Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) ...blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8
effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
Survival outcomes for patients with recurrent or advanced cervical cancer are poor. Pembrolizumab has been approved for the treatment of recurrent or metastatic cervical cancer, with an overall ...response rate of 14·3%. GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6-specific and E7-specific T-cell responses and cervical lesion regression in patients with cervical precancer. We aimed to investigate whether a combination of GX-188E therapeutic DNA vaccine plus pembrolizumab showed antitumour activity against recurrent or advanced cervical cancer.
In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced, inoperable cervical cancer, who were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically confirmed recurrent or advanced HPV-positive (HPV-16 or HPV-18) cervical cancer, and who had progressed after available standard-of-care therapy were recruited from seven hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, and 19, with one optional dose at week 46 that was at the investigator's discretion, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the overall response rate within 24 weeks assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 in patients who received at least 45 days of treatment 45 days of treatment with at least one post-baseline tumour assessment, and this is the report of a planned interim analysis. This trial is registered with ClinicalTrials.gov, NCT03444376.
Between June 19, 2018, and March 20, 2020, 36 patients were enrolled and received at least one dose of the study treatment. 26 patients were evaluable for interim activity assessment, with at least one post-baseline tumour assessment at week 10. At the data cutoff date on March 30, 2020, median follow-up duration was 6·2 months (IQR 3·5–8·1). At 24 weeks, 11 (42%; 95% CI 23-63) of 26 patients achieved an overall response; four (15%) had a complete response and seven (27%) had a partial response. 16 (44%) of 36 patients had treatment-related adverse events of any grade and four (11%) had grade 3–4 treatment-related adverse events. Grade 3 increased aspartate aminotransferase, syncope, pericardial effusion, and hyperkalaemia, and grade 4 increased alanine aminotransferase were reported in one patient each. No treatment-related deaths were reported.
Treatment with GX-188E therapeutic vaccine plus pembrolizumab for patients with recurrent or advanced cervical cancer was safe and treatment-related adverse events were manageable. This combination therapy showed preliminary antitumour activity in this interim analysis, which could represent a new potential treatment option for this patient population. This trial is ongoing.
National OncoVenture.
Treatment options for immunotherapy-refractory melanoma are an unmet need. The MASTERKEY-115 phase II, open-label, multicenter trial evaluated talimogene laherparepvec (T-VEC) plus pembrolizumab in ...advanced melanoma that progressed on prior programmed cell death protein-1 (PD-1) inhibitors.
Cohorts 1 and 2 comprised patients (unresectable/metastatic melanoma) who had primary or acquired resistance, respectively, and disease progression within 12 weeks of their last anti–PD-1 dose. Cohorts 3 and 4 comprised patients (resectable disease) who underwent complete surgery, received adjuvant anti–PD-1, and experienced recurrence. Cohort 3 were disease-free for < 6 months and cohort 4 for ≥ 6 months after starting the adjuvant anti–PD-1 therapy and before confirmed recurrence. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included complete response rate (CRR), disease control rate (DCR) and progression-free survival (PFS) per RECIST v1.1 and irRC-RECIST, and safety.
Of the 72 enrolled patients, 71 were treated. The ORR (95% CI) was 0%, 6.7% (0.2–32.0), 40.0% (16.3–67.7), and 46.7% (21.3–73.4) in cohorts 1–4, respectively; iORR was 3.8% (0.1–19.6), 6.7% (0.2–32.0), 53.3% (26.6–78.7), and 46.7% (21.3–73.4). iCRR was 0%, 0%, 13.3%, and 13.3%. Median iPFS (months) was 5.5, 8.2, not estimable NE, and NE for cohorts 1–4, respectively; iDCR was 50.0%, 40.0%, 73.3%, and 86.7%. Treatment-related adverse events (TRAEs), grade ≥ 3 TRAEs, serious AEs, and fatal AEs occurred in 54 (76.1%), 9 (12.7%), 24 (33.8%), and 10 (14.1%) patients, respectively.
T-VEC-pembrolizumab demonstrated antitumor activity and tolerability in PD-1−refractory melanoma, specifically in patients with disease recurrence on or after adjuvant anti–PD-1.
ClinicalTrials.gov identifier - NCT04068181
•T-VEC-pembrolizumab can benefit patients with PD-1-refractory advanced melanoma.•Treatment showed ORRs of 40.0–46.7% for disease progression in adjuvant setting.•Treatment showed iDCRs of 73.3–86.7% for disease progression in adjuvant setting.•T-VEC-pembrolizumab showed manageable toxicity in PD-1-refractory advanced melanoma.
Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining ...immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.
Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with
metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability.
A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.
Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.
Therapeutic combinations targeting innate and adaptive immunity and predictive biomarkers of response in esophagogastric cancer (EGC) are needed. We assessed safety and clinical utility of DKN-01 (a ...novel DKK1-neutralizing IgG4 antibody) combined with pembrolizumab and retrospectively determined DKK1 tumoral expression as a biomarker. Patients with advanced EGC received intravenous DKN-01 (150 or 300 mg) on days 1 and 15 with pembrolizumab 200 mg on day 1 in 21-day cycles. Clinical response was assessed by RECIST v1.1. Association of tumoral DKK1 mRNA expression (
-score: high ≥ upper-tertile, low < upper-tertile) with response was assessed with PD-L1 levels as a covariate. Sixty-three patients received DKN-01 150 mg (
= 2) or 300 mg (
= 61) plus pembrolizumab. Common adverse events were fatigue, anemia, blood alkaline phosphatase elevation, aspartate aminotransferase elevation, and hyponatremia. Among evaluable anti-PD-1/PD-L1-naïve patients receiving DKN-01 300 mg and pembrolizumab, objective response rate (ORR) was 11.4% (5/44) and 18.5% (5/27) in patients with gastroesophageal junction or gastric cancer (GEJ/GC). Among response-evaluable anti-PD-1/PD-L1-naïve patients with GEJ/GC and known tumoral DKK1 expression, ORR was 50% in DKK1-high and 0% in DKK1-low patients, median PFS was 22.1 vs. 5.9 weeks (HR, 0.24; 95% CI, 0.08-0.67), respectively, and median OS was 31.6 weeks vs. 17.4 weeks (HR, 0.41; 95% CI, 0.16-1.07), respectively. Association of DKK1 expression with PFS was independent of PD-L1 expression (adjusted HR, 0.21; 95% CI, 0.06-0.69). DKN-01 combined with pembrolizumab was well tolerated with no new safety signals. Antitumor activity was enriched in anti-PD-1/PD-L1-naïve patients with GEJ/GC whose tumors expressed high DKK1.
Because cancer drugs given in combination have the potential for increased tumor-cell killing, finding the best combination partners for programmed cell death 1 (PD-1) checkpoint inhibitors could ...improve clinical outcomes for patients with cancer.
To identify optimal strategies for combining PD-1 immune checkpoint inhibitors with other cancer therapies.
This cross-sectional study compiled 319 results from 98 clinical trials testing PD-1 pathway inhibitors alone or in combination with other agents among 24 915 patients with metastatic cancer. All clinical trials had a primary completion date before September 16, 2018. Data analysis was conducted from November 2018 to August 2019.
Patients with metastatic cancer were treated with PD-1 immune checkpoint inhibitors alone or with other cancer therapies.
Clinical activity was measured as objective response rates (ORRs). Combination measures included fold change from monotherapy to combination ORR, comparison of observed combination ORRs with estimated combination ORRs based on independent additivity, and a computational model to assess clinical synergy. To assess whether the ORRs of various combinations may be greater than the independent contribution of each agent, a Bliss independent activity model was used to analyze observed combination ORRs, and a Z score, measuring the difference between observed and calculated ORRs, was generated.
In 319 results from 98 clinical trials among 24 915 patients, ORRs for monotherapy were compared with combination data by indication and line of therapy, demonstrating an increased ORR in 105 of 127 results (82.7%) where ORRs were available for both PD-1 pathway inhibitor monotherapy and combination therapy. A few combinations showed increases above the Bliss-estimated activity, possibly identifying limited clinical synergy. The mean (SD) Z score for all trials was 0.0430 (0.0243). The mean (SD) Z score was 0.0923 (0.0628) for platinum chemotherapy regimen combinations, 0.0547 (0.0821) for vascular endothelial growth factor or vascular endothelial growth factor receptor tyrosine kinase inhibitor combinations, 0.0893 (0.086) for indoleamine 2,3-dioxygenase inhibitor combinations, and 0.0558 (0.0849) for cytotoxic T-lymphocyte-associated protein 4 inhibitor combinations.
In this cross-sectional study, most combination trials showed the expected benefit of combining 2 active anticancer agents, but few combination trials showed clinical synergy according to the Bliss independent activity model.
BackgroundImmunosuppressive myeloid cells in the tumor microenvironment (TME) are a critical limitation to the efficacy of immune checkpoint inhibitors (ICIs) in patients with head and neck squamous ...cell carcinoma (HNSCC). Both semaphorin 4D (SEMA4D, CD100) and MDSCs are reported to play important roles in the growth and progression of HNSCC. Preclinical and clinical data demonstrated that antibody blockade of SEMA4D promotes tumor infiltration and activation of dendritic cells and CD8+ T cell, reverses immunosuppression, including attenuation of MDSC recruitment and function, and leading to enhanced efficacy of ICIs.1 2 In a study evaluating pepinemab, a humanized SEMA4D blocking antibody, in combination with avelumab in patients with non-small cell lung cancer, the combination appeared to provide clinical benefit in patients with difficult to treat ICI-resistant and PD-L1-low tumors.3 Pembrolizumab is approved as first line therapy as monotherapy or in combination with chemotherapy in recurrent or metastatic (R/M) HNSCC, however not all patients respond to ICIs and require more effective treatments.MethodsKEYNOTE B84 (NCT04815720) is a multicenter, single-arm open-label study to evaluate the safety, efficacy, PK/PD of pepinemab in combination with pembrolizumab in subjects with locally advanced, R/M HNSCC. Subjects with measurable disease per RECIST1.1 will be enrolled, including oropharynx, oral cavity, hypopharynx and larynx, and ECOG PS of 0 or 1. Subjects who have received prior ICIs are excluded. This study will include a Safety Run-in phase (n=3–18) and a Dose Expansion (maximum n=62) phase. Pepinemab, which is well-tolerated in combination with other ICIs, will be evaluated starting with the highest intended dose of 20 mg/kg, in combination with 200 mg pembrolizumab, both administered intravenously every 3 weeks. The Dose Expansion phase will include an even distribution of subjects who have combined positive scores of <20 and ≥20. The primary efficacy endpoint is ORR, and secondary endpoints include DOR, OS, PFS, as well as exploratory biomarker analysis. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME.ResultsScreening has been initiated at several of a planned total of 18 sites. Multiplex immunohistochemistry (IHC) panels have been established to phenotype cells in the TME, including CD8+ T cells, DCs, MDSCs, Tregs, monocytes, macrophages.ConclusionsThere remains a clear unmet need for more effective immunomodulatory treatment options to overcome immunosuppressive factors in the TME. The KEYNOTE B84 study will evaluate pepinemab as a potential treatment option to overcome resistance to and enhance activity of pembrolizumab in HNSCC.Trial RegistrationNCT04815720ReferencesClavijo PE, Friedman J, Robbins Y, Moore EC, Smith E, Zauderer M, Evans EE, Allen CT. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function. Cancer Immunol Res 2019 Feb;7(2):282–291.Evans EE, Jonason AS Jr, Bussler H, Torno S, Veeraraghavan J, Reilly C, Doherty MA, Seils J, Winter LA, Mallow C, Kirk R, Howell A, Giralico S, Scrivens M, Klimatcheva K, Fisher TL, Bowers WJ, Paris M, Smith ES, Zauderer M. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies. Cancer Immunol Res 2015 Jun;3(6):689–701.Shafique MR, Fisher TL, Evans EE, Leonard JE, Pastore DRE, Mallow CL, Smith E, Mishra V, Schröder A, Chin KM, Beck JT, Baumgart MA, Govindan R, Gabrail NY, Spira AI, Seetharamu N, Lou Y, Mansfield AS, Sanborn RE, Goldman JW, Zauderer M. A Phase Ib/II Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res 2021 Jul 1;27(13):3630–3640.Ethics ApprovalThis study was approved by WIRB Copernicus Group’s Ethics Board on 11Feb2021; approval number 20210250.
BackgroundLNS8801 is an agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 results in increased melanocytic differentiation, reduced c-Myc protein levels, inhibition of proliferation, ...and enhancement of immune recognition of cancer cells. In the first-in-human study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab (NCT04130516). LNS8801 also demonstrated monotherapy activity in cutaneous melanoma (CM) patients, including a patient that is on treatment for over 3 years with no evidence of active disease.MethodsPatients with refractory CM received LNS8801 (125 mg, QD, PO) and pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective was safety and tolerability. Secondary endpoints include pharmacokinetic, pharmacodynamics, objective response rate (ORR) and disease control rate (DCR, CR+PR+SD). Presence of a consensus, fully-functional, germline GPER sequence was assessed as a potential predictive biomarker.ResultsAs of 6/15/23, 10 patients were treated. All patients received prior PD-1 and CTLA-4 directed ICIs, and were treated with a median of 2.5 prior lines of systemic therapies. 8 of 10 patients had AEs possibly related to study drugs (n=4 with grades 1–2 and n=4 with grade 3), with AST/ALT elevation, diarrhea, or fatigue occurring in more than 1 patient. Regarding efficacy, 2 had partial responses, 5 had stable disease, resulting in an ORR of 20% and DCR of 70%. Both patients with partial responses remained on treatment for > 24 weeks. Consensus germline GPER was present in 7 of 10 sequenced patients. Of patients positive for this biomarker, 2 had partial responses and 3 had stable disease, resulting in an ORR of 29% and DCR of 71%.ConclusionsLNS8801 and pembrolizumab is tolerable and demonstrates encouraging activity in patients with treatment-refractory CM, including patients who enrolled immediately after confirmed progression on ICIs. Consensus germline GPER is a promising predictive biomarker, and continues to be associated with improved outcomes in patients treated with LNS8801. These data support further development of LNS8801 in combination with pembrolizumab as a therapeutic approach to treat refractory CM patients.Trial RegistrationNCT04130516Ethics ApprovalThe study was approved by Western Institutional Review Board, the central IRB for this study. The study was also approved by local IRBs at MD Anderson, Mass General, MSKCC, and START (Advarra IRB).
BackgroundImmunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical ...and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) reverses immunosuppression, including attenuation of MDSC recruitment and function1 and promotes organization of lymphoid aggregates within tumors,2 leading to enhanced efficacy of ICIs. Pepinemab, a SEMA4D blocking antibody, in combination with avelumab was well tolerated and provided clinical benefit in patients with ICI-resistant, PD-L1-low NSCLC.3 The primary hypothesis of this proof-of-concept study is that pepinemab in combination with pembrolizumab will improve the efficacy of immunotherapy in R/M HNSCC.MethodsKEYNOTE-B84 (NCT04815720) is an ongoing single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of R/M HNSCC. The study includes immunotherapy naïve patients who have tumor PD-L1 combined positive scores (CPS) of <20 and ≥20 with an interim analysis when 36 patients complete the first tumor response assessment. The primary efficacy endpoint is ORR, and secondary endpoints include PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies are collected for evaluation of immune contexture in TME. Data presented here include pre-specified interim analysis of safety, efficacy, and biomarker assessments.ResultsThe combination appears to be well tolerated with no DLTs observed or safety signals identified by the SMC. Notably, in the PD-L1 low population (CPS<20, N=19), we observed approximately a doubling in ORR, DCR, and PFS for the combination of pepinemab and pembrolizumab, as compared to reported single agent pembrolizumab.4 Among the CPS<20 population, ORR was 21.1% (2 CR and 2 PR), DCR was 73.7%, and median PFS was 5.79 months. In contrast, in the CPS≥20 subgroup, the ORR was 17.6% (n=17), similar to ICI monotherapy for this population. Spatial multiplex IHC analysis of pre- and post-treatment tumor biopsies demonstrated an increase in activated APC, reduced recruitment of MDSC, and highly organized immune aggregates (figure 1) that corresponded with disease control.ConclusionsThe pre-specified interim analysis of the ongoing KN-B84 study showed that pepinemab in combination with pembrolizumab was well-tolerated, suggested early signs of improved anti-tumor response over single agent pembrolizumab in the difficult to treat PD-L1 low group, and provided evidence of treatment-induced biomarker changes in the TME of responder tumors, including formation of high-density lymphoid aggregates.ReferencesClavijo PE, Friedman J, Robbins Y, Moore EC, Smith E, Zauderer M, Evans EE, Allen CT. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function. Cancer Immunol Res. 2019 Feb;7(2):282–291. doi: 10.1158/2326–6066.CIR-18–0156.Olson B, Mallow C, Reilly C, et al. Neoadjuvant SEMA4D blockade with nivolumab alters suppressive myeloid cells while elevating B cell and CD26hi T cell infiltration in the tumors of patients with resectable stage III melanoma. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0613Shafique MR, Fisher TL, Evans EE, et al. A Phase Ib/2 Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res 2021, doi: 10.1158/1078–0432.CCR-20–4792Burtness B, Rischin D, Greil R, Soulières D, Tahara M, et al. Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol. 2022 Jul 20;40(21):2321–2332. doi: 10.1200/JCO.21.02198.Ethics ApprovalThis study was approved by WIRB Copernicus Group’s Ethics Board; approval number 20210250.Abstract 676 Figure 1Treatment induced improved balance of activated APC and MDSC and presence of highly organized immune aggregates consisting of high density of B cells, DC and T cell zones, and stem- like CD8, and correlate with disease control. (A, B) Representative images of on-treatment biopsies. (C) B cell density/aggregate, each dot represents one aggregate. CR: complete response SD: stable disease, PD: progressive disease.
BackgroundAnti-PD-1 therapy is the mainstay of frontline treatment for NSCLC and melanoma. However, the majority of these patients become refractory/resistant. BV is hypothesized to selectively ...deplete a subset of activated effector intratumoral regulatory T-cells (Tregs) that express CD30, potentially re-sensitizing tumors to anti-PD-1 therapy. SGN35–033 (NCT04609566) is an ongoing, multi-cohort, multicenter, open-label trial evaluating the efficacy and safety of BV+pembro in anti-PD-1 refractory solid tumors.MethodsPatients with primary refractory (progression without response or SD for <6 months) or secondary refractory (progression after response for ≥3 months or SD for ≥6 months) NSCLC or melanoma that progressed on anti-PD-1 therapy were included. Patients received 21-day cycles of BV (1.8 mg/kg) and pembro (200 mg). The primary endpoint is confirmed ORR per investigator assessment (RECIST v1.1). Exploratory biomarker analyses include T cell subsets by flow cytometry of peripheral blood at baseline and during treatment, IHC (CD8 and Foxp3) and RNAseq of tumor biopsies collected at baseline and cycle 3 day 1.Results54 patients with NSCLC (11 primary and 43 secondary refractory) and 58 patients with melanoma (17 primary and 41 secondary refractory) were enrolled. All patients were heavily pretreated (median prior lines of therapy: 3 range: 1–10). All patients’ cancer had progressed on anti-PD-1 therapy, and all patients’ melanoma had confirmed progression on anti-PD1 therapy within the last 90 days. ORR was up to 20% across cohorts and DCR ranged from 64%-80% (table 1). In an exploratory analysis, numerically higher response rates were observed in patients with tumors with higher PD-L1 expression. No new safety signals were observed. Preliminary IHC and RNAseq analysis of paired tumor biopsies from responders demonstrated increased tumor-infiltrating CD8 T cells at C3D1 post-treatment. Exploratory analyses of transcriptome-wide RNA expression indicated that responders exhibited enrichment of genes related to T cell signaling, Treg biology, and antigen presentation in baseline tumor biopsies, consistent with the hypothesized immune modulatory effects of BV.ConclusionsThese data support the potential for BV to re-sensitize anti-PD-1 resistant/refractory tumors to PD1 through CD30-directed depletion of Treg cells. Treatment with BV+pembro was associated with selective depletion of CD30+ Tregs and modulation of the tumor microenvironment to relieve Treg immunosuppression. These data support further exploration of this combination for treatment of relapsed/refractory melanoma and NSCLC. SGN35–033 is currently enrolling cohorts to investigate the activity of BV+Pembro in frontline NSCLC and head and neck cancer.AcknowledgementsThank you to the patients and their families for their participation in the study, and to all research personnel for their support of this important trial.Direct funding for this research was issued by Seagen Inc. through the joint financial support of Seagen Inc. and Merck & Co., Inc.Clinical analysis support was provided by Eeman Shaikh (Seagen Inc.). Translational research support was provided by Ryan Heiser (Seagen Inc.). Medical writing support was provided by Lauren Angotti (BioBridges LLC) with funding from Seagen Inc.Trial RegistrationNCT04609566Ethics ApprovalEthics approval was obtained from the central IRB (WCG, 20202815) prior to enrollment of patients; all protocol amendments have received IRB approval and the study is renewed annually. Patients provided informed consent prior to study enrollment.Abstract 699 Table 1Objective response rate, disease control rate, median progression-free survival, and median duration of response
PDF
