assessed safety and tolerability of intra-tumoral (IT) BMS-986299 monotherapy (Part 1A) and in combination (Part 1B) with the programmed death 1 receptor antibody nivolumab (N), and the anti-cytotoxic T lymphocyte associated protein 4 antibody ipilimumab (I) in advanced solid tumors. Eligible patients (pts) regardless of prior ICI with accessible solid tumors (≥ 2 lesions) received IT BMS-986299 administered on day 1, 8, 15, 22, 29 for Cycle 1 (C1) and on days 1, 29 until C2, 8 weeks apart across 7 dose escalation cohorts in Part 1A (75μg-4000μg; Bayesian Logistic Regression Model (BLRM). In Part 1B, BMS-986299 was given across 3 dose escalation cohorts (75μg-2000μg; BLRM Copula) with nivolumab 480 mg q4weeks and ipilimumab 1 mg/kg q8weeks (fixed dosing) from day 1 up to 24 months (m). Cross-over (CS) was allowed from Part 1A to Part 1B. Results: The study was terminated early, unrelated to safety, due to the COVID-19 pandemic and did not complete enrollment. From April 2018 to February 2022, 50 pts were treated (33; Part 1A and 17; Part 1B). Eleven pts crossed over to Part 1B. Median age of pts enrolled was 59 years and with preponderance in female gender (58.0%) and white (80.0%) pt. participation. Forty-two pts (70%) had treatment related adverse events (TRAEs). Grade (G)3/G4 TRAEs included tubulointerstitial nephritis (1; Part 1A), hepatitis (1; CS), colitis, diabetic ketoacidosis, elevated liver enzymes (1 each; Part 1B). No G5 TRAEs or dose limiting toxicities were seen. In Part 1A, 3 pts (melanoma; bladder; anal) achieved stable disease (SD). In CS cohort, 1 triple negative breast cancer (BC) pt had partial response (PR; -60%) for 27.4 m and 3 had SD (breast; cSCC, squamous oropharynx). In Part 1B, 3 pts had PR including 2 pts with hormone positive BC (1 pt with -86%; 3.2m and 1 pt with -39%; 2m) and 1 pt with cutaneous squamous cell cancer (cSCC) (-43%; 1m). Four pts in part 1B had SD (2 breast, 1 lung, 1 chondrosarcoma). All 4 responders received the combination of BMS-986299 with N + I with 3 responders receiving BMS-986299 at 2000μg and one at 300μg. 3 responders (2 breast; 1 cSCC) had prior ICI therapy. Conclusions: BMS-986299 in combination with ICI resulted in modest clinical activity in select tumor types and carried a manageable toxicity profile. However, definitive conclusions could not be drawn as the study was not powered for inference testing. Further exploration is warranted to define the role of this novel agent in the ICI refractory population. Clinical trial information: NCT03444753 .

Incidence, risk factors, and outcomes of immune-related adverse events (irAEs) in a prospective, pan-tumor population.

2662 Background: IrAEs associated with immune checkpoint inhibitors (ICIs) can result in morbidity and mortality. The incidence, spectrum, and risk factors for irAEs are usually reported from retrospective studies and clinical trials, which typically exclude patients (pts) with pre-existing autoimmune disease (AD). The prevalence and risk factors for irAEs in a diverse, pan-tumor, real-world setting is not well understood. Methods: From 06/2021 to 2/2023, we prospectively enrolled pts receiving ICIs (alone or in combination as standard-of-care) at a tertiary care center in this imCORE network study. Univariate and multivariate logistic regressions and survival curves were used to interrogate risk factors for irAE development and the relationship between irAEs, graded using CTCAE v5.0, and clinical response by RECIST 1.1. Results: 132 pts with prior ICI therapy were prospectively followed. Median age was 65 years (IQR 56-72), 35% were female, 69% were white, and 24% were black. Most common tumor histologies were: hepatocellular, renal cell, bladder, non-small cell lung, and head and neck carcinoma. 23% (n=30/132) received dual ICI (nivolumab+ipilimumab). In the whole cohort, 36.4% (n=48/132) of pts developed any-grade irAE and 10.6% (n=14/132) developed a severe irAE (grades 3-5). There were 2 fatal irAEs (n=1 hepatitis, n=1 myocarditis) representing 1.5% of the total cohort. The median time to first irAE was 1.8 months (mos; IQR 1.2-3.1) for anti-PDL1 monotherapy, 1.2 mos (IQR 0.7-2.2) for dual ICI, 4.4 mos (0.2-8.7) for PDL1+chemotherapy, and 2.1 mos (1.3-3.1) for PDL1+other. A subgroup of pts (10.6%; n=14/132) had pre-existing AD and 50% (n=7/14) had ever received immunosuppression for their AD. Among pts with AD, the incidence of irAEs was 57% (n=8/14) vs 33.9% (n=40/118) among those without AD. Antitumor response for pts with AD was 27.3% vs 25.8% those without AD. Receipt of dual ICI therapy was associated with increased risk of any-grade irAE (OR 2.87 p=0.02) and severe irAE (OR 40.9 p=0.004). Pts with any grade irAEs were significantly more likely to experience a partial/complete response vs pts without irAEs (OR 4.14 p=0.02) and this relationship was preserved after adjustment for single vs dual ICI. Pts who did not develop irAEs had an overall response rate (ORR) of 18.2%, mPFS of 3.5 mos (IQR 1.6-7.3), and mOS 7.3 mos (IQR 3.8-9.9) vs pts who developed any grade irAE who had an ORR of 37.8%, mPFS of 5.9 mos (IQR 3.3-8.8), and mOS 8.6 mos (IQR 4.9-11.4). Conclusions: In this pan-tumor, prospective cohort study of pts receiving ICI therapy in a real world setting, we identified that pts with pre-existing AD and those on dual ICI had increased risk of irAE development. This signals the need for closer monitoring, early recognition, and management of irAEs in these pts. In addition, pts who developed irAEs were more likely to experience partial or complete response in a diverse tumor cohort.

Response to immune checkpoint inhibitor (ICI) rechallenge in patients with metastatic renal cell carcinoma who progressed on prior ICI: A systematic review and meta-analysis.

4547 Background: Several immune checkpoint inhibitor (ICI)-based combination regimens are standard-of-care for first-line treatment of metastatic renal cell carcinoma (mRCC). These include dual ICI and ICI-tyrosine kinase inhibitor (TKI) combinations. While single-agent ICI is recommended as subsequent-line therapy for ICI-naïve patients, there is limited knowledge regarding efficacy of rechallenging with a different ICI or using different ICI combinations in patients who have progressed on prior ICI therapy. This is a clinically critical question as most mRCC patients would have already received ICI therapy at progression. The aim of this study is to address the above by performing a systematic review and meta-analysis. Methods: PubMed, Cochrane Library and Web of Science were systematically searched to identify studies of later-line ICI rechallenge after progression on any previous ICI in mRCC patients from database inception to December 31st, 2022. Patients who had progressed on prior ICI and rechallenged with ICI as single agent/dual/TKI combination as any subsequent line of therapy in both retrospective and prospective studies were included. Exclusion criteria were phase I or any phase studies combining ICI with unapproved drugs, case reports and case series. We calculated the pooled objective response rate (ORR) and disease control rate (DCR) using mixed effects model treating individual studies as a random effect. We further stratified studies into prospective and retrospective and performed subgroup analyses. Results: A total of 11 studies, 6 prospective and 5 retrospective with a total of 603 patients were initially identified. Out of the 6 prospective studies, 3 had an adaptive design of using salvage ipilimumab/nivolumab in patients who had either progressed or had stable disease as the best overall response on nivolumab monotherapy. These studies were excluded as they did not meet our inclusion criteria. A total of 8 studies with 400 patients were included in the final analysis. The ORR was 28% (95% CI, 0.27-0.36) and the DCR was 70% (95% CI, 0.47-0.85) with no significant differences between prospective and retrospective studies. Our ORR is higher than an earlier meta-analysis reporting an ORR of 14% with salvage ipilimumab/nivolumab after previous treatment with ICI. Conclusions: This meta-analysis demonstrates a modest ORR and an impressive DCR. Therefore, it provides strong clinical rationale to consider rechallenging with ICI-based therapy for later-line treatment of mRCC patients who have progressed on prior ICI. [Table: see text]

First-line envafolimab plus SOX chemotherapy for PD-L1 positive metastatic or recurrent gastric adenocarcinoma: A multi-centre, single-arm phase II clinical trial.

e16029 Background: Clinical evidence for PD-L1 positive metastatic or recurrent gastric adenocarcinoma patients were relatively limited in clinic, which limited the development of evidence-based medicine for these patients. Immune checkpoint inhibitor (ICI) therapy has been established as the standard treatment for advanced gastric carcinoma patients recently. Envafolimab is the first approved subcutaneous single-domain PD-L1 antibody, which has been commercialized in China for the treatment of MSI-H/dMMR advanced solid tumors. This study aimed to investigate the efficacy and safety of Envafolimab plus SOX chemotherapy for metastatic or recurrent gastric adenocarcinoma, aiming to provide further reference for clinical rational drug use for this population. Methods: This multi-centre, single-arm, open-label study was conducted to evaluate the efficacy and safety of Envafolimab in metastatic or recurrent gastric adenocarcinoma. A total of 38 patients with histologically confirmed advanced gastric adenocarcinoma were enrolled. Patients will receive Envafolimab (300 mg, s.c., day 1) plus chemotherapy (oxaliplatin 130 mg/m2, i.v., day 1, and S-1 40mg, BSA＜1.25 m2、50mg 1.25 m2＜BSA＜1.5 m2、60 mg BSA＞1.5m2, p.o., twice daily, days 1-14) every 3 weeks for 6 cycles, followed by maintenance treatment with Envafolimab plus S-1 until disease progression (PD), unacceptable toxicity, or patient refusal. Eligible patients must be histologically confirmed, advanced metastatic gastric adenocarcinoma or recurrent gastric adenocarcinoma after prior surgical treatment. Other key inclusion criteria were previously untreated, HER2-negative, PD-L1 positive (Combined Positive Score (CPS)≥1), ECOG performance status of 0 or 1, and adequate organ function. Patients with any prior ICI therapy, abnormal AFP elevation, or microsatellite-instability-high (MSI-H) status will be excluded. The primary endpoint was objective response rate (ORR) based on the RECIST version 1.1, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), etc. Adverse events were evaluated using the CTCAE v5.0 criteria. Results: Overall, thirteen patients were consecutively enrolled from March, 2022 to September 2022 and involved in this study. The median age was 62.7 years. At present, eight patients were included for efficacy analysis, and nine for safety evaluation. The ORR was 50%, and DCR was 87.5%, based on RECIST v1.1. Survival data are not mature at present. The most common TRAEs were elevated AST (75%), elevated ALT (65%) and leukopenia (42.5%). No treatment-related deaths occurred. Conclusions: Envafolimab plus chemotherapy is a promising and tolerable therapeutic regimen for patients with metastatic or recurrent gastric adenocarcinoma. Clinical trial information: NCT05237349 .

Phase II trial of XmAb20717 (vudalimab) in patients with advanced biliary tract cancers.

TPS4184 Background: For patients with advanced biliary tract cancers (BTCs), gemcitabine and cisplatin has been the standard-of-care first-line therapy, with a median overall survival (OS) of 11.7 months. More recently, TOPAZ-1 demonstrated a modest, but significant overall survival benefit (HR 0.80; 95% CI 0.66 – 0.97) to the addition of durvalumab to gemcitabine and cisplatin with a median OS of 12.8 months. However, for patients without targetable molecular variants, second-line and beyond options are limited, with FOLFOX demonstrating an overall response rate (ORR) of 5% and increase in median overall survival by 0.9 months compared to active symptom control. In patients with advanced BTCs, combination immunotherapy approaches with PD-1 or PD-L1 plus CTLA-4 inhibitors have been associated with improved ORRs of 10.8% - 23% compared to ORRs of 3 – 7% observed with single agent PD-1 or PD-L1 inhibitors. XmAb20717 (vudalimab) is a novel, bispecific antibody targeting PD-1 and CTLA-4 which demonstrated an ORR of 14.1% in a phase I dose expansion cohort of patients with advanced malignancies, including patients that had experienced disease progression on prior immune checkpoint inhibitors. Methods: We initiated a single-arm, phase II clinical trial with a Simon two-stage mini-max design to evaluate the efficacy of XmAb20717, in terms of ORR, in patients with advanced biliary tract cancers previously treated with gemcitabine-based chemotherapy. In the first stage, 13 patients evaluable for efficacy will be accrued. If no responses are observed in these 13 patients, the study will be stopped for futility. Otherwise, 14 additional patients evaluable for efficacy will be accrued to total 27 evaluable patients. If 4 or more responses are observed in these 27 patients, then the null hypothesis will be rejected. XmAb20717 (10 mg/kg) is administered intravenously on days 1 and 15 of a 28-day cycle. Important inclusion criteria include that patients with FGFR2 fusions, NTRK fusions, or IDH1 mutations must have received molecularly targeted therapy unless contraindicated or refused. Patients are not eligible if they have received prior immune checkpoint inhibitor therapy. Correlative studies will include longitudinal peripheral blood collection for circulating immune cell profiling. As of January, 2023, 8 patients have been enrolled with enrollment ongoing. Clinical trial information: NCT05297903 .

FDA analysis of toxicity profiles of oral TKIs recently approved for non-small cell lung cancer based on receipt of prior immune checkpoint inhibitor therapy.

9119 Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 are standard front-line therapy for advanced non-small cell lung cancer (NSCLC). Molecularly targeted tyrosine kinase inhibitors (TKIs) are standard of care for subsets of oncogene-driven NSCLC. Published literature suggests the possibility of increased toxicity in patients who receive ICIs followed by EGFR or ALK TKI treatment. However, the toxicity profile in patients who receive ICIs followed by TKIs with other genomic targets has not been well described. Methods: Marketing applications for TKIs in patients with NSCLC submitted to the Office of Oncologic Diseases between Jan 2019 to Dec 2022 were reviewed. Datasets were analyzed for demographics, treatment-emergent adverse events (TEAE), and prior anti-cancer therapies for TKI-treated patients in the primary efficacy population. Drug classes for which < 5% of patients received prior ICI were excluded. Grade 3-4 TEAE, serious adverse events (SAE), discontinuation TEAE and TEAE of interest (hepatotoxicity, rash, and interstitial lung disease [ILD]) were summarized. Results: 9 applications were identified and 2 were excluded. The remaining applications involved TKIs targeting EGFR exon 20 insertion, KRAS G12C, MET exon 14 skipping, and RET fusion alterations. Analyses included 867 patients; 61% received prior ICI therapy. Patient characteristics and results of analyses are presented in the table. In our pooled analysis, the incidence of Grade 3-4 AEs, SAEs, and hepatotoxicity were slightly higher in the prior ICI group, while the incidence of discontinuation TEAE, ILD, and rash were similar between groups. Analysis for hepatotoxicity was limited to reported AEs (did not include analysis of laboratory data). Review of toxicity data across individual drug classes did not show major differences compared to the overall results. Conclusions: Our analysis of safety data for newer TKIs with varied genomic targets does not appear to show excessive toxicity in patients with NSCLC who received prior ICI compared to those who did not. In future clinical trials evaluating TKIs in this population, inclusion of patients who have received prior ICI therapy should be considered when appropriate. [Table: see text]

Phase Ib/II study of XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) combination in metastatic melanoma refractory to prior immune checkpoint inhibitor therapy with and without CNS disease.

TPS9595 Background: Immune checkpoint inhibitors (ICI) have greatly improved outcomes for patients by targeting programmed cell death protein 1 (PD1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and Lymphocyte Activation Gene-3 (LAG-3) to increase immune-mediated anti-tumor response. Despite these advances, ~50% of patients with metastatic melanoma do not respond to standard of care ICI. We strive to address this unmet clinical need through a Phase Ib/II, first-in-human, multi-center trial of two bispecific antibodies targeting four different immune checkpoints: XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) in patients with melanoma refractory to ICI. This is the first trial of quadruple checkpoint inhibitor therapy. Furthermore, bispecific antibodies may allow simultaneous checkpoint blockade on the same cell and have been shown to heighten T cell activation in pre-clinical models. Two ongoing phase I trials of these bispecific antibodies with PD1 therapy have observed an immune related adverse event (irAE) rate of 20-24% with efficacy analysis ongoing (NCT03752398; NCT03849469). We postulate that treatment with XmAb23104 and XmAb22841 will enhance immune activation, overcome resistance, and improve disease control for patients refractory to traditional ICI. Methods: Eligible patients must have advanced/metastatic melanoma and have progressed on prior PD1/PD-L1 inhibitor or PD1/CTLA4 dual inhibition. Cutaneous, acral, mucosal and melanoma of unknown origin are allowed. Patient with CNS metastasis are allowed if these are asymptomatic and stable on MRI imaging obtained within 4 weeks of enrollment. Patients with prior unresolved irAE or irAE ≥ grade 3 are not allowed. XmAb23104 and XmAb22841 will be given on D1 and D15 of a 28-day cycle for 4 cycles, after which XmAb23104 (PD1 X ICOS) will be given alone for a total of 2 years. The phase I portion will be a dose escalation using standard 3+3 design of XmAb22841 (CTLA-4 X LAG3) with three dose levels (0.3 mg/kg, 1 mg/kg and 3 mg/kg). The dose of XmAb23104 (PD1 X ICOS) will remain at 10 mg/kg. These doses were selected based on results of prior early phase trials when these agents were combined with PD1. Once the P2RD of XmAb22841 (CTLA-4 X LAG3) is established, we will move on to dose escalation using a Simon’s 2-stage design. This portion will include two arms: Arm A consisting of 17 patients without CNS disease and Arm B consisting of 17 patients with CNS disease (total 34). Primary endpoints include dose limiting toxicities (DLT)/irAE and Objective Response Rate (ORR) at the time of best response by RECIST 1.1. Secondary endpoints include progression-free survival, overall survival, CNS response. At the time of this abstract submission, Cohort 1 of dose escalation has begun with the first few patients still within the DLT observation window. Clinical trial information: NCT05695898 .

A phase 2 study of an anti–PD-L1 antibody (atezolizumab) in dedifferentiated chondrosarcoma.

11533 Background: Chondrosarcoma (CS) is one of the most common bone malignancies in adults. Contrary to the indolent nature of low-grade CS, the dedifferentiated subtype (dCS), representing 5-10% of all CS, is known for aggressive behavior, high risk of relapse following resection, and poor prognosis. Expression of PD-L1 has been demonstrated in dCS samples and correlated with high numbers of tumor-infiltrating lymphocytes (Kostine, et al., Mod Pathol, 2016). Response to anti-PD1 therapy has not been evaluated prospectively. We report here the outcomes of a dCS cohort treated with the anti-PD-L1 agent, atezolizumab (atezo). Methods: Patients (pts) 2 years of age or older received intravenous atezolizumab 1200 mg (15 mg/kg with a 1200 mg cap in pediatric pts) once every 21 days. Prior immune checkpoint inhibitor therapy was not allowed. Primary objective was response rate (ORR). Imaging was carried out at the end of cycle 3 and then every two cycles; responses were evaluated per RECIST 1.1. The study employed a Simon two-stage design. If no responses were observed within 9 months of the ninth patient being enrolled, the cohort was to be terminated early. Research biopsies for immuno-pharmacodynamic (IO-PD) studies were collected at baseline, prior to C3D1, and optionally at progression. Results: Nine pts were enrolled to the dCS cohort. Three pts were female, 8 pts were White (1 unknown), all had an ECOG performance score ≤1, and their median age was 63 years (range, 53-85). Primary disease sites were pelvis (2); sternum (2); femur, hip, chest, scapula, and lung (1 each). Median duration of treatment for all pts was 9 weeks. Seven pts were evaluated for response, of whom 3 (42.9%) were documented to have stable disease (SD) as best response, lasting a median of 25.9 weeks (range, 15-38.3 weeks). Four pts had a best response of disease progression. Two pts died prior to first response assessment. No RECIST objective responses were observed; the cohort was closed due to futility. Reasons for treatment discontinuation included progression (n = 6), death (1, respiratory failure unrelated to treatment), withdrawal of consent (1), and SARS-CoV-2 infection (1). Treatment-related adverse events (TrAE), grades 1-3, occurred in 7 pts (78%). Grade 3 TrAEs occurred in 2 pts (22%), included infusion reaction, myonecrosis, and anemia. IO-PD studies are ongoing to elucidate changes within the tumor microenvironment. Conclusions: Though objective response was not seen, atezo showed stabilization of disease in 1/3 of the patients with this aggressive tumor. IO-PD results will be critical to identify determinants of atezolizumab resistance within this dCS cohort and to identify possible partners for combination therapy. Funded by NCI Contract No. HHSN261201500003I. This project was also supported in with funding and drug supply from Genentech Inc (a member of the Roche group). Clinical trial information: NCT04458922 .

Time from immune checkpoint inhibitor to sotorasib use correlates with risk of hepatotoxicity in non-small cell lung cancer: A brief report

IntroductionWe evaluated the risk factors and outcomes for patients who experienced hepatotoxicity after use of sotorasib in KRAS G12C mutated NSCLC. MethodsRetrospective review of medical records of patients with KRAS G12C mutated NSCLC who received sotorasib between May 28th, 2021, and December 31st, 2021 across all Mayo Clinic sites, with follow up until December 31st, 2022. ResultsThirty-one patients received sotorasib as standard of care treatment. Grade 3 or higher hepatoxicity was seen in 32% (10/31) patients presenting at a median of 51 days (range, 27–123) of sotorasib initiation. Baseline demographics were comparable between patients with and without ≥grade 3 hepatotoxicity, except for presence of CNS metastases and time from prior immune checkpoint inhibitor (ICI) treatment. Improvement in liver tests was observed in all patients after stopping sotorasib, and it was restarted at a lower dose in 8 patients. Despite dose reduction, hepatotoxicity requiring sotorasib discontinuation occurred in 2 patients.Twenty-eight of 31 patients had received prior ICI. Median time from prior ICI therapy was 69 days (range, 4–542). Rates of ≥grade 3 hepatoxicity were 75% (3/4), 64% (7/11) and 0% (0/13) for patients who received ICI within 30 days, 31–90 days and >90 days. None of the 3 patients without prior ICI exposure developed hepatoxicity. The median PFS and OS were 3.9 months and 9.9 months respectively. ConclusionOne-third of patients developed grade 3 or higher sotorasib induced hepatotoxicity. Risk of hepatotoxicity was higher in patients who received sotorasib within 90 days of ICI treatment.

DNA-Demethylating Agents Combined with Anti-PD-1 Inhibitors Showed Activity in Patients with Relapsed or Refractory Extranodal NK/T Cell Lymphoma Who Have Failed Immunotherapy: An Exploratory Study

Background: Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare aggressive type of non-Hodgkin's lymphoma associated with Epstein-Barr virus infection. Relapse or refractory (RR)-ENKTL cases are characterized by a high rate of relapse and dismal prognosis with limited therapeutic options. Immune check point inhibitors (ICIs) represent the cornerstone of treatment for RR-ENKTL; however, limited information is available of a rechallenge with ICIs after ICIs are discontinued due to disease progression. Epigenetic aberrations are critical as genetic abnormalities is the hallmarks of ENKTL. One of current promising strategies is that combining epigenetic and ICIs can overcome tumor resistance and enhance immunotherapy responses. Here, we assess the efficacy and safety of DNA methyltransferases inhibitors (DNMTi) plus anti-PD-1 therapy in RR-ENKTL. Methods: This trial enrolled eligible patients with histologically confirmed RR-ENKTL failing from asparaginase-based regimen or ICIs therapy; adequate organ function and bone marrow function; and at least one measurable or evaluable lesion or symptoms. Patients received standard dosage of anti-PD-1 antibodies plus decitabine (10mg/d, d1-5) or azacytidine (100mg/d, d1-5) every 21 days until disease progression, death, intolerable toxicity. Patients accept ASCT as consolidation after they obtained CR. The primary endpoints were objective response rate (ORR) based on Lugano 2016 criteria and clinical benefit rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to CTCAE 5.0. Results: From March 2020 to May 2022, 27 eligible patients were enrolled. Median age 40 years (range, 12-77), 15 (55.6%) male, 13 (48.1%) patients with stage IV of disease at screening, 11 (40.7%) patients with PINK-E score ≥ 3 points. Among them, 5(18.5%) patients had no imaging lesions, but all peripheral blood ctDNA were positive, they had high plasma EBV-DNA level(n=3), persistent fever(n=2) associated with ENKTL. The median number of prior systemic therapies was 2 (1-5), 21（77.8%）patients received ≥ 2 lines of prior systemic therapy. Twenty-two (81.5%) patients experienced prior ICIs therapy, 23(85.2%) previously received HDACi. The median time between the last dose of prior ICIs and initiation of this trial was 0.8 months (0.8 -23). Seven (25.9%) patients received decitabine, 20 (74.1%) received azacytidine. Of 22 imaging objective response evaluable patients, 13 (59.1%) achieved response (iORR) including 10 (45.5%) patients with CR (iCR). Clinical benefit analysis of 27 patients showed that clinical response(cORR) was 63.0% (17/27), 14 (59.1%) got CR (cCR). Among 5 patients with positive ctDNA alone, 4 patients achieve clinical improvement ,ctDNA negativity(n=4), EBV clearance(n=2) or fever disappearance (n=2). Among 22 patients previously received ICIs (20 patients previously received anti-PD-1 antibody plus HDACi), of these, 11 (50%) had response. After anti-PD-1 antibodies rechallenge plus DNMTi, iORR and cORR were 58.8% (10/17), 63.6% (14/22), iCR and cCR were 41.2% (7/17), 50.0% (11/22), respectively. Anti-PD-1 antibodies rechallenge plus DNMTi yielded iORR were 72.7% (8/11) and 55.6% (5/9) in patients responded to prior ICIs therapy. The difference of efficacy between decitabine and azacytidine was no significant, iORR and cORR were 60% (3/5), 58.8% (10/17) and 71.4% (5/7), 60.0% (12/20), respectively in this study. The median follow-up time was 12.1 (1.9-28.0) months, 1-year OS rate was 70.4%, median PFS rate was 12.8months. Survival results were similar with decitabine and azacytidine cohort. Sixteen (59.3%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were lymphopenia (44.4%), neutropenia (37.0%), hypothyroidism (25.9%), nausea (18.5%), hyperglycemia (11.1%). Conclusion: DNMTi combined with anti-PD-1 immunotherapy showed promising efficacy and manageable safety profile in RR-ENKTL for the first time. ICIs rechallenge is still an active and feasible strategy, further prospective studies are needed to clarify the role of rechallenge ICIs in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

1453P Phase II study of belzutifan plus cabozantinib for previously treated advanced renal cell carcinoma (RCC): Update from cohort 2 of LITESPARK-003

First-line treatment with immune checkpoint inhibitors (ICIs) is standard of care for advanced RCC. However, most patients will experience disease progression. Belzutifan, a first-in-class HIF-2α inhibitor, has shown durable responses in heavily pretreated RCC. Cabozantinib, a VEGF, AXL, and MET inhibitor, is approved for advanced RCC. The ongoing, open-label, phase 2 LITESPARK-003 study (NCT03634540) investigated belzutifan + cabozantinib in pts with no prior treatment (cohort 1) and pts with prior ICI therapy (cohort 2).

Tumor mutational burden (TMB) in immune checkpoint inhibitor (ICI)-naïve and -experienced patients with metastatic melanoma treated with lifileucel, a tumor-infiltrating lymphocyte (TIL) cell therapy.

9524 Background: Cutaneous melanoma is characterized by high TMB, which is associated with increased tumor-specific neoantigen expression (Schumacher Science 2015) and an increased response rate to ICI (Yarchoan NEJM 2019). The TMB in tumors that recur/progress after ICI is not well defined. Lifileucel is a one-time, autologous TIL cell therapy under investigation for treatment of patients (pts) with advanced melanoma. We conducted a matched case-control study of prospectively enrolled pts with advanced melanoma treated with lifileucel in the ICI-naïve (IOV-COM-202 trial, Cohort 1A [C1A]) and post-ICI (C-144-01 trial, Cohort 2 [C2]) setting to investigate the potential association between prior ICI therapy, TMB, and response to lifileucel. Methods: All pts had unresectable or metastatic melanoma. Available cases from C1A (ICI-naïve pts receiving lifileucel + pembrolizumab [pembro]) were matched to controls from C2 (pts receiving lifileucel alone after progression on anti–PD-1/PD-L1 therapy); 3 controls per case were matched at least for BRAF status and disease stage at study entry, and if possible, for anatomic site of tumor harvest. Lifileucel regimen was similar in C1A and C2. In C1A, 1 dose of pembro was given after tumor harvest and before nonmyeloablative lymphodepletion and resumed after lifileucel per standard treatment, for up to 2 y. Objective response rate (ORR) was assessed by investigators per RECIST v1.1. TMB of the resected tumor was measured using the ImmunoID NeXT (C1A) or PGDx elio (C2) platform; a validated conversion factor was used to compare TMB between platforms (Vega Ann Oncol 2021). High TMB was defined as ≥10 mut/MB. Results: Seven pts in C1A and 21 in C2 were included in the case-control study and had ORR of 71.4% and 38.1%, respectively. The percentage of pts with high TMB was 57.1% in C1A and 19.0% in C2 ( P = 0.1). ORR in the low and high TMB groups was 66.7% and 75.0%, respectively, in C1A and 41.1% and 25.0% in C2; 60% of responders in C1A and 12.5% in C2 had high TMB. In logistic regression analysis adjusted for cohort, TMB was not associated with response to lifileucel (odds ratio, 1.0; 95% CI, 0.9–1.1; P = 0.8). Data on tumor mutations and neoantigens, T-cell receptor repertoire, and tumor microenvironment profile will be presented. Conclusions: Our preliminary data indicate that the efficacy (ORR) of lifileucel may be independent of TMB, regardless of treatment setting, consistent with its proposed immune checkpoint pathway-independent mechanism of action. The percentage of patients with high TMB tended to be lower in tumors with prior ICI exposure than in those that were ICI-naïve. Clinical trial information: NCT03645928; NCT02360579.

Durvalumab (D) in combination with olaparib (O) for advanced, previously treated non-small cell lung cancer (NSCLC).

e21153 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) show variable clinical activity in individuals with advanced cancers. In the lung-MAP substudy S1400G, talazoparib alone was not sufficiently active in squamous lung cancers with homologous recombinant repair deficiency. Combinations of PARPi with immune checkpoint inhibitors (ICIs) are under investigation since preclinical studies show an immunostimulatory effect of PARPi that can potentially increase responsiveness to ICIs. To test this hypothesis, we evaluated the PARPi, O with the ICI, D in individuals with advanced NSCLC who had received at least one prior platinum-based regimen. Methods: Eligible participants were enrolled in an expansion cohort of a proof-of-concept phase I/II study (NCT02484404) and received O 300 mg PO BID with D 1500 mg IV every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results: Between July 2016 and July 2021, 15 participants with recurrent NSCLC were enrolled (median age: 66 years; stage IV: 12; adenocarcinoma 11; prior ICI: 9). After median potential follow-up of 39.6 months (mo), median PFS (mPFS) was 3.2 mo (95% CI: 0.9-7.6). Among 14 subjects with known EGFR mutation status, mPFS was longer in 11 individuals with EGFR-WT tumors (5.7 vs. 0.9 mo; p = 0.001). DNA repair mutation ( APC, BAP1, BRCA1, BRCA2, CHEK2, FANCI, FANCL and PALB2) status was known for 9 subjects; mPFS of subjects with (n = 7) or without (n = 2) DNA repair mutations was 3.2 vs. 18.1 mo (p = 0.68), respectively. Tumor PD-L1 expression > 50% (n = 3/10) and prior ICI therapy (n = 9/15) was associated with longer, albeit not statistically significant, mPFS: 7.6 vs. 1.8 mo; p = 0.22, and 5.7 vs. 1.8 mo; p = 0.39, respectively. Two (13%) partial responses, 7 (47%) stable disease and 6 (40%) cases of progressive disease were observed. Four (27%) subjects, including 3 previously treated with ICIs, achieved durable response or stability for up to 3 years. Treatment-related adverse events (TRAEs) were generally mild (grade 1 or 2). The most common TRAEs were anemia (40%), thrombocytopenia (27%), anorexia, fatigue, pain, and hypophosphatemia (each observed in 20%). Grade > 3 TRAEs occurred in 4 (27%) subjects (all hematologic). Immune-related AEs occurred in 4 (27%) individuals. Two subjects developed myelodysplasia after 12 and 36 mo of treatment. Three (20%) subjects required dose reductions or discontinuation of O due to anemia. There were no treatment-related deaths. Accrual will continue until 20 eligible participants are enrolled. Conclusions: O+D has acceptable safety and modest efficacy in an unselected population with recurrent NSCLC. Sufficient clinical activity is not observed in individuals with EGFR-mutated tumors. Genomic and immunological analyses are being performed to identify predictive biomarkers in individuals with durable benefit and will be reported. Clinical trial information: NCT02484404.

Phase 2 open-label study of pembrolizumab plus lenvatinib and belzutifan in patients with advanced solid tumors.

TPS4173 Background: There is an unmet medical need in patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and biliary tract cancer (BTC), that progresses after standard therapy. The combination of pembrolizumab (pembro; anti–PD-1 antibody) and lenvatinib (len; anti-angiogenic multikinase inhibitor) demonstrated antitumor activity and manageable toxicity in many tumor types. Hypoxia-inducible factor-2 alpha (HIF-2α) acts on multiple pathways including cell survival and proliferation, angiogenesis, genomic instability and treatment resistance. Monotherapy with the HIF-2α inhibitor belzutifan (MK-6482) impairs hypoxic signaling in cancer cells and has antitumor activity in clear cell renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease associated non-RCC tumors such as pancreatic neuroendocrine tumors. Based on the potential role of hypoxia signaling and HIF-2α in tumorigenesis and tumor progression, the combination of belzutifan with pembro and len may improve antitumor activity further in the selected tumor types. Methods: This phase 2, single-arm, open-label, multicenter study (NCT04976634) is evaluating pembro 400 mg IV Q6W + oral len 20 mg QD (8 or 12 mg QD for body weight < 60 or ≥60 kg, respectively, for pts with HCC) + oral belzutifan 120 mg QD. Eligible pts: ≥18 y old with histologically confirmed unresectable HCC (Child-Pugh A; 1L); previously treated unresectable, metastatic non–MSI-H/mismatch repair deficient CRC (3L+); metastatic PDAC (2L/3L); or locally advanced/metastatic BTC (includes intra/extrahepatic cholangiocarcinoma and gall bladder cancer; 2L+) with progressive disease (PD); measurable disease per RECIST v1.1 (verified by blinded independent central review [BICR]); ECOG PS ≤1 and archival/new tumor sample for biomarker analysis. All pts should be naïve to prior immune checkpoint inhibitor therapy, len or any HIF-2α inhibitor. The safety lead-in phase is based on the modified toxicity probability interval design with a target dose-limiting toxicity (DLT) rate of 30% and DLT-evaluable period of 21 days (3 wk/1 cycle) in ≤10 HCC pts and ≤15 pts with CRC, PDAC and BTC pooled for each dose level. The study will enroll 120 pts (30/tumor type) to receive triplet therapy for up to 2 y (for pembro) or until PD or discontinuation criteria are met. Enrollment may be expanded by an additional 70 pts/tumor type at the chosen dose level after safety and efficacy review with ≥6 mo follow-up. Primary endpoints are safety (DLTs [safety lead-in], AEs, and treatment discontinuation due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints include DOR, disease control rate and PFS per RECIST v1.1 (and mRECIST for HCC) by BICR, and OS. Efficacy analyses will report binomial proportion or Kaplan-Meier estimates with 95% CIs. Safety analyses will be descriptive. Enrollment began August 2021. Clinical trial information: NCT04976634.