PD-1 Inhibitor Monotherapy Research Articles

Neoadjuvant Immunotherapy Leads to Major Response and Low Recurrence in Localized Mismatch Repair–Deficient Colorectal Cancer

Our study aimed to evaluate the efficacy and feasibility of neoadjuvant anti-PD-1 treatment for localized mismatch repair-deficient (dMMR) colorectal cancer (CRC). The study cohort included patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy from 3 medical centers in Southern China. Main eligibility criteria included age between 18 and 75 years, ECOG performance status of 0 or 1, and receipt of ≥2 doses of PD-1 inhibitors. A total of 73 patients were included. Most of the tumors were locally advanced, including 19 (26.0%) T4a and 29 (39.7%) T4b. Most patients (79.5%) received PD-1 inhibitor monotherapy. Objective response per radiologic assessment was achieved in 62 (84.9%) patients, including 17 (23.3%) with complete response (CR) and 45 (61.6%) with partial response, with a median time to response of 9.6 weeks. Patients with T4a/4b disease had a similar response rate as those with T2-3 disease (84.0% vs 85.4%; P=.999). As of writing, a total of 50 patients have undergone surgery. Pathologic CR was achieved in most (57.1%) patients and remained high (59.5%) even among the 38 patients with T4a/4b disease. The 17 patients with CR did not undergo surgery and adopted a watch-and-wait strategy. After a median follow-up of 17.2 months (range, 3.4-45.1 months), the overall median recurrence-free and overall survivals were not reached. Among patients undergoing surgery or achieving CR, the 2-year tumor-specific disease-free and overall survival rates were both 100%. During neoadjuvant treatment, grade 3-4 adverse events occurred in 8 patients; 4 required acute intervention. Severe postoperative complications were recorded in 4 patients, 3 of whom required a second surgery. Neoadjuvant therapy with PD-1 blockade is highly effective for localized dMMR CRC, with an acceptable safety profile and low recurrence rate. This treatment holds promise for becoming the new standard of care for localized dMMR CRCs.

CTIM-01. TITLE: PHASE 1B STUDY OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD): PRELIMINARY RESULTS

Abstract BACKGROUND LMD from systemic cancer has a dismal prognosis with median survivals of 8-10 weeks. A phase 2 trial of PD-1 inhibitor monotherapy in LMD showed median overall survival (OS) of 3.6 months (Brastianos P et al., 2020). We determined the safety/efficacy of avelumab, a PD-L1 inhibitor with WBRT in patients with LMD (NCT0371768). This combination can treat the tumor directly and increase BBB permeability (Li, 2003; Nordal, 2005) allowing the increased egress of activated T cells into the meninges/CSF. METHODS Patients received concurrent avelumab 800 mg IV q2 weeks for ≤ 5 cycles (unless PD or unacceptable toxicity) with WBRT 3000 cGy in 10 fractions. Primary endpoints are safety/DLTs and OS at 3 months. Secondary endpoints are CSF T-cell/cytokine profiles (scRNAseq, phosophoproteomics etc.). RESULTS A total of 15 patients (7 breast, 7 lung & 1 other) were enrolled (n = 13 F, ages 32-79). Pts receiving anti-PD-1/PD-1L/PD-L2/CD137,CTLA-4 therapy ≤ 6 months prior were excluded. Three of 15 patients had grade 3/4 AEs (diarrhea, lymphopenia, decreased WBC count in 3 patients). Seven patients (50%) were alive at 3 or 6 months. The estimated median follow up in 14 patients is 4.75 months (range, 0.92 – 30.05 months, 95% CI is 1.32 ~ 19.82). The median PFS is 3.75 months (95% CI = 0.85-15.16) and median OS is 6.89 months (95% CI = 1.18-14.7). CONCLUSIONS The combination of avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF (analysis underway) will determine mechanisms of LMD therapeutic/resistance effects.

Cutaneous adverse events associated with PD-1 inhibitor-based therapy in patients with non-small-cell lung cancer.

Aim: To analyze the incidence and characteristics of cutaneous adverse events (CAEs) in non-small-cell lung cancer patients treated with PD-1 inhibitor-based therapy. Methods: A total of 150 non-small-cell lung cancer patients under PD-1 inhibitor-based therapy from February 2018 to September 2021 were included and were followed up with regularly. Results: Over one-half of patients (88/150; 58.7%) had CAEs. Reactive cutaneous capillary endothelial proliferation, maculopapular rash and pruritus were the most common CAEs. The incidences of CAEs were 50.0 (18/36), 67.0 (50/75) and 51.3% (20/39) with PD-1 inhibitor monotherapy, PD-1 inhibitor in combination with chemotherapy and PD-1 inhibitor in combination with antivascular/targeted therapy, respectively. Conclusion: CAEs occur frequently in PD-1 inhibitor-based therapy but are generally tolerable.

Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients.

ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3–4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.

Anti-PD-1/PD-L1 immunotherapy in conversion treatment of locally advanced hepatocellular carcinoma.

Curative surgery and locoregional therapy are radical therapies for patients with HCC. But more than 80% of HCC patients cannot be fitful for radical therapies because of local progression or distant metastasis at initial diagnosis. Among patients with unresectable locally advanced hepatocellular carcinoma (HCC), some patients can be converted to be technically resectable by conversion treatment and salvage surgery. For unresectable locally advanced hepatocellular, conversion treatment prior to salvage surgery with transcatheter arterial chemoembolization (TACE) and other locoregional therapies improve outcomes. PD-1/PD-L1 inhibitors as immune checkpoint inhibitor (ICI) therapy which show high antineoplastic activity in HCC patients by preclinical and clinical researches can also be a good choice for conversion therapy. PD-1/PD-L1 inhibitor combined with locoregional therapy plus antiangiogenic agents or not is most potential conversion therapy comparing to PD-1 inhibitor monotherapy and PD-1/PD-L1 inhibitor combined with antiangiogenic agents or CTLA-4 inhibitor. As more clinical evidence reported, PD-1/PD-L1 immunotherapy would be widely used in conversion treatment of locally advanced hepatocellular carcinoma.

Effectiveness and Safety of PD-1 Inhibitor Monotherapy for Elderly Patients with Advanced Non-Small Cell Lung Cancer: A Real-World Exploratory Study.

Background Immunotherapy represented by PD-1 blockades had become the standard of care for advanced non-small cell lung cancer (NSCLC) gradually. Unfortunately, several PD-1 inhibitor-related studies excluded elderly patients with NSCLC over 75 years of age, resulting in relatively limited evidence regarding the efficacy and safety of PD-1 in elderly patients with NSCLC clinically. Objective This study aimed to identify the effectiveness and safety of PD-1 blockade monotherapy among elderly patients with advanced NSCLC. Methods Elderly patients with advanced NSCLC (≥65 years) who received PD-1 blockade monotherapy from September 2018 to December 2021 were screened retrospectively, and a total of 68 elderly patients with NSCLC were eligible for inclusion ultimately. The PD-1 blockades in the study were the available PD-1 monoclonal antibodies that had been approved for marketing in China, including camrelizumab, sintilimab, pembrolizumab, and nivolumab. The effectiveness and safety of the patients was collected retrospectively. Additionally, the correlation between prognosis and baseline characteristic subgroups was analyzed to identify the potential risk factors for progression-free survival (PFS). Results The median age of the 68 elderly patients with advanced NSCLC was 73 years (range: 65–82 years). Best overall response during PD-1 blockade administration suggested that no patients were found with complete response, partial response was found in 14 patients, stable disease was noted in 29 patients, and 25 patients had progressive disease, yielding an objective response rate (ORR) of 20.6% (95%CI: 11.7%–32.1%) and a disease control rate (DCR) of 63.2% (95%CI: 50.7%–74.6%). Furthermore, prognostic analysis exhibited that the median progression-free survival (PFS) of the 68 patients with advanced NSCLC was 3.5 months (95%CI: 2.4–4.6) and the median overall survival (OS) was 10.5 months (95%CI: 6.3–14.7). Additionally, a total of 48 patients were observed with the treatment-related adverse reaction (70.6%) of the 68 elderly patients with NSCLC, and the incidence of grade 3 or above adverse reactions was 16.2%. Specifically, the most common adverse reactions were fatigue, diarrhea, rash, and abnormal liver function with the incidence of 25.0%, 22.1%, 16.2%, and 14.7%, respectively. Exploratory analysis between PFS and baseline characteristic subgroups suggested that ECOG performance status and number of metastatic lesions might be independent factors for PFS. Conclusion PD-1 blockade monotherapy exhibited potential effectiveness and acceptable toxicity for elderly patients with NSCLC. ECOG performance status and number of metastatic lesions might be potential risk factors to predict the PFS of elderly patients with advanced NSCLC.

Is PD-1 Inhibitor Monotherapy a New Standard Treatment for MMR-Deficient Locally Advanced Rectal Cancer?

Treatment of locally advanced rectal cancer with multimodal treatment courses can result in significant morbidity. Nonoperative management is feasible for patients with clinical complete response to neoadjuvant therapies. Several recent reports have evaluated the use of immunotherapy with checkpoint inhibition for patients with mismatch repair-deficient rectal and colon cancers, with striking results.

Brief Report: A Blood-Based MicroRNA Complementary Diagnostic Predicts Immunotherapy Efficacy in Advanced-Stage NSCLC With High Programmed Death-Ligand 1 Expression

IntroductionPatients with advanced, non-oncogene-driven NSCLC with high programmed death-ligand 1 (PD-L1) expression are eligible for treatment with immunotherapy. There is, however, an urgent medical need for biomarkers identifying cases that require additional combination with chemotherapy. We previously uncovered a myeloid-based 5-microRNA (miRNA) signature that identified responders to immunotherapy in PD-L1 unstratified patients; however, its potential utility in treatment guidance for patients with PD-L1 high tumors remained unclear. MethodsWe trained (n = 68) and validated (n = 56) a 5-miRNA multivariable Cox proportional hazards model predictive of overall survival on small RNA sequencing data of whole blood samples prospectively collected before the commencement of immunotherapy for stage IV NSCLC with PD-L1 tumor proportion score greater than or equal to 50%, treated with PD-1 inhibitor monotherapy (immunotherapy alone [IO]). Specificity was demonstrated in a control cohort treated with immunochemotherapy (ICT) (n = 31). ResultsThe revised 5-miRNA risk score (miRisk) stratified IO-treated patients and identified a high-risk group with significantly shorter overall survival (hazard ratio = 5.24, 95% confidence interval: 2.17–12.66, p < 0.001). There was a significant interaction between the miRisk score and type of treatment (IO or ICT, p = 0.036), indicating that the miRisk score may serve as a predictive biomarker for immunotherapy response. Furthermore, the miRisk score could identify a group of high-risk patients who may benefit from treatment with ICT as opposed to IO (hazard ratio = 0.35, 95% confidence interval: 0.15–0.82, p = 0.018). ConclusionsThe miRisk score can distinguish a group of patients with PD-L1 high, stage IV NSCLC likely to benefit from adding chemotherapy to immunotherapy and may support treatment decisions as a blood-based complementary diagnostic.

Regorafenib (REGO) ± PD-1 inhibitor in second-line setting for unresectable hepatocellular carcinoma (uHCC) in real-world practice.

e16148 Background: No response and resistance occurred for the most uHCC patients with the treatment of molecular targeted agents and\or anti-PD-1 inhibitors. And the second-line therapies are still unmet the ideal clinical outcome. A pilot study that assessed the effectiveness of the combination therapy of REGO + PD-1 inhibitor in second-line setting for pts with advance uHCC showed promising result. Methods: This single-center, retrospective, real-world study was conducted between Jan 2019 to Jul 2021. All patients with uHCC, who were treated with second-line REGO + PD-1 inhibitor or REGO monotherapy were evaluated. The progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS) were observed. Results: Forty-six patients with uHCC were included in the study, and most had received previous systemic treatment including targeted therapy and immunotherapy. In all pts, median treatment duration of regorafenib was 152.5 days. Median follow-up was 9.0 months. Tumor response was evaluated in 25 and 21 pts in REGO + PD-1 inhibitor and REGO monotherapy group respectively, ORR was 40% and 19.0% respectively; DCR was 88% and 71.4% respectively. Median OS was not reached in either group; the median PFS of the REGO + PD-1 inhibitor group was 11.5 months, which was significantly higher than that of the REGO monotherapy group (5.1 months) (C2=3.867; P=0.049). The most common AE grade ≥3 was diarrhea (4.3%), and was solely observed in REGO monotherapy group. Conclusions: Our preliminary findings suggested that the striking improvement in PFS and ORR were compelling in the REGO + PD-1 inhibitor group, and regardless of previous treatment, regorafenib was clinically effective for uHCC pts in second-line treatment whether in combination with PD-1 inhibitor or not in Chinese patients. And there was a trend to increased efficacy with no increased toxicity in combination therapy. Further analysis in a real-world study with a large sample size is crucial to substantiate our results.

Long-term toxicities with immune checkpoint inhibitor (ICI) in melanoma patients.

e21549 Background: The incorporation of ICI into the treatment of melanoma has greatly improved patient outcomes, but this benefit has come at the cost of exposing patients to immune-related adverse events (irAEs). A wide spectrum of irAE types has been described, and severity is known to vary from minor to life-threatening; however, the literature to date on the chronicity of irAEs is limited. Objectives: To characterize the long-term and permanent irAEs associated with ICI treatment in patients with melanoma, the treatment of irAEs and the association with survival outcomes. Methods: We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥6 months), transient (resolution over a period &lt; 6 months), or no irAEs. Overall survival was evaluated for those patients that were treated in the metastatic setting with PD1 inhibitor monotherapy. Results: Thirty-eight patients were treated in the adjuvant setting and 123 patients were treated in the metastatic setting. A total of 279 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, 15 (9.3%) experienced long-term irAEs as their longest-lasting toxicity, 34 (21.1%) developed transient irAEs only, and 46 (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (35.5%) or skin-related (32.7%). Grade ≥3 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still on treatment for long-term or permanent irAEs 6 months or more following completion of ICI therapy, including 23 patients on thyroid replacement and 22 on oral steroids. ICI treatment was temporarily interrupted for 63 (22.6%) irAEs and permanently discontinued due to irAE in 38 (13.6%) patients. Subgroup analysis of patients who received single-agent ICI in the first-line palliative setting reveals that those with longer-duration irAEs had a significantly longer median overall survival. Conclusions: Despite the significant benefits, treatment with ICIs in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients. The risk of long-term toxicity should therefore be discussed when obtaining consent for treatment. As these treatments are being used more commonly in the adjuvant setting, the impact of survivorship and the long-term management of these toxicities is increasingly important.

Anti-PD1, capecitabine, and oxaliplatin for the first-line treatment of dMMR esophagogastric cancer (AuspiCiOus-dMMR): A proof-of-principle study (AuspiCiOus).

TPS4163 Background: Doublet cytotoxic treatment demonstrates survival benefit over single drug therapies in patients with advanced esophagogastric cancer (EGC). Previous clinical data suggests an improved survival outcome in patients with microsatellite instability (MSI) treated with PD-1 inhibitor monotherapy or in combination with chemotherapy in first line palliative treatment. The positive effect of immunotherapy was only seen after a couple of months of treatment. This suggests that the patient might benefit from a short course of chemotherapy at the start of treatment. However, reports on the effects of cytotoxic treatment in MSI-high tumors range from beneficial to detrimental. Thus, the value of cytotoxic treatment, as well as the effect on the tumor immune microenvironment (TME) in MSI-high tumors is unclear. Therefore, in AuspiCious-dMMR we will study the effect of sequential treatment in patients with mismatch repair deficient (dMMR) EGC on the tumor immune microenvironment and, more specifically, the impact on the infiltration of cytotoxic T cells, before and after a short course of chemotherapy, and during treatment with PD-1 inhibition. Methods: AuspiCiOus is a multi-center, open-label, single arm (phase 2) study in patients with dMMR irresectable or metastatic EGC adenocarcinoma (NCT05177133). Patients are treated with Capecitabine and Oxaliplatin for two 3-weekly cycles, after which treatment is continued with retifanlimab (PD-1 inhibitor) for 4-weekly cycles up to progression or unacceptable toxicity, with a maximum of two years. Before treatment, after chemotherapy and after two cycles of immunotherapy fresh tumor biopsies are collected to study the primary outcome (T cell infiltration and the interferon-γ signature) as well as for translational research purposes (flow cytometry, nanostring profiling, (multicolor) immunohistochemistry and organoid culturing). Blood is collected at the same time points and on day 3 after the first course of immunotherapy for isolation of peripheral blood mononuclear cell, and determination of cytokine/chemokine profile, circulating stromal markers, and circulating tumor DNA. Also, fecal samples are collected to determine changes in the intestinal microbiome and patient reported outcome measures are used to determine quality of life. (s)AEs are assessed according to CTCAE v5 and tumor response is determined according to (i)RECIST 1.1. Key eligibility criteria are 1) histological confirmed diagnosis of untreated metastatic or irresectable HER2- adenocarcinoma of stomach or junction and 2) dMMR determination by IHC. Study is open for inclusion and three of planned 25 patients have been enrolled. Clinical trial information: NCT05177133.

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases – A multicenter cohort study

PurposeGuidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. MethodsA multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. ResultsA total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4–12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. ConclusionSystemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

Current status and advances of immunotherapy in nasopharyngeal carcinoma.

The general immune landscape of nasopharyngeal carcinoma (NPC) renders immunotherapy suitable for patients with NPC. Immune checkpoint inhibitors (ICIs) based on programmed death-1/programmed death ligand-1 (PD-1/PD-L1) blockade have made a breakthrough with the approval of PD-1 inhibitor for refractory recurrence and/or metastatic (R/M NPC) and the approval of PD-1 inhibitor in combination with gemcitabine and cisplatin as first line for R/M NPC in 2021 in China. The incorporation of ICIs into the treatment paradigms of NPC has become a clinical hot spot and many prospective clinical studies are ongoing. In this review, we provide a comprehensive overview of the rationale for immunotherapy in NPC and current status, advances and challenges of immunotherapy in NPC based on published clinical data, and ongoing trials. We focus on the clinical application and advances of PD-1 inhibitor monotherapy and its combination with chemotherapy and summarize the clinical explorations of other immunotherapy approaches, for example, combination of PD-1/PD-L1 inhibitors with antiangiogenic inhibitor with molecular targeted agents, cancer vaccines, adaptive immunotherapy, and new ICI agents beyond PD-1/PD-L1 inhibitors in R/M NPC. We also describe the clinical studies’ status and challenges of ICIs-based immunomodulatory strategies in local advanced NPC and pay attention to the biomarker application for personalized immunotherapy of NPC in the hope to provide insights for clinical practice and future clinical studies.

The concepts of rechallenge and retreatment with immune checkpoint blockade in melanoma patients

Forty to 60% of patients with advanced or metastatic melanoma respond to first-line immune checkpoint inhibitors (ICI) and half of all patients in the metastatic setting eventually progress. This review evaluated the latest long-term data from clinical trials. It also considered data from recent retrospective studies, as these address important questions for clinical practice. ‘Retreatment’ defined as ‘repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended’ and showed activity in selected patients with recurrence after regular completion of adjuvant PD-1 treatment. In melanoma patients with adjuvant PD-1 monotherapy who recur during adjuvant treatment, further treatment with PD-1 monotherapy seems to have no clinical utility, indicating the need for a therapy switch or escalation in these patients. Targeted therapy with BRAF/MEK inhibitors and ipilimumab-based therapy (alone or combined with PD-1 blockade) show clinical activity in patients who recur during and after adjuvant treatment. ‘Rechallenge’, defined as ‘repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment for unresectable or metastatic disease’, with pembrolizumab at progression in the advanced setting achieving additional disease control. If possible, ‘escalation’ (PD-1 inhibitors combined with additional agents) should be preferred to PD-1 inhibitor monotherapy rechallenge as higher response rates were demonstrated. The combination of PD-1 plus CTLA-4 was found to be more effective but not more toxic than CTLA-4 alone. Promising antitumor activity was observed for escalation to lenvatinib plus pembrolizumab, entinostat plus pembrolizumab, and relatlimab plus nivolumab. Retreatment, rechallenge and escalation are available options for patients with melanoma who relapse in the adjuvant or advanced setting.

LMD-05. Phase 1B Study of Avelumab and Whole Brain Radiotherapy (WBRT) in Patients with Leptomeningeal Disease (LMD): Preliminary Results

BackgroundLMD has a dismal prognosis with median survivals of 8–10 weeks. Recently the first phase 2 trial of PD-1 inhibitor monotherapy in solid tumor LMD showed median overall survival (OS) 3.6 months. We aimed to determine the safety/efficacy of avelumab with WBRT in patients with LMD from solid malignancies (NCT0371768). This combination can treat tumor directly and increase the permeability of the blood-brain-barrier with increased egress of activated T cells into the meninges/CSF and facilitated Avelumab entry into the CSF.HypothesisCombination radioimmunotherapy will produce an activated immunocyte/cytokine profile in CSF.MethodsPatients received concurrent Avelumab 800mg IV q2weeks x≤5 cycles with WBRT 3000cGy, 10 fractions. Primary endpoints: Safety/DLTs and OS at 3 months. Secondary endpoints: CSF T-cell/cytokine profiles (scRNAseq/phosophoproteomics) and clinical outcomes, to be performed when all 15 patients are accrued to minimize batch effects.ResultsTen patients (5 breast, 4 lung & 1 undifferentiated sinonasal carcinoma) were enrolled (n=8 females, n=2 males, ages 32–79); n=1 patient did not complete WBRT. Patients who received anti-PD-1/PD-1L/PD-L2/CD137/CTLA-4 therapy within 6 months prior to enrollment were excluded. 30% had grade 3 AEs at least possibly related to treatment (n=3 diarrhea, lymphopenia, decreased WBC count). There were no grade 4–5 toxicities. Six patients (66.7%) were alive at 3 months. The estimated median follow up in 9 patients (regardless whether patients failed or not) is 10.49 months (range, 0.95–19.82 months, 95% CI) and the estimated median follow up survival was 19.8 months assessed using the reverse Kaplan-Meier method. Median PFS is 4.27 months (range, 0.30–16.73 months, 95% CI).ConclusionsIn this pilot study, combination of Avelumab and WBRT is safe, and demonstrates encouraging activity in patients with solid tumor LMD. Multiple platform interrogation of CSF may determine mechanisms of LMD therapeutic effects and differentiate responders from non-responders.

A multi-institutional retrospective analysis of immune checkpoint inhibitor efficacy in gynecologic cancers

<h3>Objectives:</h3> Immune checkpoint inhibitor (ICI) therapy is the standard-of-care in several solid tumor malignancies, including gynecologic cancers (GYN). Several recent approvals are based on histology-agonistic trials where the relative efficacy in GYN cancers is lacking. Also, real-world efficacy data on ICI therapy in GYN malignancies are limited. The response rates to ICI rechallenge and the histologies most likely to respond are unknown. This study evaluates and characterizes clinical response to ICI therapy in GYN cancers. <h3>Methods:</h3> An IRB approved retrospective review was performed on adult women with gynecologic malignancies treated with ICI, not under clinical trial, between January 2000 and June 2020 at the Mass General Brigham Integrated Health Care System and the Dana-Farber Cancer Institute. Variables analyzed included patient demographics, disease characteristics, overall response rates (ORR), time to response, duration of response (DOR), and progression free survival (PFS). <h3>Results:</h3> Database review identified 129 eligible patients. The primary sites of disease were uterus (40%), vulvovaginal (22%), ovary (21%), and cervix (17%). Most patients received PD-1 inhibitor monotherapy (80.6%), 16.3% of patients received combination CTLA-4 and PD-1 inhibitor therapy. Monotherapy with anti-PD-L1 and anti-CTLA4 represented 2.3% and 0.8%, respectively. The ORR across all disease sites was 45%. The complete response rate, partial response rate, and stable disease rates were 24%, 62%, and 14%, respectively. The ORR in cervical cancer was 54.5%, 51.9% in uterine cancer, 35% in vulvar cancer, and 33.3% in ovarian cancer. The overall median time to response and DOR was 2.5 months and 4.5 months, respectively. Median DOR/PFS (months) were 10/13 (uterine), 3/5 (ovary) 3.8/7 (cervix), 5/7.8 (vulvar). Twenty-eight patients received a subsequent line of ICI therapy, and of these, 11 responded, including 3 patients (all with vulvar or cervical cancer) who had not responded to 1st line therapy. Eight patients experienced responses in both lines. The only 2 patients with ovarian cancer who responded to second-line ICI had a previous response (and subsequent progression) to first-line ICI. Of nine patients receiving third-line ICI treatment, there was only 1 response in a patient with vulvar melanoma. There were no responders to the fourth rechallenge with immunotherapy. <h3>Conclusions:</h3> Overall, 45% of patients responded to initial ICI therapy, with the majority experiencing a PR. Patients with uterine cancer benefited the longest from ICI therapy. Most patients who responded to second-line therapy were those who responded to initial therapy. All patients who responded to ICI rechallenge without an initial response had vulvar or cervical cancer. Patients with ovarian cancer who did not respond to initial ICI therapy were unlikely to respond to subsequent lines. The use and timing of ICI in GYN malignancies should consider primary site and patterns of prior response.

Impact of KRAS mutational variant on response to immunotherapy in metastatic NSCLC.

e21127 Background: KRAS alterations constitute the most common driver mutations in metastatic non-small cell lung cancers (mNSCLC) and occur in approximately 30% of patients. KRAS mutational subtype as well as the presence of co-mutations has been associated with altered activation of downstream signaling pathways in preclinical models. We hypothesize that different KRAS G12C mutational subsets will be associated with variable clinical outcome and response to therapy. To this end, we have performed a retrospective analysis of survival and treatment outcomes by KRAS mutation subtype (G12C vs non-G12C). Methods: A review of KRAS-mutated mNSCLC patients treated with immunotherapy between 2013 and 2020 was conducted. Patient demographics, smoking status, KRAS mutational subtype, co-mutations and PD-L1 status were collected. Overall response rate (ORR) and progression-free survival (PFS) were analyzed in each subgroup. Results: 98 KRAS mutant mNSCLC patients were treated with immune checkpoint inhibitors (ICI): 37% with a KRAS G12C mutation, 62% with a non-G12C mutation. Patients with a G12C mutation were more likely to be of Caucasian ancestry (86% vs 56%; p = 0.01) whereas all other characteristics were similar between the groups including smoking history, PD-L1 expression ≥50% (61% vs 40%) and the presence of a TP53 co-mutation (48% vs. 54%); all p &gt; 0.05. Treatment patterns were similar between the groups, with PD-1 inhibitor monotherapy given in 86% vs 79% of KRAS G12C and non-G12C patients. Overall response rate was 51% vs 27% in G12C vs non-G12C (p = 0.03). PFS was superior in G12C mutants (19.6 months vs 4.0 months), even after adjusting for smoking history, TP53 co-mutation status and PD-L1 expression (adjusted HR 0.51; p = 0.02). In subgroup analyses, the superiority in PFS was driven by the G12C mutants with high PD-L1 expression (n = 19): 26.8 months in G12C, PD-L1 high vs 4.7 months in G12C, PD-L1 low vs. 4.7 months in KRAS transversion mutations, PD-L1 high vs 4.0 months in transversion mutations, PD-L1 low vs. 3.0 months in transition mutations; p &lt; 0.001. Conclusions: The presence of a KRAS G12C mutation is associated with improved ORR and PFS after treatment with ICI compared to non-G12C mutations in mNSCLC. The greatest benefit in PFS was observed in the subgroup with G12C mutation and high PD-L1 expression. Differential activation of downstream signaling associated with specific KRAS codon 12 mutation variants may modulate the composition of the tumor immune microenvironment thereby contributing to the variable response to immunotherapy. Further understanding on these molecular mechanisms may direct the development of new treatment strategies in KRAS mutant lung cancers.

Baseline lesion number as an efficacy predictive and independent prognostic factor and its joint utility with TMB for PD-1 inhibitor treatment in advanced gastric cancer.

Background:We previously reported tumor mutation burden (TMB) as a potential prognostic factor for patients with advanced gastric cancer (AGC) receiving immunotherapy. We aimed to comprehensively understand the impact of tumor burden and TMB on efficacy and prognosis in immunotherapy-treated AGC patients.Methods:A total of 58 patients with refractory AGC receiving PD-1 inhibitor monotherapy from a phase Ib/II clinical trial (ClinicalTrials.gov identifier: NCT02915432) were retrospectively included. Univariate and multivariate logistical regression analyses and the Cox proportional hazards model were performed for prognostic value of baseline factors. Factors reflecting baseline tumor burden, including baseline lesion number (BLN), the maximum tumor size (MTS) and the sum of target lesion size (SLS) were analyzed. The objective response rate (ORR) and disease control rate (DCR) were compared by Chi-square test.Results:In univariate analysis, high BLN was associated with poor median progression-free survival (mPFS) [1.7 months versus 3.4 months; hazard ratio (HR), 2.696, p < 0.05] and median overall survival (mOS) (3.2 months versus 7.6 months; HR, 1.997, p < 0.05), while high TMB was a positive prognostic factor. In multivariable analysis, both BLN and TMB were independent prognostic factors for mOS (BLN: HR, 2.782, p < 0.05; TMB: HR, 0.288, p < 0.05), while MTS or SLS had no association with survival. Better ORR and DCR were observed in the low BLN group (15.4% versus 5.3%, p > 0.05; 86.96% versus 54.29%, p < 0.05). When combining BLN and TMB, the best efficacy and survival were observed in the BLNlowTMBhigh group (ORR: 37.5%, DCR: 62.5%, mPFS and mOS: not reached). The worst efficacy and survival were shown in the BNLhighTMBlow group [ORR: 0% (0/15); DCR: 13.3%; mPFS: 1.7 months; mOS: 2.7 months (all p < 0.05)].Conclusions:BLN, rather than factors regarding baseline tumor size, is perhaps a potential predictor for benefit from immunotherapy and its combination with TMB could further risk-stratify patients with AGC receiving immunotherapy.

Phase I Studies in Hematologic Malignancy: 20-Year Experience from Cancer Therapy Evaluation Program (CTEP) at National Cancer Institute/National Institutes of Health

Background Phase I study is an essential step of drug development to assess safety, but more recently also to investigate initial insights into potential patient therapeutic response. In the last two decades, treatment of hematologic malignancy has changed dramatically from chemotherapy to targeted agents such as monoclonal antibodies, small molecule inhibitors and immunotherapy. We leveraged a large cohort of phase 1 studies to assess trends in toxicity, response and survival outcomes over time. Methods We reviewed the database of all investigator-initiated phase 1 oncology trials treated patients with hematologic malignancies sponsored by CTEP at the NCI between 2000 and 2019. We report the rates of grade 5 toxicity, response to treatment, and survival outcome following enrollment to the trials. Univariate associations of rates of Grade 5 toxicities possibly, probably, or definitely attributable to treatment and response rate with disease type, year of study activation, or whether each type of treatment was administered were assessed through likelihood ratio tests of a generalized linear mixed model. Results Overall, 3,308 patients were treated in 161 trials. Median age of the patients was 61 (range: 0-96) and 61% were male. Acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was the most common enrolled malignancy diagnosis (N=1,768) followed by lymphoma (N=921), acute lymphoblastic lymphoma (ALL: N=193) and myeloma (N=153). Forty percent of the trials used an investigational agent as a monotherapy, while 60% of the trials used combination treatment. The most commonly used non-chemotherapy investigational agents were monoclonal antibodies and HDAC inhibitors (28 trials each), followed by DNMT inhibitors (18 trials) and proteasome inhibitors (17 trials). Overall, 468 patients died during trials of which 60 were attributed to the treatment (grade 5 toxicity: 1.81%, 95%CI: 1.36-2.27%). There was a trend of higher grade 5 toxicity in patients with AML/MDS (2.43%) compared to patients with lymphoma (0.98%), ALL (1.55%) or myeloma (0.65%) (p=0.066). Treatment with a PD-1 inhibitor was associated with significantly higher risk of grade 5 toxicities (7.14%, 95%CI: 1.95%-12.3%), compared to patients who did not receive a PD-1 inhibitor (1.65%, 95%CI: 1.21%-2.09%) (odds ratio [OR]: 4.93, 95%CI: 1.54-15.8). The deaths mostly occurred in trials combining a PD-1 inhibitor and a CTLA-4 inhibitor (6 death in 77 pts), although the grade 5 toxicity rate did not significantly differ from PD-1 inhibitor monotherapy (1 death in 21 pts). There was no significant difference in grade 5 toxicity among the time periods when trials were activated (Table. 2000-2005 vs 2006-2012 vs 2013-2019). Baseline characteristics associated with higher risk of grade 5 toxicity were age (OR: 1.02 by 1 year increase in age, 95%CI: 1.01-1.04, p=0.007) and performance status ≥2 at enrollment (OR: 1.56, 95%CI: 1.02-2.39, p=0.039). Response assessment was available in 2,404 patients. Overall response rate (ORR) and CR rate (CRR) from all trials were 25.1% (95%CI: 23.3-26.8%) and 14.7% (95%CI: 13.3-16.2%), respectively. The patients with lymphoma experienced significantly higher ORR (42.8%) compared to patients with AML (18.2%), ALL (13.3%) or myeloma (13.3%). There is a significant increase in both ORR and CRR over time (Table. p&amp;lt;0.001), but the trend of change was different in each disease by investigational agents tested during the period. Monoclonal antibodies, iMIDs, CDK inhibitors and BTK inhibitors were non-chemotherapy agents associated with higher response rate. Overall survival (OS) was available in 2,664 patients. The median OS among all patients after enrollment in phase 1 studies was 277 days (95%CI: 245-305 days). Patients with ALL had significantly shorter median OS (86 days) compared to patients with AML/MDS (255 days), lymphoma (289 days) or myeloma (median not reached). Conclusion There has been a significant improvement of ORR in CTEP sponsored phase I studies in the last 20 years. Grade 5 toxicity rate remained low, but higher age and poor performance status were associated with higher risk. Participation in phase I studies should be encouraged in patients with hematologic malignancies. Table Disclosures No relevant conflicts of interest to declare.

Efficacy of local therapy for oligoprogressive disease after programmed cell death 1 blockade in advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have dramatically changed the strategy used to treat patients with non‐small‐cell lung cancer (NSCLC); however, the vast majority of patients eventually develop progressive disease (PD) and acquire resistance to ICIs. Some patients experience oligoprogressive disease. Few retrospective studies have evaluated clinical efficacy in patients with oligometastatic progression who received local therapy after ICI treatment. We conducted a retrospective analysis of advanced NSCLC patients who received PD‐1 inhibitor monotherapy with nivolumab or pembrolizumab to evaluate the effects of ICIs on the patterns of progression and the efficacy of local therapy for oligoprogressive disease. Of the 307 patients treated with ICIs, 148 were evaluated in our study; 42 were treated with pembrolizumab, and 106 were treated with nivolumab. Thirty‐eight patients showed oligoprogression. Male sex, a lack of driver mutations, and smoking history were significantly correlated with the risk of oligoprogression. Primary lesions were most frequently detected at oligoprogression sites (15 patients), and 6 patients experienced abdominal lymph node (LN) oligoprogression. Four patients showed evidence of new abdominal LN oligometastases. There was no significant difference in overall survival (OS) between the local therapy group and the switch therapy group (reached vs. not reached, P = .456). We summarized clinical data on the response of oligoprogressive NSCLC to ICI therapy. The results may help to elucidate the causes of ICI resistance and indicate that the use of local therapy as the initial treatment in this setting is feasible treatment option.