Prior Immune Checkpoint Inhibitor 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 PO3-06-10: Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study

Abstract Background Sacituzumab govitecan (SG) is approved for treatment of metastatic triple negative breast cancer (mTNBC) in the second line and beyond. Little is known about the real-world outcomes of SG. We aim to evaluate the real-world effectiveness and toxicity outcomes of SG in heterogenous heavily pretreated mTNBC patients (pts) to investigate the consistency of the outcomes in comparison to the clinical trial population. Methods A multi-center retrospective study of pts with mTNBC treated with SG in the US from January 2021 until May 2023 was conducted. Demographics and clinicopathological variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs), HER2 immunohistochemistry (IHC) score at time of metastasis, clinical response, clinical benefit rate (CBR) defined as (complete response, partial response (PR) or stable disease (SD) > 6 months) and last follow-up were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. Univariate and multivariate cox regression models examined RDI and survival outcomes. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results A total of 111 pts were analyzed. The median age was 58 years (range 29-84). The majority of pts were heavily pretreated: 59.1% received >3 prior lines of treatment (Tx) in the metastatic setting, 54.1% received prior immune checkpoint inhibitor (ICI), 8.1% received prior olaparib. 55% of pts had significant disease burden defined by >=3 organs involved by metastatic disease, with 22.5% having brain metastasis at the time of initiation of SG. Of note, 51% had primary refractory disease defined as relapse within 12 months of completion of adjuvant chemotherapy. 98.1% experienced any grade AEs, with the most common being anemia 63.1%. Grade 3 AEs occurred in 51.4% pts with neutropenia being the highest 32.4% followed by anemia 14.4%, diarrhea 7.2% and fatigue 7.2%. Tx interruptions and dose reductions due to AEs occurred in 52.3% of patients and Tx discontinuation rate due to AEs was 11.8%. Elderly pts (defined as >65 years) did not have higher rates of dose reductions due to AEs compared to young pts (< = 65 years) (37.8% vs 59.7 %), p=0.043). The median RDI is 92% (interquartile range (IQR) 33%-100%). The median RDI in elderly pts was 94% (IQR 50%-100%). Among pts in which response was assessed, objective response rate (ORR) was 26.6% (25 pts had PR), and 38.3% had SD. Interestingly, the rate of alopecia was higher in pts who had PR as the best response (28%), compared to 5.6% in pts who had SD, and 3% in progressive disease (PD) p=0.004. The median prior line of therapy in pts who had PR and SD as best response was 2 (IQR 1, 5) (IQR1, 12), respectively, compared to a median of 3 (IQR 1, 7) in pts with PD, p< 0.001. The CBR was 49% (46/94). The median duration of clinical benefit was 7 months IQR (2, 16) with median overall survival of 13 months IQR (2.5, 39) compared to 5.7 months IQR (0.03, 27) in pts without clinical benefit (p< 0.001). 56.9% (62/109) of pts had HER2 low disease and the clinical benefit rate in this subgroup was 14.3% (23/62). Conclusion: In a heavily pretreated cohort, SG retains clinical activity and tolerability in mTNBC. This is reassuring given pts on clinical trials tend to be healthier compared to real-world clinical practice. Citation Format: Sabah Alaklabi, Arya Mariam Roy, Paola Zagami, Nicole Held, Saba Shaikh, Lubna Chaudhary, Yara Abdou, Shipra Gandhi. Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study [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 PO3-06-10.

A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation.

468214 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancers (NSCLC) in China. Glecirasib (Jacobio, Beijing, PRC) is a potent and highly selective covalent oral inhibitor of KRAS G12C. Methods: This phase 2 single-arm study (NCT05009329) of glecirasib was conducted in China at 43 sites, enrolling participants with locally advanced or metastatic KRAS G12C mutated NSCLC. Subjects must have received prior platinum-based therapy and an immune checkpoint inhibitor (ICI) as well as appropriate targeted agents for any actionable mutations per local standards. Primary study objective is overall response rate (ORR) assessed by independent review committee (IRC). The secondary study objectives include duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Here we report topline results from this pivotal study. Results: A total of 119 patients with NSCLC harboring KRAS G12C mutation were enrolled and treated with single agent glecirasib at 800mg daily (median follow up 10.4 months). The median age was 62 years, 79% was male and 21% was female, and 80.7% had ECOG PS 1. The prior lines of therapy include 1-3, with 94.1% (112/119) patients having received prior platinum-based therapy and ICI. Confirmed ORR was 47.9% (56/117; 95% CI, 38.5%-57.3%) and confirmed DCR was 86.3% (101/117; 95% CI, 78.7%-92%) assessed by IRC. Median PFS per IRC was 8.2 months (95% CI, 5.5 – 13.1), and median OS was 13.6 months (95% CI, 10.9 – NE). Median DOR has not been reached (95% CI, 7.2 – NE ). Overall, treatment-related adverse events (TRAEs) of any grade were observed in 97.5% of subjects. Most common TRAEs [≥15%] were anemia (56.3%), blood bilirubin increased (48.7%), alanine aminotransferase increased (35.3%), aspartate aminotransferase increased (35.3%), hypertriglyceridemia (28.6%) and γ-Glutamyl transferase increased (15.1%). Grade 3 and 4 TRAEs were observed in 39.5%. No grade 5 TRAEs occurred. Most of patients can stay on the treatment and 5.0% patients discontinued the treatment due to TRAE. In contrast to other FDA approved KRAS G12C inhibitor, Gleciasib has 6.7% of nausea, 7.6% vomiting, 3.4% diarrhea in which only one grade 3 nausea is reported. Conclusion: The pivotal phase 2 study of Glecirasib has met the primary endpoints and demonstrates impressive ORR and PFS with promising clinical activity for patients with KRAS G12C mutated advanced NSCLC. Glecirasib is well tolerated, with an extremely low gastrointestinal toxicity profile, which may improve patient compliance with oral therapy. Clinical trial information: NCT05009329 .

Abstract CT133: A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer

Abstract Background: TIM3 is an inhibitory immunoreceptor linked to decreased activity of immune cells in the tumor microenvironment. S095018 is a human anti-TIM3 IgG2 antibody which blocks binding of phosphatidyl serine to TIM3 promoting the stimulation of T-cells, dendritic cells (DCs) and macrophages. Sym021 is a humanized IgG1 antibody that inhibits binding of PD-1 with its ligands PD-L1 and PD-L2. Preclinical data demonstrated that Sym021 combined with S095018 results in enhanced immunostimulatory antitumor activity. Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancer whose disease progressed under treatment with at least one line of systemic therapy and who had not received prior treatment with PD-1/-L1 inhibitors (NCT04641871). The dose/schedule of Sym021 and S095018 was 3mg/kg IV Q2W and 10mg/kg IV Q2W, respectively. Primary endpoints included overall response rate (ORR) using RECIST v1.1 and incidence/severity of adverse events. Key secondary endpoints included PK parameters, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results As of 31-Oct-2023, 35 patients with stage IV biliary tract cancer (34 cholangiocarcinoma, 1 gallbladder adenocarcinoma) received S095018 in combination with Sym021. All patients were naïve to prior immune checkpoint inhibitor treatment. Twenty-two patients (62.9%) had received 1 prior antineoplastic systemic treatment for advanced/metastatic disease, 34.3% had received ≥2 prior treatments for advanced/metastatic disease. Overall, 34 patients (97.1%) discontinued treatment, 85.7% due to disease progression. Best overall response was 2 PR (5.7%), 11 SD (31.4%), 18 PD (51.4%) and 4 not evaluable. Median PFS and OS were 1.9 months (90% CI 1.8-3.7) and 13.4 months (90% CI 8.2-27.1) respectively. Disease control rate (CR+PR+SD) with SD≥16 weeks, ≥24 weeks and ≥12 months was 28.6%, 22.9% and 8.6% respectively. Treatment emergent adverse events of any grade occurring in >5% of patients included fatigue, pruritus, alkaline phosphatase increase, amylase increase, IRR (each 8.6%) and hypothyroidism, hyperthyroidism, AST increase, lipase increase and myalgia (each 5.7%). Exploratory biomarker analyses in paired tumor biopsies (N=18) showed an intratumoral increase in CD8 T-cell density, as well as upregulation of gene signatures related to IFNg signaling, antigen presentation, T-cell activation and cytotoxicity upon treatment. Baseline tumor biopsies from the two patients who achieved confirmed PR showed high PD-L1 expression. Conclusions: S095018 in combination with Sym021 exhibited antitumor activity in patients with advanced/metastatic recurrent biliary tract cancer who had not received prior treatment with PD-1/-L1 inhibitors. The combination was well tolerated without new safety signals. Further biomarker analysis is ongoing. Citation Format: Francois Ghiringhelli, Richard Kim, Teresa Macarulla, Irene Moreno, Albiruni Razak, Jordi Rodon, Chih-Yi Liao, Thomas Marron, Judith Raimbourg, Helene Kaplon, Julia Geromini, Najah Harouki, Christelle Rodrigues, Pauline Darcel, Niels Jorgen Skartved, Rikke Hald, Daleen Lopez-Ravnborg, Peng He, Xenophon Ianopoulos, Vasileios Askoxylakis, Nehal J. Lakhani, Sarah Davis, Amit Mahipal. A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract 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 CT133.

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.

Cabozantinib with immune checkpoint inhibitorversus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

Multicentre phase II trial of cabozantinib in patients with hepatocellular carcinoma after immune checkpoint inhibitor treatment

Prospective data on treatment after immune checkpoint inhibitor (ICI) therapy in hepatocellular carcinoma (HCC) are lacking. We conducted a phase II multicentre study on cabozantinib after ICI treatment in HCC. This is an investigator-initiated, single-arm, clinical trial involving academic centres in Hong Kong and Korea. Key eligibility criteria included diagnosis of HCC, refractoriness to prior ICI-based treatment, and Child-Pugh A liver function. A maximum of two prior lines of therapy were allowed. All patients were commenced on cabozantinib at 60mg/day. The primary endpoint was progression-free survival (PFS). Forty-seven patients were recruited from Oct 2020 to May 2022; 27 and 20 patients had received one and two prior therapies, respectively. Median follow-up was 11.2 months. The median PFS was 4.1 months (95% CI 3.3-5.3). The median overall survival (OS) was 9.9 months (95% CI 7.3-14.4), and the 1-year OS rate was 45.3%. Partial response and stable disease occurred in 3 (6.4%) and 36 (76.6%) patients, respectively. When used as a second-line treatment (n= 27), cabozantinib was associated with a median PFS and OS of 4.3 (95% CI 3.3-6.7) and 14.3 (95% CI 8.9-NR) months, respectively. The corresponding median PFS and OS were 4.3 (95% CI 3.3-11.0) and 14.3 (95% CI 9.0-NR) months, respectively, for those receiving ICI-based regimens with proven benefits (n= 17). The most common grade 3-4 treatment-related adverse event was thrombocytopenia (6.4%). The median dose of cabozantinib was 40mg/day. The number of prior therapies was an independent prognosticator (one vs. two; hazard ratio= 0.37; p= 0.03). Cabozantinib demonstrated efficacy in patients who had received prior ICI regimens; survival data for second-line cabozantinib following first-line ICI regimens provide a reference for future clinical trial design. The number of prior lines of treatment may be considered a stratification factor in randomised studies. Prospective data on systemic treatment following prior immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) are lacking. This phase II clinical trial provides efficacy and safety data on cabozantinib in patients who had received prior ICI-based treatment. Exploratory analyses showed that the performance of cabozantinib differed significantly when used as a second- or third-line treatment. The above data could be used as a reference for clinical practice and the design of future clinical trials on subsequent treatment lines following ICIs. NCT04588051.

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.

Cabozantinib Plus Atezolizumab or Cabozantinib Alone in Patients With Advanced NSCLC Previously Treated With an Immune Checkpoint Inhibitor: Results From the Phase 1b COSMIC-021 Study

IntroductionWe evaluated efficacy and safety of cabozantinib plus atezolizumab or cabozantinib alone in advanced NSCLC previously treated with an immune checkpoint inhibitor (ICI). MethodsCOSMIC-021 (NCT03170960) is a phase 1b, multicenter study in advanced solid tumors. This analysis included patients with stage IV non-squamous NSCLC without actionable genomic aberrations in EGFR, ALK, ROS1, or BRAF-V600E who progressed on one prior ICI and less than or equal to two prior lines of systemic anticancer therapy. Patients received cabozantinib 40 mg orally/day plus atezolizumab 1200 mg intravenously every three weeks (combination cohort) or cabozantinib 60 mg orally/day (single-agent cabozantinib cohort). Primary end point of the combination cohort was objective response rate per Response Evaluation Criteria in Solid Tumors v1.1 by investigator. Outcomes in the single-agent cabozantinib cohort were exploratory. ResultsEighty-one patients assigned to combination therapy and 31 assigned to single-agent cabozantinib received greater than or equal to one dose of study treatment. Median (range) follow-up was 26.1 months (12.1–44.2) and 22.4 months (1.5–29.0), respectively. Objective response rate was 20% (95% confidence interval: 11.7%–30.1%) in combination cohort and 6% (95% confidence interval: 0.8%–21.4%) in single-agent cabozantinib cohort. Treatment-related adverse events (TRAEs) occurred in 86% of patients in the combination cohort and 90% in the single-agent cabozantinib cohort; grade 3/4 TRAEs were 44% and 48%, respectively. There were two grade 5 TRAEs: pneumonitis (n = 1, combination) and gastric ulcer hemorrhage (n = 1, single-agent). Neither PD-L1 expression in tumor cells nor tumor mutation burden correlated with outcomes. ConclusionsCabozantinib plus atezolizumab demonstrated modest clinical activity and manageable toxicity in advanced NSCLC after progression on prior ICI.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Outcomes of enfortumab vedotin (EV) therapy in relation to prior immune checkpoint inhibitor (ICI) in patients (pts) with advanced urothelial cancer (aUC).

570 Background: EV is FDA approved for the treatment of aUC after disease progression with chemotherapy and/or ICI, and in combination with Pembrolizumab (P) for cisplatin ineligible pts in the first line. Reported response rate (RR) for EV+P is higher than EV alone and a retrospective study showed prior ICI is associated with higher grade of EV-related skin toxicity, suggesting immunogenic interaction. Herein we evaluated whether prior ICI correlates with improved response to EV monotherapy. Methods: This single-center retrospective study compared outcomes between pts with aUC who were treated with ICI immediately prior to EV (iICI) vs pts who did not receive immediate prior ICI (niICI). We also evaluated outcomes in pts who received ICI at any time prior to EV, with or without intervening treatments, compared to pts who never received ICI. Demographics and treatment details were extracted through chart review. RR (Complete Response + Partial Response) were compared between groups using χ2 test. Univariable and multivariable Cox regression models were used for comparing Progression free (PFS) and Overall (OS) survival. Multivariable models were adjusted for visceral metastasis presence and performance status (PS) at EV initiation (C1D1). Results: We identified 55 pts in the iICI group and 23 in the niICI. Table 1 summarizes patient characteristics. ICIs included Pembrolizumab, Atezolizumab, Nivolumab, and Avelumab. Median PFS for EV was 5.0 vs 2.0 months and OS 11.0 vs 7.1 months in iICI vs niICI group respectively. A statistically significant Hazard Ratio (HR) for PFS [HR: 1.72, 95% Confidence Interval (95CI): 1.03, 2.89, P=0.04] and OS (HR: 2.02, 95CI: 1.13, 3.60, P=0.02) was found in the univariable analysis. In the multivariable analysis HR was 1.56 (95CI: 0.91, 2.68, p= 0.11) for PFS and 1.79 (95CI: 0.97, 3.30, p=0.06) for OS. RR to EV was 43.6% (95CI: 0.33, 0.56) vs 43.5% (95CI: 0.14, 0.69), P= 0.99. In our cohort 70/78 (89.7%) pts received ICI prior to EV with or without intervening treatments. When comparing these pts to pts who never received ICI no significant difference was found in PFS, OS or RR. Conclusions: In our study, EV was associated with longer PFS and OS when given immediately after ICI compared to following other therapies. However, in the most parsimonious model examined, the p-value did not reach a significance threshold of p<0.05. Larger prospective studies are needed to better understand the mechanism behind this trend and identify the optimal sequence or combination of EV with other treatments in aUC. [Table: see text]

Camrelizumab plus apatinib after progression on immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma (CAP 02 Re-challenge): A single-arm multicenter, phase II trial.

364 Background: The optimal therapies for patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed after immune checkpoint inhibitors (ICIs) are unclear. This phase II single-arm study aimed to assess the efficacy and safety of re-challenge with camrelizumab plus apatinib in this population. Methods: This study enrolled patients with unresectable locally advanced, locally recurrent, or metastatic ESCC who had experienced prior progression on ICI treatment. Enrolled patients received camrelizumab 200 mg intravenously every two weeks along with daily oral apatinib 250 mg. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal of consent. The primary endpoint was the confirmed objective response rate (ORR). Secondary endpoints included disease control rate (DCR), duration of response (DOR), time to response (TOR), progression-free survival (PFS), overall survival (OS), 3- and 6-month PFS rates, 6-, 9- and 12-month OS rates, and safety. Results: From September 1, 2021, to March 29, 2023, 49 eligible patients were enrolled and given treatment. Among 38 treated patients who had at least one post-baseline efficacy measurement, the ORR and confirmed ORR were 36.8% (95% CI 21.8–54.0) and 13.2% (95% CI 4.4–28.1); the DCR was 89.5% (95% CI 75.2–97.1); the median DOR was 3.0 months; and the median TOR was 2.2 months. Among the 49 treated patients, the median PFS was 4.6 months (95% CI 3.8–6.5) and OS was 7.5 months (95% CI 5.5–13.6). Patients who were both PD-L1 positive and had responded to previous ICI therapy had the longest median PFS (5.7 months, 95% CI 3.9–not reached) and OS (9.6 months, 95% CI 7.5–not reached). Grade ≥ 3 treatment-related adverse events occurred in 34.7% of patients (17/49). Conclusions: This study showed promising efficacy and an acceptable safety profile of camrelizumab plus apatinib for patients with advanced ESCC who had progressed after ICI therapy. The subset of patients who were both PD-L1 positive and had a prior ICI response seemed to benefit most. Clinical trial information: NCT03736863 .

Pan-cancer assessment of antineoplastic therapy-induced interstitial lung disease in patients receiving subsequent therapy immediately following immune checkpoint blockade therapy

BackgroundDrug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown.MethodsThis study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel.ResultsOf 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%–8.7%) and 7.2% (95% CI 4.0%–11.5%), respectively. There were significant differences according to cancer type (Gray’s test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%–18.0%) at 3 months and 14.2% (95% CI 7.3%–23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%–29.7%) vs 4.3% (95% CI 0.3%–18.2%) at 3 months; and 21.7% (95% CI 7.9%–39.9%) vs 4.3% (95% CI 0.3%–18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64–45.33; Fine–Gray P = .12).ConclusionsPatients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model.

Because prior immune checkpoint inhibitor (ICI) therapy in cancer patients presenting with COVID-19 may affect outcomes, we investigated the beta-coronavirus, murine hepatitis virus (MHV)-1, in a lethal pneumonia model in the absence (Study 1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study 2). In Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production. Study 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophagecolony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model. In Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.

Dosimetric predictors of radiation pneumonitis in patients with prior immunotherapy exposure: A multi-institutional analysis

Background and purposeCombining immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) may magnify the radiation pneumonitis (RP) risk. Dosimetric parameters can predict RP, but dosimetric data in context of immunotherapy are very scarce. To address this knowledge gap, we performed a large multicenter investigation to identify dosimetric predictors of RP in this under-studied population. Materials and methodsAll lung cancer patients from five institutions who underwent conventionally-fractionated thoracic intensity-modulated radiotherapy with prior ICI receipt were retrospectively compiled. RP was defined per CTCAE v5.0. Statistics utilized logistic regression modeling and receiver operating characteristic (ROC) analysis. ResultsThe vast majority of the 192 patients (median follow-up 14.7 months) had non-small cell lung cancer, received PD-1 inhibitors, and did not receive concurrent systemic therapy with TRT. Grades 1–5 RP occurred in 21.9%, 25.0%, 8.3%, 1.6%, and 1.0%, respectively. The mean MLD for patients with grades 1–5 RP was 10.7, 11.6, 12.6, 14.7, and 12.8 Gy, respectively. On multivariable analysis, tumor location and mean lung dose (MLD) significantly predicted for any-grade and grade ≥ 2 pneumonitis. Only MLD significantly predicted for grade ≥ 3 RP. ROC analysis was able to pictorially model RP risk probabilities for a variety of MLD thresholds, which can be an assistive tool during TRT treatment planning. ConclusionThis study, by far the largest to date of dosimetric predictors of RP in the immunotherapy era, illustrates that MLD is the most critical dose-volume parameter influencing RP risk. These data may provide a basis for revising lung dose constraints in efforts to better prevent RP in this rapidly expanding ICI/TRT population.

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.

1898P Comparative real-world effectiveness of PD-1/L1 inhibitor (PD-1i) plus cabozantinib (cabo) vs cabo after progression with prior immune checkpoint inhibitor (ICI) treatment (Rx) in metastatic clear cell renal cell carcinoma (mccRCC)

1898P Comparative real-world effectiveness of PD-1/L1 inhibitor (PD-1i) plus cabozantinib (cabo) vs cabo after progression with prior immune checkpoint inhibitor (ICI) treatment (Rx) in metastatic clear cell renal cell carcinoma (mccRCC)

ORCHID: A phase II study of Olaparib in Metastatic Renal Cell Carcinoma Patients HarborIng a BAP1 or Other DNA Repair Gene Mutations

Abstract Background DNA damage repair genes alterations (DDRa) are frequent events in renal cell carcinoma (RCC), including BAP1 and other DDRa. Olaparib is a poly ADP ribose polymerase inhibitor (PARPi) that is FDA-approved for the treatment of several malignancies with DDRa. Preclinical models demonstrated synthetic lethality with PARPi in RCC cell lines including BAP1 mutant lines. Here we report an interim analysis of the ORCHID study investigating the clinical activity of single agent olaparib in patients (pts) with advanced RCC (aRCC) harboring BAP1 other select DDRa. Methods We conducted a single center, single arm, investigator-initiated Phase 2 trial of olaparib in pts with aRCC. Eligible pts harbored select DDRa and had prior therapy with immune checkpoint inhibitors (ICIs) and/or VEGF-TKI. Pts were treated with olaparib at an initial dose of 150mg twice which was increased to 300mg twice daily after one month if well tolerated. The primary endpoint is disease control rate (DCR) by RECIST v1.1 (including complete response (CR), partial response (PR), and stable disease (SD) >6 months). Secondary endpoints included objective response rate (ORR), progression free survival (PFS), and safety. Results Eleven pts were enrolled with a median age of 59 years (48-72) including 9 pts with clear cell RCC and 2 pts with unclassified RCC. Most pts had BAP1 mutations (Table). 36% of pts had history of brain metastasis. Median number of prior lines of therapies was 2 (1-6) and all pts received prior ICI. The study met the pre-specified Simon’s 2 stage design for the first stage with 22% DCR in the evaluable pts (2/9), including deep PR (>70% reduction in tumor volume) and SD of 10 months. Both pts harbored BAP1 mutations. An additional pt with BRCA1 mutation had 20% decrease in measurable disease. There were no treatment related adverse events resulting in study discontinuation. Conclusions This is the first study investigating single agent PARPi in RCC with the interim trial analysis indicating promising activity of olaparib in aRCC pts with BAP1 mutations including one pt with deep PR. These results support further development of PARPi in this setting.

Real-world efficacy and safety of cabozantinib following immune checkpoint inhibitor failure in Japanese patients with advanced renal cell carcinoma.

Real-world data of cabozantinib after failure of immune checkpoint inhibitors for advanced renal cell carcinoma in Japanese population are limited. Additionally, prognostic factors of cabozantinib in this setting are still unknown. We retrospectively evaluated data of 56 patients treated with cabozantinib subsequent to failed immune checkpoint inhibitors at four institutions. Regarding the efficacy profile, progression-free survival, overall survival and objective response rate were assessed. In terms of the safety profile, rate of adverse events, dose reduction and treatment interruption were assessed. Furthermore, risk factors of progression-free survival were analyzed. Twenty-nine patients (52%) were treated with cabozantinib as second-line therapy. Most frequent prior immune checkpoint inhibitor treatment was nivolumab plus ipilimumab combination therapy as first-line therapy (n=30, 54%). Median progression-free survival and overall survival were 9.76 and 25.5months, respectively, and objective response rate was 34%. All patients experienced at least one adverse event, and grade≥3 adverse events were observed in 31 patients (55%). Forty-four (79%) and 31 (55%) patients needed dose reduction and treatment interruption, respectively. Multivariate analysis showed that reduced initial dose (i.e. <60mg) (hazard ratio: 2.50, P=0.0355) and presence of lymph node metastasis (hazard ratio: 2.50, P=0.0172) were independent factors of shorter progression-free survival. Cabozantinib in Japanese patients with advanced renal cell carcinoma who failed immune checkpoint inhibitors was efficacious and had a manageable safety profile. These results appear to be similar to those of previous clinical trials.

Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma.

The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking. We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method. The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies.