Anti PD-L1 Monoclonal Antibody Research Articles

Abstract PO1-19-10: Durvalumab + datopotamab deruxtecan in patients with PD-L1 positive advanced/metastatic triple-negative breast cancer: Arm 8 of the phase 1b/2, open label, platform BEGONIA study

Abstract Background: Patients (pts) with advanced/metastatic triple-negative breast cancer (a/mTNBC) have limited treatment options and poor prognosis. Immune checkpoint inhibitors combined with chemotherapy is the standard of care for pts with PD-L1 positive tumors; still, most pts progress within a year, highlighting a need for new treatments. BEGONIA is an ongoing Simon 2-stage, multicenter, multi-arm platform study evaluating the safety and efficacy of durvalumab (D), an anti–PD-L1 monoclonal antibody, with or without paclitaxel, in combination with novel oncology therapies as first-line treatment for a/mTNBC (NCT03742102). Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a plasma stable, tumor selective, tetrapeptide-based cleavable linker. TROP2 is broadly expressed on breast and other epithelial tumors and Dato-DXd monotherapy showed antitumor activity in heavily pretreated mTNBC pts (Bardia SABCS 2022 P6-10-03). Pts treated with Dato-DXd+D in Arm 7 of BEGONIA showed a 74% objective response rate (ORR) with median 7.2 months follow-up (Schmid SABCS 2022 PD11-09). Although responses were observed in both PD-L1–high and –low-expressing tumors, most pts (87%) had PD-L1–low-expressing tumors. In Arm 8 of BEGONIA, pts determined to have PD-L1 positive tumors by pre-existing/local testing will be recruited and treated with Dato-DXd+D to evaluate efficacy and safety in a PD-L1–high population. Methods: Eligible female pts are aged ≥18 years with untreated unresectable, locally advanced or mTNBC; ≥6 months between completion of treatment for earlier-stage breast cancer and recurrence of distant disease; ≥12 months since prior taxane therapy; ECOG PS 0/1; adequate organ function; and ≥1 nonirradiated measurable lesion. For inclusion in Arm 8, a PD-L1 positive tumor as determined by local immunohistochemistry (IHC) testing is required (either pre-existing or obtained during prescreening). Exclusion criteria for Arm 8 are clinically significant corneal disease; history or suspicion of interstitial lung disease/pneumonitis; underlying pulmonary disorder; prior exposure to immune-mediated therapy; or prior treatment with an ADC containing a topoisomerase I inhibitor. Arm 8 will evaluate Dato-DXd (6 mg/kg) + D (1120 mg) given intravenously every 3 weeks until disease progression or unacceptable toxicity. Tumors will be assessed per RECIST v1.1 every 6 weeks for 48 weeks, then every 12 weeks thereafter. A safety run-in will not occur for Arm 8, as Dato-DXd+D was evaluated in Arm 7 and was tolerable with no DLTs reported. Part 1 of Arm 8 will enroll 30 pts. The primary endpoint of Part 1 is safety and tolerability. A futility analysis will be performed with an option to expand Arm 8 to Part 2, where an additional 27 pts will be enrolled if expansion criteria are met. The primary endpoint for Part 2 is ORR. Secondary endpoints include ORR (Part 1 only), testing for antidrug antibodies and treatment pharmacokinetics (Part 1 only), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). ORR will be summarized with descriptive statistics and 95% Clopper-Pearson confidence intervals. Kaplan-Meier analysis will be used for DoR, PFS, and OS. All tumor response and survival endpoints will be based on investigator assessments. Additional PD-L1 testing with the VENTANA PD-L1 (SP263) Assay will be performed on pretreatment tumor samples; high expression is defined as ≥10% of the tumor area populated by PD-L1–expressing tumor or immune cells. TROP2 expression will be assessed by IHC. Enrollment is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Cynthia Ma, Robert Huisden, Ross Stewart, Katrin Heider, Petra Vuković, Neelima Denduluri. Durvalumab + datopotamab deruxtecan in patients with PD-L1 positive advanced/metastatic triple-negative breast cancer: Arm 8 of the phase 1b/2, open label, platform BEGONIA 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 PO1-19-10.

Timing of anti–PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma

AbstractMore than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1–associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti–PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell–associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19– tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.

Abstract 1863: Evaluation of BDB101, a first-in-class TLR7/8 dual agonist conjugated to an anti-PD-L1 mAb, in cancer treatment

Abstract Background Responses to antiPDL1 checkpoint inhibitors (CPIs) in many tumors are governed by the PDL1 expression on tumor and immune cells in the tumor microenvironment (TME). Increasing PDL1 expression on cells may enhance the response to CPIs. Tolllike receptor (TLR) agonists have shown to induce PDL1 expression in the TME and may enhance the antitumor effects of CPIs. The effective dose of TLR agonist administered to patients is limited by systemic toxicities. To overcome this limitation, one approach is to conjugate the TLR agonist to an antibody. This allows for delivery and release of higher doses of the TLR agonist in the TME while limiting systemic exposure.BDB001 is an intravenously (IV) delivered TLR7/8 dual agonist that activates both the innate and adaptive immune system. In clinical trials, BDB001 has been well tolerated and shown promising antitumor responses in monotherapy and in combination with antiPDL1 therapy (Patel M. et al, SITC 2020 and SITC 2021). To further enhance the antitumor effect and allow for increased concentration of the TLR7/8 dual agonist in the TME, we developed BDB101, a proprietary firstinclass TLR7/8 dual agonist - antiPDL1 monoclonal antibody (mAb) conjugate using our TollLike receptor Agonist Conjugate (TLAC) platform. Here we report on the preclinical and nonhuman primate (NHP) evaluation of BDB101. Methods BDB101 utilizes a cleavable linker, allowing for the TLR7/8 dual agonist payload to be released in the TME and enabling a bystander effect. BDB101 was assessed for in vitro TLR7/8 dual agonist activity and PDL1 binding, and in vivo antitumor efficacy in immune competent mouse models. The pharmacokinetic and pharmacodynamic effects of BDB101 was evaluated in NHP. Results The conjugated TLR7/8 dual agonist did not change the PDL1 binding specificity of the antibody, and the uncleaved conjugate did not activate TLR7 or TLR8. In the C26 mouse model, a BDB101 mouse surrogate showed a significantly more robust antitumor effect compared to the TLR7/8 dual agonist or the antiPDL1 mAb alone. In NHP, a single IV infusion of BDB101 showed no significant differences in PK parameters between BDB101 and the total antiPDL1 mAb. BDB101 demonstrated remarkable in vitro stability in human plasma for up to 21 days. In NHP, BDB101 was also very stable with minimal release of free TLR7/8 dual agonist payload. Pharmacodynamic studies in NHP were consistent with PK behavior. Conclusions BDB101 exhibits robust preclinical efficacy and prolonged stability in NHP. The low rate of free TLR7/8 dual agonist payload released into the systemic circulation from the conjugated form of BDB101, should minimize the risk of systemic TLR7/8 dual agonist exposure, while maintaining the ability to deliver the payload to the TME. These results indicate that BDB101 will likely have a good in vivo therapeutic window and strongly support the clinical development of BDB101. Citation Format: Jing Yang, Robert H. Andtbacka, Walter Lau, Lixin Li. Evaluation of BDB101, a first-in-class TLR7/8 dual agonist conjugated to an anti-PD-L1 mAb, in cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1863.

Exploring the potential of combining IL-2-activated NK cells with an anti-PDL1 monoclonal antibody to target multiple myeloma-associated macrophages

Multiple myeloma (MM) is an incurable disease, characterized by malignant plasma cells in the bone marrow. MM growth is largely dependent on the tumor microenvironment (TME), consisting of complex cellular networks that shape a tumor-permissive environment. Within the TME, tumor-associated cells (TAC) comprise heterogeneous cell populations that collectively support immunosuppression. Reshaping the TME toward an immunostimulatory environment may enhance effectiveness of immunotherapies. Here, we investigated interactions between donor-derived natural killer (NK) cells and TAC, like tumor-associated macrophages (TAM) and M1 macrophages, and assessed whether anti-tumor effector functions of NK cells could be enhanced by an ADCC-triggering antibody targeting macrophages. Monocytes were polarized in vitro toward either M1 or TAM before co-culture with high-dose IL-2-activated NK cells. NK cell responses were assessed by measuring degranulation (CD107a) and IFN-γ production. We found that NK cells degranulated and produced IFN-γ upon interaction with both macrophage types. NK cell responses against PD-L1+ M1 macrophages could be further enhanced by Avelumab, an anti-PD-L1- and ADCC-inducing antibody. Additionally, NK cell responses were influenced by HLA class I, shown by stronger degranulation in NK cell subsets for which the corresponding HLA ligand was absent on the macrophage target cells (KIR-ligand mismatch) compared to degranulation in the presence of the HLA ligand (KIR-ligand match). Our results suggest that NK cells could, next to killing tumor cells, get activated upon interaction with TAC, like M1 macrophages and TAMs, and that NK cells combined with PD-L1 blocking antibodies with ADCC potential could, through IFN-γ secretion, promote a more immune-favorable TME.

An MMAE-loaded PDL1 active targeting nanomedicine for the precision treatment of colon cancer.

Tumor-active-targeting drugs such as antibody-drug conjugates have emerged as promising accurate therapeutic agents. However, their complex preparations risk compromising the targeting ability of the fragment antigen binding (Fab) region and promote aggregation over long-term storage. Here, we propose a tumor-active-targeting nanomedicine, aPDL1-PLG-MMAE, that effectively targets programmed death-ligand 1 (PDL1) high-expressing tumors and delivers monomethyl auristatin E (MMAE). aPDL1-PLG-MMAE consists of an anti-PDL1 monoclonal antibody (aPDL1) and poly(L-glutamic acid) (PLG) grafted Fc-III-4C peptide/Val-Cit-PAB-MMAE (Fc-PLG-MMAE). Fc-PLG-MMAE was obtained by conjugating the Fc-III-4C peptide and Val-Cit-PAB-MMAE to PLG via amide condensation. The strong affinity between the fragment crystallizable (Fc) region of aPDL1 and the Fc-III-4C peptide enabled aPDL1 and Fc-PLG-MMAE to self-assemble into aPDL1-PLG-MMAE after four hours of coincubation in PBS. As this nanomedicine can be quickly prepared for immediate use, the required antibodies can be stored separately from the Fc-PLG-MMAE portion for extended periods, which also facilitates transport. Moreover, aPDL1-PLG-MMAE demonstrated robust tumor recognition and targeting effects on MC38 colon cancer cells, resulting in potent therapeutic efficacy without significant toxicities.

Safety and effectiveness of avelumab in patients with curatively unresectable merkel cell carcinoma (MCC) in a real-world setting: A post-marketing surveillance in Japan.

e21528 Background: Avelumab is an anti–PD-L1 monoclonal antibody that was approved in Japan for the treatment of patients with curatively unresectable MCC in Sept 2017. Because the number of Japanese patients with MCC participating in the global Phase II JAVELIN Merkel 200 study was limited (3 patients), Japan was mandated to conduct an all-case surveillance as a post-marketing surveillance (PMS) study. In the all-case surveillance, safety and efficacy information is accumulated with respect to a defined period of time or a defined number of post-approval prescription cases and is provided as real-world data. This report summarizes the results of the final analysis of this MCC PMS. Methods: This PMS is a multicenter, non-comparative, prospective, observational study. Since Nov 2017 (following approval in Japan), all patients with MCC who received at least one dose of avelumab in Japan were enrolled, and case report forms (CRF) were collected for all patients who started treatment through Oct 2019. Results: As of Sept 22, 2021, 152 patients from 86 sites were enrolled, and CRFs were collected from 77 patients. Of the 75 patients (53 sites) who met the analysis adequacy criteria, 48% were female, and the median age at the start of avelumab treatment was 77.0 years (42-95 years). Of the treatment lines in which avelumab was administered, 93.3% (70/75) were prescribed as first-line therapy. The incidence of adverse reactions was 61.3% (46/75), and 9.3% (7/75) discontinued treatment due to adverse reactions. Grade 3 and 4 adverse reactions occurred in 12.0% (9/75) and 4.0% (3/75), respectively; no grade 5 adverse reactions were reported. Infusion reactions were reported in 28.0% (21/75). The objective response rate (proportion of patients whose best response was assessed by the investigator as a complete or partial response) up to 1 year after the start of avelumab treatment was 45.3% (95% CI: 33.8, 57.3). The 1-year overall survival rate was 59.6% (95% CI: 47.0, 70.1). Conclusions: This study report is the first real-world evidence collected and analyzed from actual clinical use of avelumab in patients with curatively unresectable MCC in the East Asia region. Despite the different baseline patient characteristics, avelumab therapy in clinical practice had a manageable safety profile with no new safety concerns and has shown similar efficacy to that observed in the JAVELIN Merkel 200 trial.

Efficacy and safety of the anti–PD-L1 monoclonal antibody socazolimab for recurrent or metastatic cervical cancer: Results from the phase I dose-escalation and expansion study.

5526 Background: The study (NCT03676959) is an open-label, phase I study investigating the safety and efficacy of the recombinant, fully human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody socazolimab for recurrent or metastatic cervical cancer. Methods: Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. Primary endpoints of the dose-expansion phase were safety and overall response rate (ORR) of the 5mg/kg dose. Efficacy was assessed by a third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as the evaluation standard. Pharmacokinetics and pharmacodynamics were also studied. Results: One hundred four patients were enrolled. Twelve patients were included in the dose-escalation phase, with one complete and two partial responses in the 5mg/kg treatment group. Ninety-two patients (5mg/kg) were enrolled in the dose-expansion phase, with 54 patients (59.3%) expressing baseline PD-L1-positive tumors. ORR was 15.4% (95% CI, 8.7 to 24.5%). Median PFS was 4.44 months (95% CI, 2.37 to 5.75 months), and the median OS was 14.72 months (95% CI, 9.59 to NE months). ORRs for PD-L1-positive and PD-L1-negative patients were 16.7% and 17.9%, respectively. Treatment-related grade 3 to 4 adverse events occurred in 7.7% of patients. No treatment-related deaths had occurred. Conclusions: Our study demonstrates that socazolimab has remarkable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti–PD-1/PD-L1 monoclonal antibodies. Clinical trial information: NCT03676959. [Table: see text]

Absolute eosinophil count predicts clinical outcomes and toxicity in non-small cell lung cancer patients treated with immunotherapy

ObjectivesImmune checkpoint inhibitors (ICIs) have led to a paradigm shift in non-small cell lung cancer (NSCLC) treatment. We investigated absolute eosinophil count (AEC) as a predictor of clinical outcomes and toxicity in NSCLC patients receiving ICIs. Materials and MethodsAEC was retrospectively collected at baseline and during treatment from 158 advanced NSCLC patients treated with single agent anti-PD1/anti-PDL1 monoclonal antibody in first or subsequent line of therapy at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between January 2016 to October 2020. ResultsWe found a significant association between high baseline AEC (≥130/μL) and better clinical outcomes. The response rates were 64.4% and 35.6% for patients with high and low AEC, respectively (p = 0.009). The high-AEC group showed a significantly longer PFS and OS than the low-AEC group (mPFS = 7.0 months, 95% CI 5.0–10.0 vs 2.5 months, 95% CI 2.0–4.0, p = 0.007 and mOS = 9.0 months, CI 95% 7.0–15.0 vs 5.5 months, 95% CI 4.0–8.0, p = 0.009, respectively). An increased risk of immune-related adverse events (irAEs) was reported in the high-AEC group (p = 0.133). IrAEs resulted an independent prognostic factor for both better outcomes (mPFS = 8.0 months, 95% CI 7.0–12.0 vs 2.0 months, 95% CI 2.0–3.0, p<0.001; mOS = 13.0 months 95% CI 9.0–19.0 vs 4.0 months 95% CI 3.0–6–0, p<0.001) and response to ICIs (response rate = 33.8% vs 14.9%, disease control rate = 72.0% vs 32.1%, p<0.001). ConclusionHigh baseline AEC value (≥130/μL) is a predictive biomarker of clinical benefit and irAEs occurrence in NSCLC patients treated with ICIs.

Viral Infection and Lung Cancer Immunotherapy.

Immunotherapy with immune checkpoint inhibitors (mainly anti-PD1 and anti-PDL1 monoclonal antibodies) became a standard of care in non-small cell lung cancer (NSCLC) patients. Most of the clinical trials excluded patients with hepatitis B (HBV), hepatis C (HCV), and human immunodeficiency virus (HIV) active infection (1–10). Despite the progress in treatment of these infections, they remain an unresolved clinical problem when lung cancer immunotherapy should be initiated in an NSCLC patient. This manuscript summarizes the data from the literature concerning this subgroup of patients including the rationale for immunotherapy initiation depending on the HBV, HCV, or HIV infection status; the risk of adverse events; and the efficacy compared to non-infected patients. One of the crucial questions is how the candidates to immunotherapy should be screened for HBV, HCV, and HIV infections. The year 2020 brought the world a new but dynamic viral problem—severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). The incorporation of known data in oncology guidelines became a burning need, and then, which group of the infected patients can be treated with immunotherapy despite the infection. Oncologists should also know if these patients should receive antiviral therapy and what are the safe combinations in these settings. We also indicate which of the adverse events should be monitored carefully during checkpoint inhibitor treatment.

BEGONIA: Phase 1b/2, open-label, platform study of the safety and efficacy of durvalumab (D) ± paclitaxel (P) with novel oncology therapies for first-line metastatic triple-negative breast cancer (mTNBC): Addition of arm 7, D + datopotamab deruxtecan (Dato-DXd; DS-1062).

TPS1105 Background: Patients (pts) with mTNBC have limited treatment options and poor prognosis. The combination of immune checkpoint inhibitors with chemotherapy shows promise, but only a subset of pts with mTNBC derive benefit, highlighting the need for new combinations. BEGONIA is an ongoing Simon 2-stage, multicenter, multi-arm platform study evaluating the safety and efficacy of D, an anti–PD-L1 monoclonal antibody, with or without P, in combination with novel oncology therapies as first-line treatment for mTNBC (NCT03742102). Dato-DXd is an antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody, a stable tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. Dato-DXd displayed encouraging clinical activity with a manageable safety profile in heavily pretreated pts with metastatic NSCLC in the phase 1 TROPION-PanTumor01 (NCT03401385) study. TROP2 is highly expressed on breast and other epithelial tumors, and a TROP2 ADC showed activity in heavily pretreated pts with mTNBC (Bardia, NEJM 2019). Methods: Eligible female pts are aged ≥18 years with untreated unresectable, locally advanced or mTNBC, ≥12 months since prior taxane therapy, ECOG PS 0/1, adequate organ function, and ≥1 nonirradiated measurable lesion. For Arm 7, pts are excluded if they have clinically significant corneal disease, history of interstitial lung disease/pneumonitis, underlying pulmonary disorder, or prior treatment with an ADC containing a topoisomerase I inhibitor. Arm 7 will evaluate D (1120 mg) + Dato-DXd (6 mg/kg) given intravenously every 3 weeks until disease progression or unacceptable toxicity. Part 1 of each arm includes a total of 30 pts with a safety run-in (n=6) to observe dose-limiting toxicities, identify the recommended phase 2 dose (RP2D), and detect an efficacy signal for part 1 expansion. The primary endpoint of part 1 is safety and tolerability. Secondary endpoints include investigator-assessed objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Once the RP2D has been established for part 1, a futility analysis will be performed with an option to expand the cohort to an additional 27 pts if expansion criteria are met. The primary endpoint for part 1 is ORR. Tumors will be assessed every 6 weeks per RECIST v1.1. Kaplan-Meier analysis will be used for PFS and OS. PD-L1 and TROP2 expression will be assessed by immunohistochemistry. Enrollment is ongoing. Clinical trial information: NCT03742102 .

Associations between longitudinal pretreatment BMI and neutrophil/lymphocyte ratio(NLR) and progression-free(PFS) and overall survival(OS) in advanced NSCLC patients treated with single agent anti-PD-1/anti-PDL1 monoclonal antibodies(mAbs).

e21189 Background: Several parameters that have been associated with outcomes in patients with metastatic NSCLC treated with anti-PD1/PDL1 mAbs include tumor PD-L1 expression, tumor mutational burden, and baseline NLR. Further investigation into clinical correlates of benefit with immune checkpoint inhibitors remains an unmet need. Methods: The objective of this retrospective study was to examine the potential influence of pretreatment cachexia and chronic inflammation in patients with NSCLC that received second- or third- line single agent anti-PD1/PDL1 mAbs. Weight, BMI, and NLR, as well as longitudinal changes in these variables from at least six-weeks prior to initiation of treatment were correlated with progression-free and overall survival (PFS/OS). These associations were assessed using statistical methods for time-to-event analysis. Results: 192 patients were included: 59% female, 72% Caucasian, 18% African American, 79% current or former smokers. 185 patients had pretreatment NLR values and 63% and 42% had NLR ratios &gt; 3.5 and &gt; 5, respectively. 187 patients had pretreatment weight and BMI available. Of these, 63% had a loss in BMI prior to initiation of anti-PD1/PDL1 mAbs, 29% with &gt; 5% loss. Any BMI loss as well as BMI loss &gt; 5% over the time period prior to treatment initiation were associated with shorter PFS (p &lt; 0.01, 2.1 vs 4.37 mos for loss &gt; 5% vs ≤ 5%) and change in BMI assessed in continuous scale was also associated with PFS (HR = 0.94, p &lt; 0.05). Similarly, any BMI loss and BMI loss &gt; 5% were associated with shorter OS (p &lt; 0.01. 7.33 vs 12.23 mos for loss &gt; 5% vs ≤ 5%) and change in BMI and baseline BMI assessed in continuous scale were additionally associated with OS (HR = 0.97 and 0.94, p &lt; 0.05). Baseline NLR &gt; 5 was associated with shorter PFS (p &lt; 0.01) and baseline NLR assessed in continuous scale was negatively associated (HR = 1.01, p &lt; 0.05). Moreover, pre-treatment NLR &gt; 5 and baseline NLR &gt; 3.5 were associated with shorter OS (p &lt; 0.05). Pre-treatment NLR, baseline NLR, and %change in NLR, assessed in continuous scale, were negatively associated with OS (HR = 1.04, 1.02, 1.12, p &lt; 0.01). Conclusions: This retrospective study identified clinical features of NLR and BMI at treatment initiation and in the immediate pre-treatment period that were associated with PFS and OS on anti-PD1/PDL1 mAbs therapy. These parameters can easily be investigated in the front-line population. They may also have utility in identifying patients that would benefit from therapeutic strategies to reverse weight loss and inhibit immunosuppressive effects associated with elevated NLR in order to increase the effectiveness of immunotherapy.

Abstract SP033: How and when to use immunotherapy and related toxicities

Abstract Targeting the immune system is an active therapeutic approach for a subgroup of patients with metastatic triple negative breast cancer (TNBC). In a breast cancer subtype in which new treatment strategies are greatly needed, the medical community welcomes this progress with great excitement. Single-agent anti PD-L1 and PD1 monoclonal antibodies have been evaluated in patients with locally advanced or metastatic TNBC. Although very limited efficacy was achieved in pre-treated patients, 1 out of 4 patients achieved an objective response when treated in the first-line setting. Of interest, many of these responses were long lasting. In 2019, atezolizumab was approved in combination with nab-paclitaxel in patients with metastatic TNBC whose tumors are positive for PD-L1 expression (≥1%) on immune infiltrate, evaluated by the VENTANA PD-L1 (SP142) antibody. However, when combined with paclitaxel, atezolizumab does not improve neither progression-free survival nor overall survival. On the other hand, pembrolizumab in combination when paclitaxel, nab-paclitaxel or carboplatin + gemcitabine has improved progression-free survival when PD-L1 expression was 10 or more (CPS score) evaluated by the 22C3 antibody. Unfortunately, the optimal platform to assess PD-L1 status is unknown, as it is the optimal cut-off value. Other biomarkers, such as mutational tumour burden or tumour infiltrating lymphocytes are not ready to be used in the clinic yet. Thus, biomarkers that can identify a broader group of patients who could benefit from this approach are urgently needed. Also, the combination of different immune checkpoint inhibitors between them or with other drugs, such as targeted therapy, may expand immunotherapy indication to more patients. Immune-related toxicities are closely associated with the known mechanisms of action of both PD-1 and PD-L1 antibodies, after restarting the anticancer immune system. The overall incidence is about 22% for all grades and 4% for high grades, being more frequent for patients treated with anti-PD-1 (all grades 27%) compared with anti-PD-L1 (all grades 17%). The most frequent organ specific immune-related adverse events were the endocrine system (7%), skin (5%), pulmonary system and gastrointestinal tract (4% each). Of note, immune-related deaths were reported in 0.34% of patients, the vast majority due to pneumonitis. When combined with chemotherapy, non-immune-related toxicities were reported with the same frequency as with chemotherapy alone. Citation Format: J Cortes. How and when to use immunotherapy and related toxicities [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP033.

Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study

Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study

Myeloma Induce Fapα+ Macrophage to Remodel Immune Microenvironment Which Lead to Anti-PD-1 Dilemma

Background: Multiple myeloma (MM) is a hematologic cancer which is characterized by clonal immune globulin. In recent years, FAPα+ fibroblast has been found in many tumor microenvironments, and play an important role in tumor immune escape. Furthermore, we find monocyte-derived macrophages can also express FAPα+ under existence of MM cell line. Objective Explore the impact of FAPα+ Macrophage in MM immune microenvironment. Methods Western blot(WB) and flow cytometry(FCM) was used to detect the expression of FAPα+ on macrophages. WB was used to detect the PDL1 altering. FCM was used to detect FAPα+ PDL1+macrophages in patient with myeloma. FCM was used to detect apoptosis of CD4+/CD8+ T cells and MM cells. Results: 1.MM cell line can induce FAPα+ expression on Macrophage through TGFβ1 or CSF1. 2.Over-expression FAPα on macrophage can promote the expression of PDL1 and knock-down FAPα can reduce PDL1. 3.FAPα can increases mRNA PDL1 and partially inhibits ubiquitination mediating autophagy of PDL1. 4.Over-expression FAPα on macrophage can induce CD4+/CD8+T cell apoptosis and knock-down FAPα can reduce T cell apoptosis. 5. FAPα inhibitor combined with anti-PDL1 or anti-PD1 monoclonal antibody can promote CD138+MM cell apoptosis. Conclusions: MM can induce macrophage expressing FAPα to further promote PDL1 expression and mediate MM immune escape. Combination of FAPα inhibitor with anti-PDL1 or anti-PD1 monoclonal antibody may facilitate immunotherapy effect in MM treatment. Key words: FAPα, Macrophage, PDL1, T cell, Immunotherapy Disclosures No relevant conflicts of interest to declare.

Real-world clinical outcomes in avelumab-treated patients (pts) in the United States (U.S.) from SPEAR-Merkel: Study informing treatment pathway decisions in Merkel cell carcinoma (MCC).

269 Background: MCC is a rare, aggressive disease associated with poor prognosis. Avelumab, a fully human anti–PD-L1 monoclonal antibody, was the first immune checkpoint inhibitor approved by the FDA for the treatment of metastatic MCC (mMCC). In the JAVELIN Merkel 200 trial (Clinical trial information: NCT02155647), avelumab resulted in durable responses and a high objective response rate (ORR) in pts with mMCC. This retrospective descriptive study assessed real-world clinical outcomes in avelumab-treated pts with locally advanced MCC (laMCC) and mMCC in a US community oncology setting. Methods: This study included data on avelumab-treated laMCC and mMCC pts from 1/1/17 to 3/31/19 within The US Oncology Network. Study data were captured through 9/30/19 using structured fields and chart review of iKnowMed electronic healthcare records. Real-world ORR was assessed. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 33 pts initiated treatment with avelumab (laMCC n = 11; mMCC n = 22) and were followed up for a median of 10.9 months (range, 0.5-27.2 months). Median age was 77 years (range, 44-90+ years), 78.8% of pts were male, and the majority (84.8%) of pts were treated in the first-line setting. During treatment, 27.2% of pts had emergency department visits and 39.4% were hospitalized; 1% and 23.1%, respectively, were treatment related. Clinical outcomes are reported in the table. Conclusions: This is the first study to examine pts with laMCC treated with avelumab in a real-world setting. Although the sample population is small, results suggest the clinical benefits in the real world in pts with mMCC treated with avelumab are consistent with benefits reported in the JAVELIN Merkel 200 trial. [Table: see text]

Role of pleural and peritoneal metastasis in immune checkpoint inhibitors efficacy patients with non-small cell lung cancer: real-world data from a large cohort in France.

Checkpoint inhibitors (CKI) targeting PD-1 or PD-L1 are major therapies for the treatment of non-small cell lung cancer (NSCLC). Despite numerous studies of biological biomarkers, we currently lack a marker to predict CKI primary resistance. The aim of this study was to isolate clinical markers associated with the absence of efficacy of CKI used as monotherapy in NSCLC. We conducted a retrospective analysis of 172 patients treated with anti-PD1 or anti-PDL1 monoclonal antibodies (mAb) for advanced NSCLC at the Dijon Cancer Center. Baseline characteristics were compared using the Chi squared test between responders and non-responders. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test for univariate analysis. Cox regression models were used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS). Among 172 patients included, 149 (86.5%) received CKI after platinum chemotherapy. Response rate (RR) was 16%, median progression-free survival (PFS) was 2.5months (95% CI 0.7-30months) and median overall survival (OS) was 10months (95% CI 0.7-46.8months). By univariate analysis, WHO performance status ≥ 1, presence of bone, liver and pleuroperitoneal metastasis were associated with poor PFS and OS. Multivariate analysis showed that only pleuroperitoneal metastasis was independently associated with PFS and OS. Patients with pleuroperitoneal metastasis and WHO performance status ≥ 1 had a < 10% chance of yielding a benefit from CKI. Our data support the hypothesis that pleuroperitoneal metastasis is a major predictive factor affecting CKI efficacy in NSCLC patients and may be used to avoid CKI monotherapy for such patients.

Real-world clinical outcomes in avelumab-treated patients (pts) in the United States (U.S.) from SPEAR-Merkel –Study informing treatment Pathway dEcisions in Merkel cell cARcinoma (MCC).

e22029 Background: MCC is a rare, aggressive disease associated with poor prognosis. Avelumab, a fully human anti–PD-L1 monoclonal antibody, was the first immune checkpoint inhibitor approved by the FDA for the treatment of metastatic MCC (mMCC). In the JAVELIN Merkel 200 trial (Clinical trial information: NCT02155647), avelumab resulted in durable responses and a high objective response rate (ORR) in pts with mMCC. This retrospective descriptive study assessed real-world clinical outcomes in avelumab-treated pts with locally advanced MCC (laMCC) and mMCC in a US community oncology setting. Methods: This study included data on avelumab-treated laMCC and mMCC pts from 1/1/17 to 3/31/19 within The US Oncology Network. Study data were captured through 9/30/19 using structured fields and chart review of iKnowMed electronic healthcare records. Real-world ORR was assessed. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 33 pts initiated treatment with avelumab (laMCC n = 11; mMCC n = 22) and were followed up for a median of 10.9 months (range, 0.5-27.2 months). Median age was 77 years (range, 44-90+ years), 78.8% of pts were male, and the majority (84.8%) of pts were treated in the first-line setting. During treatment, 27.2% of pts had emergency department visits and 39.4% were hospitalized; 1% and 23.1%, respectively, were treatment related. Clinical outcomes are reported in the table. Conclusions: This is the first study to examine pts with laMCC treated with avelumab in a real-world setting. Although the sample population is small, results suggest the clinical benefits in the real world in pts with mMCC treated with avelumab are consistent with benefits reported in the JAVELIN Merkel 200 trial. Clinical trial information: NCT02155647 . [Table: see text]

Abstract P1-19-03: JAVELIN PARP Medley, a phase 1b/2 study of avelumab plus talazoparib: Results from advanced breast cancer cohorts

Abstract Background: Avelumab, a human IgG1 anti–PD-L1 monoclonal antibody, has shown antitumor activity and a manageable safety profile in several tumor types. Talazoparib, an orally available PARP inhibitor, is approved for the treatment of patients with deleterious or suspected deleterious germline BRCA1/2-mutated HER2− locally advanced (LA) or metastatic (M) breast cancer (BC). Preclinical data suggest that PARP inhibitors may have synergistic activity when administered in combination with immune checkpoint inhibitors. We report results from patients with LA/MBC enrolled in the phase 1b/2, multicohort JAVELIN PARP Medley study (NCT03330405). Methods: In phase 1b (cohort 1), patients with advanced solid tumors who had received ≥1 prior standard of care chemotherapy (CT) regimen were treated with avelumab 800 mg IV every 2 weeks (Q2W) in combination with talazoparib 1.0 mg orally once daily (QD) (dose de-escalation to 0.75 or 0.5 mg permitted following toxicity). In 2 phase 2 cohorts, eligible patients had either LA/M triple-negative BC (TNBC, cohort 2A) or LA/M hormone receptor positive (HR+), HER2−, DNA damage repair defect-positive BC (cohort 2B). Patients in cohort 2A had received 0 to 2 prior CT regimens (no progression on prior platinum-based CT) and patients in cohort 2B had received prior standard of care hormone therapy in either the adjuvant and/or LA/M setting followed by 0 to 2 prior CT regimens (no progression on prior platinum-based CT). The primary endpoint for phase 1b was first-cycle dose-limiting toxicities (DLTs) and for phase 2 was objective response (investigator assessed per RECIST v1.1). Adverse events (AEs) were characterized using National Cancer Institute Common Terminology Criteria for AEs v4.03. Results: By the data cutoff on December 24, 2018, 34 patients had been treated in cohorts 1 and 2. Twelve patients with advanced solid tumors were treated in cohort 1 (including 2 patients with TNBC); 3 patients (25.0%) had a first-cycle DLT: grade 3 neutropenia, (n=1) and grade 3 thrombocytopenia, (n=2). Best overall response (BOR) was partial response (PR) in 1 patient, stable disease (SD) in 3, progressive disease (PD) in 6, and non-complete response/non-PD in 1 patient with metastatic castration-resistant prostate cancer and non-measurable disease at baseline; 1 patient was not evaluable for response. Both patients with TNBC had a BOR of SD and remained on treatment for ≥9 months. Objective response rate in this pre-treated and heterogenous population was 8.3% (95% CI, 0.2, 38.5). Based on the phase 1b data, the recommended phase 2 dose was avelumab 800 mg Q2W and talazoparib 1 mg QD. By data cutoff, 22 patients had been treated in cohorts 2A (n=19) and 2B (n=3); median age was 56 and 50 years, respectively. In cohort 2A, 12 patients were evaluable for disease assessment; BOR was PR in 1, SD in 6, and PD in 5. All 3 patients in cohort 2B were non-evaluable for response at data cutoff. Treatment-related AEs (TRAEs) of any grade occurred in 11 patients (91.7%) in cohort 1, and 18 (94.7%) patients in cohort 2A. In cohort 2A, the most common TRAEs were anemia (57.9%), nausea (26.3%), fatigue (21.1%) and thrombocytopenia (21.1%); 9 patients (47.4%) had grade ≥3 TRAEs. There were no treatment-related deaths. Safety data from cohort 2B are not reported owing to low patient numbers. Observed pharmacokinetic (PK) data for avelumab 800 mg Q2W were similar to simulated data derived from a population PK model developed using 10 mg/kg dosing. Conclusions: Avelumab 800 mg Q2W administered in combination with talazoparib 1 mg QD in patients with advanced solid tumors, showed preliminary antitumor activity and a manageable safety profile, which was comparable to the safety profiles of the single agents. The study is ongoing; updated safety and efficacy data, and biomarker data will be presented. Citation Format: Timothy A Yap, Panagiotis Konstantinopoulos, Melinda L. Telli, Smita Saraykar, J Thaddeus Beck, Matthew D. Galsky, Jame Abraham, David R. Wise, Mustafa Khasraw, Gabor Rubovszky, Mikhail Dvorkin, Anil A Joy, Mateusz Opyrchal, Daria Stypinski, Colombe Chappey, Ross Stewart, Rossano Cesari, Anita Scheuber, Aditya Bardia. JAVELIN PARP Medley, a phase 1b/2 study of avelumab plus talazoparib: Results from advanced breast cancer cohorts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-03.

Avelumab flat dose regimen: Justification for use in advanced renal cell carcinoma (aRCC).

32 Background: Avelumab, an anti–PD-L1 monoclonal antibody, was recently approved for the treatment of aRCC in combination with axitinib and was previously indicated for the treatment of metastatic Merkel cell carcinoma (MCC) and platinum-treated advanced/metastatic urothelial carcinoma (UC). Although avelumab was approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), it was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (popPK), exposure-efficacy and exposure-safety modeling and simulations in MCC and UC (Novakovic AM, et al. Clin Pharmacol Ther. 2019). The justification for the recommended flat-dose regimen for avelumab as combination therapy with axitinib in aRCC is presented. Methods: Simulated exposure metrics (eg, area under the curve) from the previous popPK model (data from 1,827 patients with solid tumors across 3 clinical trials) for both weight-based and flat-dose regimens were compared with the exposure metrics obtained from treatment-naive patients with aRCC enrolled in 2 clinical studies (N = 488 from NCT02493751 and NCT02684006) who received avelumab (10 mg/kg Q2W) + axitinib (5 mg orally twice daily). Avelumab exposure-response relationships for safety and efficacy were also analyzed. Endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs) and immune-related (ir)AEs, and progression-free survival (PFS) by independent review. Results: The administration of weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to simulated reference exposures of the flat-dose regimen in the solid tumor population. Avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or IRRs, although there was a weak association with an increased probability of any-grade irAEs. Conclusions: The similar exposures observed for both avelumab dosing regimens in aRCC, and in prior studies in the MCC and UC populations, suggest that the 800 mg Q2W flat-dose regimen will maintain the benefit-risk ratio for avelumab + axitinib for treatment-naive patients with aRCC. Clinical trial information: NCT02493751 . Clinical trial information: NCT02684006.

Proceedings From the Clinical and Scientific Innovations in Oral and Maxillofacial Surgery Conference 2019

Proceedings From the Clinical and Scientific Innovations in Oral and Maxillofacial Surgery Conference 2019