Prior Checkpoint Inhibitor Therapy Research Articles

Final Analysis of a Noninterventional Study on Cabozantinib in Patients With Advanced Renal Cell Carcinoma After Prior Checkpoint Inhibitor Therapy of the German Interdisciplinary Working Group on Renal Tumors (IAG-N)

BackgroundEfficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC). ObjectiveTo evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies. Design, setting and participantsPatients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany. InterventionsCabozantinib was administered as a standard of care. Outcome measurements and statistical analysisAdverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized. Results and limitationsAbout 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study. ConclusionsCabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.

A phase 1 study of IO102-IO103 vaccine plus pembrolizumab in patients with BCG-intolerant or unresponsive non-muscle invasive bladder cancer (NMIBC).

TPS716 Background: Pembrolizumab, an anti-PD1 antibody, is a treatment option for high-risk BCG-unresponsive NMIBC, but has a modest complete response (CR) rate of 41% at 3 months, and a median duration of CR of 16.2 months. IO102-IO103 is a novel immune-modulating cancer vaccine that stimulates activation of T cells targeting indoleamine-2,3-dioxygenase 1 (IDO1) and PDL1-positive cells, resulting in potentially increased susceptibility to anti-PD-1 blockade. Combination IO102-IO103 with nivolumab showed encouraging clinical activity and tolerability in previously anti-PD-1 naïve metastatic melanoma patients (NCT03047928). The existing data for synergistic effects of IO102-IO103 in combination with anti-PD1 therapy and the known expression of IDO in urothelial carcinoma lend rationale to this phase I trial designed to assess the feasibility, safety, and toxicity of IO102-IO103 plus pembrolizumab in patients with BCG-intolerant or unresponsive NMIBC. Methods: This open-label, single arm, phase 1 study enrolls patients with BCG-unresponsive or intolerant high-risk NMIBC who are ineligible for or have declined cystectomy and have adequate ECOG performance status (0-2), hematologic function, and end organ function. High-risk NMIBC is defined as T1, high-grade Ta, or CIS/Tis, with predominantly urothelial cell histology. Exclusion criteria include known active autoimmune disorders requiring immunosuppressive therapy or prior checkpoint inhibitor therapy. Eligible patients will be treated with pembrolizumab 200 mg IV on Day (D) 1, and IO102-IO103 85 mcg SQ on D1 and 8 of a 21-day cycle for the first two cycles, after which IO102-IO103 dosing will be D1 only, with treatment for up to 2 years. The primary endpoints of feasibility, safety, and toxicity will be evaluated by CTCAE v5.0 criteria and will be met if ≥10 patients out of 12 are able to complete the first cycle without experiencing pre-specified treatment-limiting toxicities. Key secondary endpoints include CR rate at 3 months, median duration of response, and cystectomy-free survival at 18 months. Biopsy specimens and serial urine and blood samples will be collected to evaluate potential biomarkers of response. Clinical trial information: NCT05843448 .

Phase 2 study of bintrafusp alfa in recurrent/metastatic olfactory neuroblastoma.

TPS6116 Background: Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a rare malignant tumor of the nasal cavity, believed to arise from the basal cells of the olfactory neurosensory epithelium. ONB is often locally advanced at diagnosis with high rates of spread both locoregionally and systemically. Current therapy for locoregional disease is local resection with adjuvant (chemo-) radiotherapy. Actionable mutations are rare, and treatment options for recurrent or advanced, non-resectable, disease are limited and include off-label combination chemotherapy (most frequently platinum-containing) and somatostatin-directed therapies (ONB expresses somatostatin receptors). These are based on limited data, with response rates poorly characterized. Bintrafusp alfa is a first-in-class, bifunctional TGF-β “trap”/anti-PD-L1 fusion protein. Analysis of ONB has demonstrated both PD-1/PD-L1 (London et al, 2018) and TGF-β ligand expression (Romani et al, 2021). Pre-clinical and clinical data in advanced solid tumors demonstrate enhanced antitumor activity with combination PD-L1/TGF-β blockade, with responses observed independently of high PD-L1 levels (Strauss et al, 2020). Thus, combination PD-L1/TGF-β blockade in ONB is a rational approach in a setting of unmet clinical need. Methods: This study is a Phase 2 single-site, single-arm clinical trial of bintrafusp alfa (1200mg IV every 2 weeks for up to 26 doses) for patients with recurrent or metastatic ONB. Participants must co-enroll to the ONB Natural History study at the NCI (NCT4755205). Patients must not be candidates for local therapy, have received at least 1 line of systemic therapy (including a platinum salt), have RECIST 1.1 measurable disease and have adequate organ function. Prior checkpoint inhibitor therapy is permitted with patients cohorted according to checkpoint exposure; up to 21 checkpoint-naïve and 8 checkpoint-resistant patients will be enrolled. The primary objective is objective response rate by RECIST 1.1 with secondary endpoints including safety and tolerability, duration of response and overall survival; exploratory endpoints include pharmacokinetic analyses, PD-L1 and immune cell correlative analyses. The trial follows a Simon two-stage design, requiring ≥1 response in the first 12 patients. Tumor biopsy at enrollment is optional. Imaging for response assessment is planned for 8-week intervals and PET scan (preferably 68Ga-DOTATATE) will be obtained for all patients at baseline and first restaging, then on an individualized basis per radiology advice. This study is presently open at the NCI with 5 patients enrolled as of January 2023. Clinical trial registry:NCT05012098. Clinical trial information: NCT05012098 .

OATH trial: A phase II clinical trial evaluating the combination of onapristone with anastrozole for women with hormone receptor positive endometrial cancer—Preliminary results.

5601 Background: Endometrial cancer is the most common gynecologic cancer and is primarily treated with chemotherapy. Many endometrial cancers though express hormone receptors and may respond to hormonal therapy, a potentially attractive non-chemotherapy alternative in such a population of women. The aim of OATH is to investigate the potential of dual hormonal blockade through the combination of antiprogesterone and anti-estrogen therapy via the administration of onapristone extended release (ONA) plus anastrozole (ANA), respectively. OATH is an open-label, multicenter, investigator-initiated, non-randomized, phase 2 study to evaluate the safety and efficacy of ONA + ANA in patients (pts) with endometrial cancer (EC). ClinicalTrials.gov Identifier: NCT04719273. Methods: Pts received ONA 50 mg twice daily plus ANA 1 mg once daily and were treated until progressive disease (PD) or unacceptable toxicity. Co-primary endpoints were 4-month progression-free survival (PFS) rate and overall response rate (ORR). A sample size of 25 pts will achieve 80% power to detect an improvement in 4-month PFS estimates from 25% (historical) to 52% and an improvement in response rate from 15% (historical) to 37%, using two-sided exact test at 5% significance level. Secondary endpoints include PFS, disease control rate (DCR), and safety. Results: As of January 20, 2023, 14 pts were enrolled. Median age was 67 years (44-80). ECOG performance status was 0 (36%), and 1 (64%). Number of prior chemotherapy regimens was 0 (1 pt,7%), 1 (9 pts, 64%) and 2 (4 pts, 29%). Seven (50%) pts received radiotherapy and 3 (21%) pts received prior checkpoint inhibitor therapy. Median treatment duration was 4.2 (1.0-19.9) months, and 8 pts remain on treatment. Adverse events were mainly grade 1 and 2. The most common treatment-related adverse events (AEs) and abnormal laboratory values were hot flashes (36%), alanine transferase (ALT) increased (29%), aspartate aminotransferase (AST) increased (29%), nausea (29%), and diarrhea (21%). No treatment-related serious AE, deaths on treatment, or treatment-related drug discontinuations were reported. The 4-month PFS Kaplan-Meier rate was 63.5%. Among 13 pts who had at least one tumor assessment after baseline, the best overall response was: 1 complete response, 1 partial response (response rate: 15.4%), 9 (69%) stable disease, and 2 (15.4%) progressions. Updated results will be presented. Conclusions: Preliminary results of dual hormonal blockade using ONA and ANA in heavily pretreated pts with EC suggest that this combination ONA + ANA has promising activity and is well tolerated. Clinical trial information: NCT04719273 .

Abstract CT188: ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial

Abstract Background: γ9δ2 T cells are part of the innate-like immune response to malignancies and have the ability to bridge to the adaptive immune response via cytokine release (e.g., IFNγ and TNFα). Butyrophilin 3A is a novel checkpoint molecule required to activate γ9δ2 T cells highly expressed on immune and malignant cells, and the target of a monoclonal antibody ICT01. ICT01 induces activation/migration of γ9δ2 T cells from the blood to induce immune remodeling of the tumor microenvironment at doses ≥700 μg being tested in the ongoing EVICTION clinical trial (NCT04243499) (AACR 2021, CT034). In vitro studies showed that ICT01 induces upregulation of PD-1 on γ9δ2 T cells and that the combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale for evaluating this combination. Methods: EVICTION is an ongoing Phase 1/2a, international, open-label trial with Group C assessing ICT01 (IV Q3W) plus pembrolizumab (200mg IV Q3W) in patients with bladder cancer, HNSCC, melanoma, or NSCLC who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations by i/RECIST 1.1 were conducted every 8 weeks. Results: Five Group C patient cohorts have been enrolled and treated with ICT01 doses of 700μg, 2mg, 7mg, 20mg or 75mg (n=30) plus pembrolizumab, with the 200mg ICT01 cohort enrolling currently. To date, no DLTs have been observed with the combination. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency up to 75mg (100%, n=6), without any increase in severity, and rarely recur with subsequent dosing. ICT01+pembrolizumab induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥700 μg), which was sustained for 21 days at 75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and returned to baseline by 24 hrs post dose. Baseline γ9δ2 T cell count also correlated with increases in tumor infiltration of γδ, CD3, and CD8 T cells, confirming the ability to remodel the TME, and the potential to select/enrich patients with higher baseline γ9δ2 T cell counts. Sixteen patients (9/16 pembro-experienced, 5/16 received >1 prior CPI) were efficacy-evaluable at ≥Week 8 by RECIST1.1 at ICT01 doses up to 20 mg, with an observed disease control rate of 44% including 3 confirmed PRs beyond 6 months: bladder (2mg), melanoma (2mg), NSCLC (7mg). The Ipi/Nivo-refractory melanoma patient with PR also achieving a CR on their non-target lesion brain metastasis at 6 months. Data from the 75 and 200mg cohorts will be presented. Conclusion: The immune remodeling of the TME by ICT01-activated γ9δ2 T cells is associated with clinical benefit in CPI-experienced patients when used in combination with pembrolizumab. The selection of patients with higher baseline γ9δ2 T cells may improve the response profile to this novel therapeutic combination in CPI-failure patients, which will be tested in the Phase 2a portion of EVICTION starting in Q2 2022. Citation Format: Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, Paul Frohna. ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT188.

Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1.

2500 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 (IL-2) receptor (IL-2R) to preferentially activate antitumor CD8+ T cells and natural killer (NK) cells with minimal expansion of immunosuppressive regulatory T cells. It is sterically occluded from binding to the high-affinity IL-2R, leveraging antitumor effects of the IL-2 pathway but mitigating toxicity associated with preferential binding of IL-2 to the high-affinity IL-2R. Methods: ARTISTRY-1 (NCT02799095) is a 3-part, first-in-human, phase 1/2 study of IV nemvaleukin alone and in combination with pembrolizumab in pts with advanced solid tumors. Parts A (dose escalation to 10 µg/kg/day), B (monotherapy in pts with melanoma or renal cell carcinoma [RCC]), and C (combination) included nemvaleukin 3 or 6 µg/kg/day ´ 5 and pembrolizumab every 21 days. Investigator-assessed antitumor activity (confirmed responses as per RECIST v1.1) and safety are reported as of 29 October 2021. Results: In Part A (N = 46), nemvaleukin recommended phase 2 dose was 6 µg/kg/day IV; maximum tolerated dose not reached. One pt had dose-limiting toxicity (grade 4 acute kidney injury) at 10 µg/kg. Pts in Parts B and C were heavily pretreated (1–9 prior lines of therapy, including prior checkpoint inhibitor therapy). Durable antitumor activity was observed for nemvaleukin monotherapy, including in RCC (objective response rate [ORR], 18.2% [4/22]) and in melanoma (ORR, 8.7% [4/46]), with 2 partial responses (1 unconfirmed) in 30 pts with cutaneous melanoma (ORR, 6.7%) and 2 PRs (1 unconfirmed) in 6 pts with mucosal melanoma (ORR, 33.3%). Durable antitumor activity was also observed for combination therapy (ORR, 16.1% [22/137]; disease control rate [DCR], 59.9%), including in platinum-resistant ovarian cancer (PROC; ORR, 28.6% [4/14]; DCR, 71.4%), with 2 complete responses and 2 PRs (1 unconfirmed) in 14 pts. Forty-three pts remain on therapy. The most frequent grade 3/4 treatment-related adverse events in Parts B and C, respectively, were anemia (9%, 10%), neutropenia (34%, 9%), and decreased neutrophil count (12%, 9%). Safety was consistent with previous reports. In pharmacodynamic studies, nemvaleukin monotherapy induced robust expansion of CD8+ T and NK cells, with minimal effect on regulatory T cells. Conclusions: ARTISTRY-1 showed proof of principle for preferential expansion of CD8+ T cells and NK cells by nemvaleukin. Nemvaleukin was generally well tolerated and demonstrated promising efficacy. Durable responses were observed with monotherapy and combination therapy in heavily pretreated pts across a range of tumors, warranting further investigation. The US FDA granted nemvaleukin Fast Track designation for treatment of mucosal melanoma and PROC, and Orphan Drug designation for mucosal melanoma. Clinical trial information: NCT02799095.

Final analysis of a non-interventional study on cabozantinib in patients with advanced renal cell carcinoma after prior checkpoint inhibitor therapy (CaboCHECK).

357 Background: Data for cabozantinib after IO-combinations in metastatic renal cell carcinoma (mRCC) remain scarce. We therefore evaluated safety and effectiveness of cabozantinib after failure of IO-based therapies. Methods: Data from patients (pts) with mRCC and cabozantinib treatment after IO-based therapy was retrospectively collected from medical records. Primary endpoint was the incidence of serious adverse events (SAEs). Response rate was assessed clinically (CRR) and/or according to RECIST 1.1. Overall Survival (OS) and Progression Free Survival (PFS) were assessed from start of therapy and data were compared for pts with starting dose of 60 mg (cohort A) vs < 60 mg (cohort B) in a post-hoc analysis. Descriptive statistics and KM-plots were utilized, where appropriate. Results: This final analysis (cut off 08-Oct-21) assessed 56 eligible pts (71.4% male) with median age of 66 yrs. 87.5% (n = 49) had previous nephrectomy. 66.1% (n = 37) had clear cell RCC. 89.3% (n = 50) had ≥2 previous lines. ECOG ≤1 was 33.9% (n = 19). IMDC factors were 0 in 2 (3.6%), ≥1 in 21 (37.5%), missing in 31 pts (55.4%). 62.5% (n = 35) started at reduced dose. 55.4% (n = 31) required dose reductions and 1.8% (n = 1) discontinuation. Median treatment duration was 6.1 months (m). PR was 10.7% (n = 6), SD 19.6% (n = 11), PD 12.5% (n = 7) and missing in 57.1% (n = 32). Median OS and PFS were 15.34 m (95% CI 8.94, 20.93) and 6.34 m (95% CI 5.29, 8.25) in the ITT, 10.48 m (95% CI 6.01, 34.14) and 6.51 m (95% CI 2.99, 10.87) in cohort A and 16.46 m (95% CI 9.56, 23.33) and 6.34 m (95% CI 4.86, 8.71) in cohort B, respectively. All grade AEs and grade 3-5 AEs were 87.5% (n = 49) and 44.6% (n = 25) in the ITT, 95.0% (n = 19) and 55.0% (n = 11) in cohort A and 85.7% (n = 30) and 40.0% (n = 14) in cohort B. SAEs were reported in 21.4% (n = 12) of pts, which were 30.0% (n = 6) of cohort A and 17.1% (n = 6) of cohort B. Treatment related SAEs were reported in 10.7% (n = 6) of pts, which were 15.0% (n = 3) in cohort A and 8.6% (n = 3) in cohort B. Conclusions: Cabozantinib directly after IO therapy was safe and feasible. No new safety signals were reported. A reduced starting dose was frequently utilized and was not associated with adverse outcomes. Our data supports the use of cabozantinib after IO-failure. Major limitation was the retrospective nature of our study.[Table: see text]

Abstract P2-14-17: A phase 1b study of PVX-410 vaccine in combination with pembrolizumab in metastatic triple negative breast cancer (mTNBC)

Abstract Background: Immunotherapy with checkpoint inhibition is active in mTNBC. Both pembrolizumab and atezolizumab are FDA approved for programmed cell death ligand 1 positive (PDL1+) mTNBC. Vaccines may further induce host immune response and enhance therapeutic activity of checkpoint inhibitors. PVX-410 (PVX) (OncoPep, Inc.) is a novel, HLA-A2 restricted, tetra-peptide vaccine, with 3 of its 4 antigens (XBP1[2 splice variants] and CD138) commonly overexpressed in TNBC. We present results from a phase 1b study evaluating the immune response, safety and tolerability, and clinical activity of PVX and pembrolizumab (PEM) in mTNBC. Methods: Eligibility for this phase 1b multi-center, single-arm study included HLA-A2+, PD-L1 unselected female patients (pts) ≥18 years with metastatic or inoperable locally advanced TNBC, measurable disease, and any number of prior therapies, including prior checkpoint inhibitor therapy. Pts received 6 doses of 800µg PVX emulsified in Montanide ISA 720 VG by subcutaneous injection co-administered with intramuscular Hiltonol weekly for 6 weeks (wks) followed by booster vaccine doses at wks 10 and 28, with concurrent intravenous 200 mg PEM every 3 wks starting with the second PVX dose. Therapy was given until progressive disease, unacceptable toxicity or a maximum of 24 months. Blood samples were scheduled for immune response assessment at baseline and at weeks 2, 5, 10, 28, and 52 post-treatment initiation. The primary objective was PVX- specific immune response at week 10. Immune response was defined as a ≥2-fold change over baseline in the proportion of CD3+CD8+ T cells that expressed IFNγ and the proportion of CD3+CD8+ T cells positive for PVX tetramers following an in vitro stimulation of PBMC with PVX peptides using a flow cytometric assay. Secondary objectives were immune response at wk 28, safety and tolerability, and clinical endpoints (RR, CBR, DCR, DoR, PFS, and OS). Results: Between 3/2018 and 8/2020, 19 pts enrolled. Median age was 62 yrs (range 46-79), with median 2 (range 0-9) lines of prior therapy for metastatic disease. Median disease-free interval among 16 pts with prior early TNBC was 3.3 years. Among 19 enrolled patients, 16 were available for analysis at the time of abstract submission. Among the 16, 10 pts were evaluable at week 10 and 7(70%) demonstrated a PVX specific immune response. There were 6 patients who progressed before week 10, of whom 3 (50%) had a positive immune response at the EOT visit. Immune response persisted in all evaluable pts assessed at week 28 (n=4). Immune response data for all evaluable patients will be updated at the presentation. Among 19 patients evaluable for safety analysis, the most common adverse events (AEs) attributable to PVX (grade ≥2) included: fatigue (21%), arthralgia (11%) injection site reaction (5 %) pain (5%) lymphocyte count decreased (5%), maculopapular rash (5%) and skin infection (5%) . There were two grade 3 AEs attributed to PEM (AST elevation, hyponatremia) and one grade 4 AE (ALT elevation). There were no grade 5 AEs. The clinical benefit rate (CR+PR+SD for ≥16 weeks) was 31.6% with no confirmed partial or complete responses. Best overall response was SD in 9 (47%) patients. Analysis of additional clinical endpoints including PFS and OS is ongoing and will be presented at the meeting. Conclusions: PVX plus PEM is safe with manageable toxicity in pts with mTNBC. No new unexpected adverse events were identified. Immune response data show PVX induces antigen-specific T cell expansion as observed by increases in PVX tetramer and IFN positive T cells. Clinical disease control was observed with a CBR of 31.6%. Based on these promising immune response results in this pretreated population, a phase 2 study with PVX+PEM in combination with standard chemotherapy in treatment naïve, PD-L1+ mTNBC is underway (NCT04634747). Citation Format: Steven J Isakoff, Nadine M. Tung, Jun Yin, Nabihah Tayob, Joanne Parker, Julie Rosenberg, Aditya Bardia, Laura Spring, Hannah Park, Maya Collins, William T. Barry, Mariano Severgnini, Doris Peterkin, Sara M. Tolaney. A phase 1b study of PVX-410 vaccine in combination with pembrolizumab in metastatic triple negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-17.

Clinical features of drug-induced hypersensitivity syndrome to BRAF inhibitors with and without previous immune checkpoint inhibition: a review.

Cutaneous reactions to BRAF inhibitors are common, but severe reactions resembling or consistent with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are relatively rare. Several reports suggest that cutaneous reactions including DRESS/DIHS to BRAF inhibitors are more frequent and severe in the setting of previous immune checkpoint inhibition (ICI). To characterize existing literature on these reports, we queried the PubMed/MEDLINE database for cases of DIHS/DRESS to BRAF inhibitors. We identified 23 cases of DIHS to BRAF inhibitors following checkpoint inhibition and 14 cases without prior checkpoint inhibitor therapy. In both cohorts, DIHS occurred relatively early, with median time to onset from drug exposure of 8-10days. Patients who received prior ICI were less likely to have peripheral eosinophilia (26% vs 71%), atypical lymphocytes (9% vs 50%), renal involvement (61% vs 79%), hepatic involvement (52% vs 86%), and lymphadenopathy (9% vs 43%) compared to patients who did not receive prior ICI. Thrombocytopenia was more common with prior ICI (17% vs 7%). Only patients who received prior ICI experienced hypotension (26%) during the course of their DIHS. All cases of BRAF-induced DIHS generally improved on systemic steroids/supportive care, and no cases of death were identified. Dermatologists should consider a diagnosis of DIHS following BRAF inhibitor initiation, particularly in the setting of past checkpoint inhibition, with atypical features including relatively rapid onset and steroid responsiveness, lack of peripheral eosinophilia, lymphocytosis, or lymphadenopathy, and increased risk of thrombocytopenia and hypotension.

AdvanTIG-302: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (OCI) plus tislelizumab (TIS) versus pembrolizumab (PEM) in programmed death ligand-1 (PD-L1) selected, previously untreated, locally advanced, unresectable or metastatic non-small cell lung cancer (NSCLC).

TPS9128 Background: Monotherapy with programmed death 1 (PD-1)/PD-L1 antibodies has improved clinical outcomes for patients (pts) with non-oncogenic driven NSCLC but clinical responses are limited by primary and secondary resistance, and improvements in durability of response are required. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is a co-inhibitory, immune checkpoint receptor upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. OCI (BGB-A1217) is a novel, humanized mAb that binds to TIGIT with high affinity and specificity, which has demonstrated competent binding with C1q and all Fcγ receptors while inducing antibody-dependent cellular cytotoxicity. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-302 is a Phase 3, multicenter, international, randomized, double-blind study (NCT04746924) investigating OCI in combination with TIS compared with PEM in adult pts (≥ 18 years of age) with PD-L1 selected, previously untreated, locally advanced, unresectable or metastatic NSCLC without oncogenic EGFR or ALK mutation. Approximately 605 pts will be randomized 5:5:1 to receive: OCI 900 mg intravenously (IV) plus TIS 200 mg IV every three weeks (Q3W; Arm A), PEM 200 mg IV plus placebo IV Q3W (Arm B) or TIS 200 mg IV plus placebo IV Q3W (Arm C). Pts will be treated until disease progression, loss of clinical benefit, intolerable toxicity or withdrawal of consent. Stratification factors include histology (squamous vs non-squamous) and region (Asian vs non-Asian). Cross-over is not permitted. Key eligibility criteria include histologically confirmed disease, PD-L1 expression ≥ 50%, no known EGFR or ALK mutations and no prior checkpoint inhibitor therapy. Dual primary endpoints are investigator-assessed progression-free survival (PFS; RECIST v1.1) and overall survival (Arms A and B) in the Intention-to-Treat population. Secondary endpoints include PFS (assessed by Blinded Independent Review Committee), investigator-assessed overall response rate and duration of response, safety and tolerability, and patient-reported health-related quality of life (EORTC-QLQ-C30, QLQ-LC13 and EQ-5D-5L; Arms A and B). Exploratory endpoints include disease control rate, clinical benefit rate and time to response. This study will also evaluate the association between biomarkers and response or resistance. Study enrollment has begun and recruitment is ongoing. Clinical trial information: NCT04746924.

Results from the phase Ib of the SENSITIZE trial combining domatinostat with pembrolizumab in advanced melanoma patients refractory to prior checkpoint inhibitor therapy.

9545 Background: Anti-PD-1 +/- anti-CTLA4 antibodies are the current standard of care immunotherapy for advanced melanoma. However, a significant proportion of patients do not achieve disease control. Epigenetic modulation, particularly histone deacetylase (HDAC) inhibition, can overcome tumor escape mechanisms and thus might increase the susceptibility to immunotherapy. Methods: Advanced unresectable/metastatic cutaneous melanoma patients primary refractory or non-responding to prior checkpoint inhibitor (CI) therapy were treated with domatinostat at 5 different dose levels (DL) (100 mg (QD), 200 (QD), and 200 mg (BID) using two different schedules (D1-14 and D1-21 q3w) in combination with pembrolizumab (2 mg/kg) q3w to evaluate safety and tolerability. Tumor assessments were performed every 12 weeks and assessed using irRECIST. Sequential tumor biopsies were taken for gene expression analysis and peripheral blood for pharmacokinetic (PK) analysis. Results: We report on preliminary results from the phase Ib part of the ongoing study, data cut-off Feb 1st, 2021 a total of 40 patients have been enrolled. Patient characteristics show that the median number of pretreatments at stage IV was 3, 65 % of patients stage M1c (AJCC 7 or 8) and 35 % with elevated LDH at trial inclusion. Treatment emergent adverse events (AEs) related to domatinostat reported in ≥ 10% of patients were: diarrhea (23%), nausea (20%), fatigue (20%), rash (15%), pyrexia (13%), blood alkaline phosphatase increased (13%), vomiting (10%), dyspnea (10%), all grade 1 and 2 - except one maculo-papular rash grade 3. In total, 8 patients (20 %) developed ≥ grade 3 AEs, with no treatment-related deaths. Patterns of AEs resembled the known safety profiles of domatinostat and pembrolizumab with no increase of immune related AEs for the combination. Maximum tolerated dose was not reached. Four patients discontinued treatment per protocol due to AEs grade 3. We observed clinical activity with 1 complete response, 2 confirmed partial responses and 9 stable diseases (6 confirmed), resulting in a disease control rate of 30% in highly pretreated patients throughout all DLs. Notably, 3 out of 7 patients achieved disease control in DL 3 (domatinostat 200 mg BID D1-14, q3w) and were on treatment ≥ 1.5 years, indicating a trend of dose-dependent clinical activity. Domatinostat treatment resulted in a trend to higher intra-tumoral expression of MHC/APM genes and a more inflamed tumor microenvironment reflecting enhanced T cell infiltration. Conclusions: The combination of domatinostat and pembrolizumab was safe and well tolerated. The observed clinical activity in advanced melanoma patients refractory to previous checkpoint inhibition and the favorable translational findings warrant further development of domatinostat in combination with CI in melanoma and beyond. Clinical trial information: NCT03278665.

Results of a phase 1 dose-escalation study of AMV564, a novel T-cell engager, alone and in combination with pembrolizumab in patients with relapsed/refractory solid tumors.

2555 Background: Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive tumor environment and are a barrier to immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immunosuppressive factors. AMV564 is a potent T cell engager that selectively depletes MDSC while promoting T cell activation and proliferation, via preferential binding to areas of high CD33 density. Methods: In this 3+3 dose escalation study, patients with relapsed/refractory solid tumors for whom no recognized standard therapy exists received AMV564 once daily via subcutaneous (SC) injection on Days 1-5 and 8-12 of a 21-day cycle, either alone or in combination with pembrolizumab (200 mg IV q3w). Study endpoints included incidence and severity of adverse events (AEs), pharmacokinetics (PK), and preliminary anti-tumor activity (using RECISTv1.1 criteria). Results: As of January 29, 2021, 20 patients were dosed in 3 monotherapy dose cohorts (15, 50, and 75 mcg/day), and 10 patients were dosed in 3 combination therapy cohorts (5, 15, and 50 mcg/day). Enrolled patients were: median age 64 years, 47% female, had received median 3.5 prior lines of therapy; 7 patients (35%) had received prior checkpoint inhibitor therapy (6 monotherapy patients, 1 combination therapy patient). No dose-limiting toxicity was observed and a maximum-tolerated dose was not reached in either the monotherapy or combination therapy cohorts. The most common treatment-related AEs (occurring in > 10% of patients, in order of decreasing frequency) in the monotherapy cohort were pyrexia, injection site reactions, fatigue, anemia, hypotension, pruritis, chills, and nausea. There were 2 cases of grade 2 cytokine release syndrome (CRS) at 75 mcg/day, both of which resolved after anti-IL6 therapy and study treatment was resumed. The most common treatment-related AEs in the combination cohorts (> 10% frequency) were injection site reaction, pyrexia, fatigue, pruritis, and anemia. No cases of CRS were noted in the combination cohorts. In preliminary PK analysis, estimated median plasma half-life for AMV564 after SC injection was > 48 hours, with dose-related increases in peak plasma concentration. Clinical responses were seen with monotherapy and combination therapy, including a complete response (CR) in a monotherapy-treated patient with ovarian cancer refractory to all standard therapies and anti-PD-1 therapy. Conclusions: AMV564 was well tolerated across multiple dose levels as monotherapy and in combination with pembrolizumab. Subcutaneous injection resulted in clinically relevant plasma exposures. Single-agent and combination therapy anti-tumor activity was observed. Further exploration of AMV564 clinical efficacy in expansion cohorts is ongoing. Clinical trial information: NCT04128423.

Randomized phase II study of pembrolizumab (P) alone versus pegilodecakin (PEG) in combination with P as first-line (1L) therapy in patients (pts) with stage IV non-small cell lung cancer (NSCLC) with high PD-L1 expression (CYPRESS 1).

9563 Background: Pembrolizumab (P) is an immune checkpoint inhibitor (CPI) approved to treat 1L advanced NSCLC pts with high PD-L1 expression. PEG + CPI has demonstrated promising efficacy in NSCLC pts in a phase I trial (IVY; NCT02009449; Naing et al., 2019 Lancet Oncol), providing rationale for this randomized phase II trial (CYPRESS 1; NCT03382899). Methods: CYPRESS 1 was an open label phase II trial, for treatment-naïve, ECOG 0-1, PD-L1 high (22C3 clone TPS ≥ 50%), Stage IV NSCLC pts, without known EGFR/ALK mutations. Pts were randomized 1:1 to arm P (received 200mg IV on day 1 of a 21-day cycle) v. arm PEG+P (received P as above + PEG daily of 0.8 mg if weight ≤80kg and 1.6mg if weight> 80 kg up to 35 cycles in each arm). Pts were stratified by tumor histology and must have no prior history of cancer or prior CPI therapy. Primary endpoint was ORR (per RECIST v1.1 by investigator) Secondary endpoints included PFS, OS, and safety. Exploratory endpoints included ORR and PFS by blinded independent central review (BICR). Immune activation biomarkers (baseline and change from baseline) were assessed by serum immunoassay, IHC, and sequencing. Results: As of Dec 6, 2019, 101 pts were randomized to PEG+P (n=51) or P (n=50). Median follow-up time was 10.0 months (95% CI [8.4, 11.1]). Results for PEG+P versus P were: ORR per investigator was 47% v. 44% (p=0.76), ORR per BICR was 53% v. 46%(p=0.78), mPFS per investigator was 6.3 v. 6.1 months with HR = 0.94 (95% CI [0.54, 1.63];p=0.82), mPFS per BICR was 6.4 v. 7.2 months with HR = 1.10 (95%CI [0.62, 1.96]; p=0.74), and mOS was 16.3 months v. not reached with HR = 1.36 (95% CI [0.66, 2.77]; p-value=0.40). Gr ≥3 treatment related adverse events (TRAEs) were 62% for PEG+P versus 19% for P. Gr ≥3 TRAEs with ≥10% incidence included anemia (20% vs. 0%) and thrombocytopenia (12% vs. 2%). Biomarker data on immunostimulatory signals of the IL-10R pathway will be included. Conclusions: Adding PEG to P did not lead to improvement in ORR, PFS, or OS, in 1L advanced NSCLC with high PD-L1 expression. PEG+P arm demonstrated expected safety profile but overall higher toxicity compared to pembrolizumab alone. Clinical trial information: NCT03382899 .

Abstract B105: Phase IB combination study of copanlisib and nivolumab in advanced solid tumors and lymphomas

Abstract Background: The PI3K pathway is frequently dysregulated in cancer, promoting tumorigenesis by facilitating aberrant cell growth, blocking apoptotic signaling, and suppressing immune surveillance in the tumor microenvironment (TME). The TME contains regulatory immune cells such as FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells, M2 macrophages, and N2 neutrophils, maintaining an immunologically isolating sheath. PI3K inhibition has been shown to slow tumor growth by inducing apoptosis and sensitizing tumors to T cell-mediated cytotoxicity. Copanlisib is a potent PI3K inhibitor, and combination with the PD-1 checkpoint inhibitor nivolumab is hypothesized to result in robust anti-tumor T cell responses. Materials and Methods: Open label phase I trial of copanlisib and nivolumab following a 3+3 design with an expansion phase at the maximally tolerated dose (MTD). Flat-dose nivolumab is administered intravenously (IV) on day 1 while copanlisib is administered IV weekly on days 1, 8 and 15 of a 28-day cycle; there is a 2-week copanlisib run-in during cycle 1 (expansion phase) to enable assessment of pharmacodynamic (PD) endpoints. Prior checkpoint inhibitor therapy is not permitted. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses are assessed by CT using RECIST 1.1 and iRECIST. Exploratory PD objectives include assessments on blood and tissue samples collected at baseline and post copanlisib -/+ nivolumab treatment; these studies will evaluate immune cell populations, PD-1/PD-L1 levels, markers of T cell activation/inhibition (Zap70 pY493 and SHP2 pY542), and apoptosis biomarkers using validated immunofluorescence and flow cytometry assays. Results: As of July 2019, 16 pts have been enrolled with 6 pts in the expansion phase; 14 pts are evaluable for toxicity. The MTD for the combination is copanlisib 60 mg days 1, 8 and 15 plus nivolumab 480 mg day 1 (recommended doses for each individual agent, 28-day cycles); no DLTs were identified. Median age on study is 62 (range 38-77). One pt (rectal cancer) has experienced a confirmed partial response (PR), and 4 pts have achieved stable disease (SD; 1 pt remains on study ≥10 months). Five pts are too early to assess for response. Tissue for molecular analysis and/or genomic sequencing has been collected for all patients. Adverse events include: grade 3 hypertension (1 pt, requiring dose reduction) and infusion-related reaction (hypertension, 1pt); grade 1/2 events include hypertension (7 pts), hyperglycemia (5 pts), nausea (5 pts) and infusion-related reaction (hypertension, 4 pts). Preliminary PD assessments show increases in the number of CD8+ T cells in peripheral blood samples after treatment, with changes in phospho-biomarkers of T cell activation (Zap70-pY493 and SHP-pY542). Conclusions: The combination is tolerable using the approved doses of each individual agent and shows treatment-induced immune PD changes as well as early anti-tumor activity. Enrollment at the expansion stage is ongoing (NCT03502733). Funded by NCI Contract No. HHSN261200800001E. Citation Format: Geraldine O'Sullivan Coyne, Timothy A Yap, Nancy Moore, Arjun Mittra, Naoko Takebe, Lamin Juwara, Sabrina Khan, Ecaterina Ileana Dumbrava, Howard Streicher, Richard Piekarz, Elad Sharon, Funda Meric-Bernstam, Ralph Parchment, Tony Navas, King Leung Fung, James Mitchell, Kristin Fino, Sandra Montez, Austin Doyle, Laurence Rubinstein, James H Doroshow, Alice P Chen. Phase IB combination study of copanlisib and nivolumab in advanced solid tumors and lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B105. doi:10.1158/1535-7163.TARG-19-B105

Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor–Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors

Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments. To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer-cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+ T cells and FoxP3+ regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti-programmed death receptor (ligand) 1 therapy. Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. ClinicalTrials.gov identifier: NCT02598960.

1370P - Phase Ib/II study (SENSITIZE) assessing safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcome of domatinostat in combination with pembrolizumab in patients with advanced melanoma refractory/non-responding to prior checkpoint inhibitor therapy

BackgroundMany advanced melanoma patients are refractory and do not respond to checkpoint inhibition (CI) alone. Epigenetic modulation of tumors to enhance their immunogenicity, alter the tumor microenvironment and thus increase the chance of response to immunotherapy is one clinical approach. In an open label Phase Ib/II multi-center study (‘SENSITIZE’) we investigated the combination of the HDAC inhibitor domatinostat and pembrolizumab in patients with advanced melanoma. MethodsAdvanced stage melanoma patients who were refractory or non-responding to prior checkpoint inhibitor therapy were treated with domatinostat (orally) at increasing dose levels in 3 different dose cohorts in combination with pembrolizumab (2mg/kg) q3w intravenously in a modified “rolling six” study design to evaluate the safety and tolerability of the combination treatment. Tumor assessment was initially performed after 12 weeks. Tumor biopsies were taken for immunohistochemical and gene expression analysis, peripheral blood for PK/PD analysis. ResultsAt time of data cut-off on May 8th, 2019 (study ongoing), a total of 23 patients were enrolled into the study. The safety profile indicates that domatinostat-specific adverse events add to the known safety profile of pembrolizumab, but no exacerbation of immune-related adverse events in rate and severity has been observed so far. Domatinostat alone and in combination was considered safe. First signs of efficacy have been observed, including patients one with a partial response and two with stable disease per irRECIST 1.1. Tumor biopsies at baseline showed a domatinostat-induced alteration of the tumor microenvironment including infiltration of CD8+ T cells, the presence of PD-1/ PD-L1 positive cells, and changes on gene expression levels. Furthermore, a dose-dependent PK profile has been observed. ConclusionsDomatinostat given in combination with pembrolizumab is safe and tolerable and might increase anti-tumor activity in these CI-unresponsive melanoma patients by alteration of the immune tumor microenvironment. Clinical trial identificationNCT03278665. Legal entity responsible for the study4SC AG. Funding4SC AG. DisclosureP.A. Ascierto: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. F. Hermann: Full / Part-time employment: 4SC AG. R. Bartz: Full / Part-time employment: 4SC AG. D. Schadendorf: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. All other authors have declared no conflicts of interest.

Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma.

2538 Background: There is a high unmet medical need for effective treatments for patients with recurrent, metastatic, or persistent cervical cancer. Most patients are young and survival rates are poor. ORR for second line therapies is between 4 and 14% for chemotherapy and recently approved immunotherapy. Adoptive cell transfer using tumor infiltrating lymphocytes (TIL) have demonstrated durable responses in some patients with recurrent cervical cancer thus offering the potential for long-term disease control. Methods: Study C-145-04 is an ongoing, open-label, multicenter Phase 2 clinical trial evaluating the safety and efficacy of LN-145 TIL therapy in patients with advanced cervical cancer who have undergone at least one prior line of chemotherapy. Prior checkpoint inhibitor therapy is an exclusion criterion. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include duration of response (DOR), disease control rate (DCR), and LN-145 safety. Tumors surgically harvested at local institutions are shipped to central GMP facilities for TIL generation in a 22-day manufacturing process. Final LN-145 TIL product is cryopreserved and shipped to sites. Patients receive one week of preconditioning lymphodepletion (cyclophosphamide, fludarabine), a single LN-145 infusion, followed by up to 6 doses of IL-2 (600,000 IU/kg). Results: As of 4 Feb 2019, 27 efficacy-c patients have received Gen 2 of LN-145, with a mean age of 47 years and 2.6 mean prior lines of therapy. Preliminary efficacy results: ORR was 44% (1 CR, 9 PR, 2 uPR), DCR was 89% at 3.5-month median study follow-up with 11/12 patients maintaining their response. Improved responses were observed in 4 patients with longer follow-up. Mean TIL cells infused was 28x109. Median IL-2 doses administered was 6.0. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. Conclusions: LN-145 results in 44% ORR in previously treated cervical cancer patients with acceptable safety and efficacy profile. LN-145 offers patients a viable therapeutic option warranting further investigation. Clinical trial information: NCT03108495.

Viagenpumatucel-L (HS-110) plus nivolumab in patients with advanced non-small cell lung cancer (NSCLC) after checkpoint inhibitor treatment failure.

9109 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with the gp96-Ig fusion protein that functions as an antigen chaperone for cross presentation and dendritic cell activation. DURGA is a multi-cohort study evaluating the combination of HS-110 and anti-PD-1 monoclonal antibodies in patients with advanced NSCLC. We report on Cohort B, consisting of patients with progressive disease (PD) after receiving a minimum of 4 months of treatment (tx) with a checkpoint inhibitor (CPI) at any time prior to study entry. Methods: Patients (pts) with previously treated NSCLC received weekly HS0110 (1 X 107 cells) intradermally for 18 consecutive weeks and nivolumab IV 240 mg every 2 weeks until intolerable toxicity or PD. Tissue was tested at baseline for PD-L1 expression (≥ 1% or < 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined as > 10% CD8+ lymphocytes in the tumor stroma. The primary endpoint was objective response rate by RECIST 1.1. Results: As of the September 2018 data cut-off, 20 pts were enrolled. 18 pts (90%) had PD after both chemotherapy and CPI, and 14 (70%) had CPI as their most recent line of tx. The median number prior tx lines was 2 [range 1 to 6]. 3 pts (15%) achieved partial response and 8 pts (40%) had stable disease. Disease control rate was 55%. Progression-free survival (PFS) was 2.7 months (95% CI, 1.8 – 4.0 months) with a median follow up of 6 months. Pts experiencing injection site reactions (ISR) had improved PFS (median NR vs 2.2 months; HR 0.23, p = 0.063) compared to those without ISR. Of 3 patients with confirmed response, 2 were TIL low/PD-L1 positive, and one was TIL high/PD-L1 negative. All pts experienced at least one adverse event (AE), 80% of which were grade 1 or 2. The most common AEs were fatigue (42%), cough and dyspnea (22.6% each) and anemia (16.1%). There were no grade 5 AEs. Conclusions: The combination of HS-110 and nivolumab is well tolerated. Pts continue to be enrolled in this cohort and early data suggest that the addition of HS-110 to nivolumab may restore responsiveness after tumor progression on prior CPI therapy. Clinical trial information: NCT02439450.

Clinical Responses to CAR.CD30-T Cells in Patients with CD30+ Lymphomas Relapsed after Multiple Treatments Including Brentuximab Vedotin

Background:Infusion of chimeric antigen receptor modified T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) in the absence of lymphodepleting chemotherapy has been shown to be safe with responses seen in patients (pts) with relapsed/refractory (r/r) CD30+ lymphomas (Ramos et al., JCI 2017). We present here the results of a phase 1b/2 trial of CD30.CAR-Ts administered after lymphodepleting chemotherapy in pts with r/r CD30+ Hodgkin (HL) and Non-Hodgkin lymphoma (NHL).Methods:The primary objective of the phase 1b portion of the study was to determine the recommended phase 2 dose level (RP2DL) of CD30.CAR-Ts using a standard 3+3 design. Two dose levels were tested: 1 x 108 CAR-Ts/m2 (DL1) and 2 x 108 CAR-Ts/m2 (DL2). For lymphodepletion, the first 8 pts (including the first 3 pts treated at DL1) received 2 days of bendamustine (benda) 90 mg/m2, while the 10 remaining pts received 3 days of benda 70 mg/m2 and fludarabine (flu) 30 mg/m2, except for one pt who received only 1 day of benda and flu due to possible benda toxicity. Inclusion criteria were age ≥ 18 years, CD30+ disease, and r/r HL or NHL having failed ≥2 prior therapies.Results:At the time of data cut off (7/1/2018), 18 pts with a median age of 40.5 years (range: 23-70) had received CD30.CAR-Ts and undergone response assessment. Sixteen pts had HL, 1 had enteropathy associated T cell lymphoma, and 1 had Sezary syndrome. All pts were heavily pre-treated with a median of 8.5 prior therapies (range: 4-17). All pts had received prior brentuximab vedotin and 13 had prior checkpoint inhibitor therapy. Fourteen pts had prior autologous stem cell transplant (SCT) and 7 had prior allogeneic SCT.Treatment was well tolerated with no dose limiting toxicities; as a consequence, the highest dose level of CAR-T cells (2 x 108 CAR-Ts/m2) was given as the RP2DL. Three pts developed cytokine release syndrome (CRS) (grade 1: 2 pts and grade 2: 1 pt). Grade 1 CRS resolved spontaneously, while the pt with grade 2 CRS responded to tocilizumab. No neurotoxicity was observed.Out of the 18 pts, 4 were in a complete response (CR) before infusion due to bridging chemotherapy and remained disease free at 6 wk follow up. Two of these pts have since relapsed with PFS of 3.8 months and 11.9 months while the other 2 pts are still in CR after 1 year of follow up. The 14 pts with evidence of disease pre-lymphodepletion were included in efficacy analysis. Of these 14 pts, 6 had a CR (43%, all in the benda/flu cohort), 1 had partial response (7%), 2 had stable disease (14%) and 5 had progressive disease (35%) at disease assessment. No responses occurred in the 3 pts treated at DL1. At median follow up of 138 days, the median PFS was 129 days. The median PFS for the 3 evaluable pts who received benda at DL1 was 55 days vs 172 days for the 9 pts who received benda/flu at DL2 (p = 0.039). The median PFS for the 2 evaluable pts at DL2 who received benda lymphodepletion was 85.5 days but this was not included in the comparison due to small sample size. Two out of 14 evaluable pts remain in CR at 1 year.Using PCR on peripheral blood, CD30.CAR-Ts were found to be increased in the circulation of all pts, peaking at wk 2 post infusion, with increasing CAR-T cells in pts receiving greater number of CAR-T cells or more robust lymphodepletion (3.4x103 ± 2.9x103 copies/ug of DNA for DL1-beda vs. 61x103 ± 41x103 for DL2-benda vs. 59x103 ± 22x103 for benda/flu). These differences were confirmed by flow cytometry (CD3+CAR+ cells = 13%±9% for DL1-benda vs 21%±10% for DL2-benda vs 35%±8% for benda/flu). Persistence was also related to dose level and lymphodepletion (0.06x103 ± 0.01x103 vs 0.44x103 ± 0.41x103 vs 28x103 ± 15x103/ug of DNA at wk 4 for DL1-benda, DL2-benda, and benda/flu, respectively). Although both lymphodepletion regimens reduced the lymphocyte counts, only the combination of benda/flu was found to have a significant increase in IL-15 and IL-7 cytokines (13 fold, p<0.01 and 3 fold, p=0.016, respectively) that was sustained for 2 wks post infusion.Conclusions:We show that CD30.CAR-Ts combined with lymphodepletion with benda/ flu are safe and at 2 x 108 CAR T cells/m2 demonstrate excellent antitumor activity for pts with r/r CD30+ lymphomas. We also find that the addition of flu is critical for enhancing cytokines important for T cell growth and persistence. Finally, we demonstrate a significant PFS advantage in pts with r/r CD30+ lymphoma who received the highest dose level combined with benda and flu. DisclosuresGrover:Seattle Genetics: Consultancy. Park:G1 Therapeutics: Consultancy; Gilead: Speakers Bureau; Seattle Genetics: Research Funding; Teva: Research Funding; Rafael Pharma: Consultancy; BMS: Consultancy; BMS: Research Funding; Seattle Genetics: Speakers Bureau; Teva: Consultancy; Takeda: Research Funding. Dittus:Seattle Genetics: Consultancy. Serody:Merck: Research Funding.

1129O - Stage 2 enrollment complete: Sitravatinib in combination with nivolumab in NSCLC patients progressing on prior checkpoint inhibitor therapy

1129O - Stage 2 enrollment complete: Sitravatinib in combination with nivolumab in NSCLC patients progressing on prior checkpoint inhibitor therapy