Clinical and biochemical parameters as predictors of response to checkpoint inhibitors (CPI): A single institution experience.

e14590 Background: The benefit of CPI is limited to a subgroup of patients. Significant toxicity and financial burden make it imperative to identify biomarkers predictive of clinical benefit. We aimed to analyze if immune related adverse events (irAE), laboratory parameters (besides PD-L1 status), prior chemotherapy and concomitant medication use could predict response to CPI. Methods: 216 consecutive patients treated at RPCI with single/multiple CPI from 2011 to 2016 were identified. Demographics, irAE (CTCAE v4.03), concomitant medication use, response (RECIST v1.1) and laboratory parameters were recorded. Progression free (PFS) and overall survival (OS) were calculated. Clinical benefit (responder) was defined as objective response or stable disease with PFS ≥ 6 months. Statistical analysis was performed using SAS v9.4. Results: 185/216 patients (86%) had clinical outcomes with first CPI available (55.7% melanoma, 28.1% lung, 10.8% kidney, 3.8% bladder, 1.6% others), 14% died before disease assessment. Median age was 61 years; 64% were males. 31% were responders (R); 69% non-responders (NR). Median PFS and OS for R were not reached and for NR were 4.7/7 months (p < 0.001). 26% R developed rash vs. 12% NR (p = 0.02). irAE diarrhea was associated with better OS (p = 0.03); rash with better PFS (p = 0.007) and OS (p = 0.05). Concomitant beta-blocker/NSAID use was noted in 35%/28% R vs 20%/12% NR (p = 0.04; p = 0.01). Higher median absolute eosinophil (AEC) and absolute lymphocyte count (ALC) were noted in R (400 and 2000/µl in R vs. 300 and 1600/µl in NR; p = 0.008 and 0.024). NR were noted to have a higher median lactate dehydrogenase (LDH) of 565 vs. 503 (p < 0.001). AEC > 100/µl and ALC > 1000/ µl were associated with better OS (P = 0.03; P = 0.001). Absolute neutrophil count (ANC) > 7500/µl and leucocyte count > 8750/ µl were associated with inferior PFS (p = 0.005; P = 0.02) and OS (p = 0.002; p = 0.03). Pre-CPI chemotherapy did not correlate with response to CPI. Conclusions: Among irAE, diarrhea and rash predicted improved outcomes. Eosinophilia, lymphocytosis, neutrophilia, leukocytosis and LDH could serve as potential prognostic biomarkers to CPI. Prospective studies are warranted to validate these findings.

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Impact of concomitant medication use and immune-related adverse events on response to immune checkpoint inhibitors

Immunotherapy ◽

10.2217/imt-2019-0064 ◽

2020 ◽

Vol 12 (2) ◽

pp. 141-149 ◽

Cited By ~ 5

Author(s):

Shipra Gandhi ◽

Manu Pandey ◽

Nischala Ammannagari ◽

Chong Wang ◽

Mark J Bucsek ◽

...

Keyword(s):

Adverse Events ◽

Clinical Benefit ◽

Immune Checkpoint Inhibitors ◽

Concomitant Medication ◽

Checkpoint Inhibitors ◽

Metastatic Cancer ◽

Medication Use ◽

Significant Difference ◽

Β Blockers ◽

The Impact

Aim: Patients receiving checkpoint inhibitors (CPI) are frequently on other medications for co-morbidities. We explored the impact of concomitant medication use on outcomes. Materials & methods: 210 metastatic cancer patients on CPI were identified and association between concomitant medication use and immune-related adverse events with clinical outcomes was determined. Results: Aspirin, metformin, β-blockers and statins were not shown to have any statistically significant difference on clinical benefit. 26.3% patients with clinical benefit developed rash versus 11.8% without clinical benefit (p < 0.05) on multivariate analysis. Conclusion: Use of common prescription and nonprescription medications in patients with multiple co-morbidities appears safe and does not have an adverse effect on CPI efficacy. The presence of rash predicted for a better response.

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Phase I/II trial of pembrolizumab and cabozantinib in the treatment of metastatic renal cell carcinoma (mRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4544 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4544-4544

Author(s):

Elizabeth R Kessler ◽

Junxiao Hu ◽

Geetika Srivastava ◽

Douglas Jerome Kemme ◽

Praveena Iruku ◽

...

Keyword(s):

Phase I ◽

Primary Endpoint ◽

Clinical Benefit ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Controlled Trial ◽

Objective Response ◽

Risk Category ◽

Serious Adverse Events ◽

Line Therapy

4544 Background: Checkpoint inhibitors (CPI) and vascular endothelial growth factor receptor inhibitors (VEGFi) are standard treatments for patients (pts) with mRCC. This phase I/II study evaluated the safety and efficacy of the novel combination of pembrolizumab (pembro) and cabozantinib (cabo). The phase I dose escalation data was presented at ASCO GU 2019. We now report the objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity of patients in the phase II dose expansion. Methods: Eligible pts had metastatic clear cell (ccRCC) or non-clear cell (nccRCC) histology, normal organ function, ECOG 0-1, and no prior exposure to pembro or cabo. Pts could be treatment-naïve or have received prior CPI and/or VEGFi. Pts were dosed at the recommended phase 2 dose of pembro 200 mg IV Q3W in combination with cabo 60 mg PO QD. Scans were obtained every 9 weeks. Treatment beyond progression, in the setting of continued clinical benefit, was allowed. The primary endpoint was ORR. Simon’s two-stage design was implemented to test the null hypothesis that ORR ≤ 0.20 versus the alternative that ORR ≥ 0.50. Results: Forty pts were enrolled, of which 34 pts (85%) had ccRCC and 6 pts (15%) had nccRCC. This was first-line treatment for 15 pts (38%) and second- and subsequent-line therapy for 25 pts (62%). IDMC risk category was favorable in 15%, intermediate in 72.5%, and poor in 12.5% of pts. Prior therapies included VEGFi in 17 pts (43%), CPI in 17 pts (43%), and 9 pts (23%) had both prior VEGFi and CPI in combination or sequentially. At a median follow up of 17.8 months (mo), the ORR was 60% (95% CI 0.458-1.00), clinical benefit rate (CBR) was 92.5% (95% CI 0.817-1.00), median time to response was 4.2 mo; median duration of response was 8.4 mo. Three of six nccRCC pts achieved partial response. Median PFS was 10.4 mo (95% CI 6.3 mo-NR). Median OS was not reached. Twelve patients remain on treatment. The most common grade 1 and 2 (G1/2) treatment-related AEs were diarrhea (53%), fatigue (49%), weight loss (47%), nausea (43%), and dysgeusia (43%). Twenty-five patients (47%) experienced a treatment-related G3 AE and there were no G4 related AEs. Thirteen pts experienced serious adverse events, 8 of which were related to treatment: G3 transaminitis and hypoglycemia were attributed to the combination; G3 pancreatitis, nephritis, and pneumonitis attributed to pembro; G3 pulmonary embolus, confusion due to reversible posterior leukoencephalopathy (RPLS), and stroke attributed to cabo. There was one treatment-related death in the pt with RPLS, possibly related to cabo. Conclusions: This study of the combination of pembrolizumab 200mg and cabozantinib 60mg met the primary endpoint of ORR. Benefit was seen in first- and subsequent-line therapy. The safety profile was manageable. This combination warrants further confirmation in a randomized controlled trial. Clinical trial information: NCT03149822.

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Efficacy and toxicity of immunotherapy with immune checkpoint inhibitors in gynecologic cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18092 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18092-e18092

Author(s):

Michelle Kuznicki ◽

Amy Joehlin-Price ◽

Peter Graham Rose ◽

Haider Mahdi

Keyword(s):

Stable Disease ◽

Immune Checkpoint ◽

Clinical Benefit ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Gynecologic Cancer ◽

Objective Response ◽

Complete Response ◽

Rank Test ◽

First Line

e18092 Background: There is limited data on outcomes for gynecologic cancer patients treated with immune checkpoint inhibitors (ICI) outside the scope of clinical trials. Here we present our Institutional experience with a cohort of endometrial (EC) and ovarian cancer (OC) treated with ICI. Methods: 59 patients who received ICI were included (23 OC and 36 EC). Progression-free (PFS) and Overall survivals (OS) were determined by Kaplan-Meier (KM) curve and log rank test. Comparison of duration of response (DOR) and stable disease (DOSD) was done with unpaired t-test or one-way ANOVA. Rates of objective response (ORR) including partial response (PR) and complete response (CR), and stable disease (SD) were compared by Fischer’s exact test. Results: Median age was 66 years. 23 patients were microsatellite stable (MSS), 23 microsatellite instability high (MSI-H). Median number of prior lines was 2 (0-11). PFS and OS for EC and OC were overlapping; therefore outcomes for both were combined [(PFS 6.4m OC vs 7.3 m EC, p = 0.61), (OS 15.9 m OC vs 14.2 m EC, p = 0.78)]. Response rates consisted of 20.3% PR, 8.5% CR, 37.3% SD. Differences in responses were noted for clear cell carcinoma (CC) (33.3% PR, 11.1% CR, 33.3% SD) and MSI-H (36.4% PR, 18.2% CR, 22.7% SD) compared to MSS (11.8% PR, 0% CR, 47% SD). MSI-H had higher ORR vs. MSS (54.1% vs 11.8%, p = 0.0078). CC trended toward improved ORR vs. MSS (44.4% vs 11.8%, p = 0.14). PFS was improved for MSI-H vs. MSS (10m v 5.0m, p = 0.03). OS for CC compared to any other histology was improved (NR vs 12.8m respectively, p = 0.009). 5 recurrent MSI-H EC patients received ICI as first line monotherapy. Responses included 4 PR and 1 SD (80% ORR, 100% clinical benefit). PFS was 9.2m (3.3-13.3). 80% remained progression-free at last follow up. Overall, 38.9% experienced toxicity: hypothyroidism (15%), dermatitis (5%), pneumonitis (10%), LFT elevation (2%), amylase/lipase elevation (3%), colitis or diarrhea (5%), uveitis (2%) or nephritis (5%). 10% of patients required discontinuation of ICI secondary to toxicity. Trends for PFS and OS favored improved outcomes in patients with toxicity vs. no toxicity [(PFS 12.9m vs 5.6m, p = 0.07), (OS 22.9m vs 13.1m, p = NS)] respectively. Conclusions: In this study, immunotherapy with ICI outcomes favor MSI-H and CC compared to MSS disease. CC had promising OS compared to other histology types. ICI showed promising efficacy in MSI-H EC with 100% clinical benefit rate in chemonaive patients. First line ICI should be investigated in these patients. Positive correlation between toxicity and outcome is noted and will be further investigated.

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Predictors of Response and Survival in Immune Checkpoint Inhibitor-Treated Unresectable Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers12010182 ◽

2020 ◽

Vol 12 (1) ◽

pp. 182 ◽

Cited By ~ 7

Author(s):

Pei-Chang Lee ◽

Yee Chao ◽

Ming-Huang Chen ◽

Keng-Hsin Lan ◽

Chieh-Ju Lee ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Advanced Hepatocellular Carcinoma ◽

Factors Associated ◽

Radiologic Evaluation ◽

Predictors Of Response ◽

Pugh Class

Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC patients. Ninety-five patients who received nivolumab or pembrolizumab for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on RECIST v1.1. Factors associated with outcomes were analyzed. Of 90 patients with evaluable images, the objective response rate (ORR) was 24.4%. Patients at Child–Pugh A or received combination treatment had higher ORR. Early alpha-fetoprotein (AFP) >10% reduction (within 4 weeks) was the only independent predictor of best objective response (odds ratio: 7.259, p = 0.001). For patients with baseline AFP ≥10 ng/mL, significantly higher ORR (63.6% vs. 10.2%, p < 0.001) and disease control rate (81.8% vs. 14.3%, p < 0.001) were observed in those with early AFP reduction than those without. In addition, early AFP reduction and albumin-bilirubin (ALBI) grade or Child–Pugh class were independent factors associated with OS in different models. In conclusion, a 10-10 rule of early AFP response can predict objective response and survival to ICI treatment in unresectable HCC. ALBI grade and Child–Pugh class determines survival by ICI treatment.

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KMT2A/C mutations function as a potential predictive biomarker for immunotherapy in solid tumors

Biomarker Research ◽

10.1186/s40364-020-00241-0 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Rui Zhang ◽

Hao-Xiang Wu ◽

Ming Xu ◽

Xiaoyan Xie

Keyword(s):

Solid Tumors ◽

Clinical Benefit ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Gene Mutations ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Underlying Mechanism ◽

Cancer Subtypes ◽

Histone H3 Methylation

AbstractEpigenetic factors play important roles in tumor immunology. Histone-lysine N-methyltransferase 2 (KMT2) family genes exert histone H3 methylation, but its role in immunotherapy remains unclear. Our study is the first to investigate the correlation between KMT2 gene mutations and the clinical benefit of immune checkpoint inhibitors (ICI) treatment. We firstly collected a primary ICI-treated cohort (n = 546) and found that patients with KMT2A/C mutations yielded better prognosis in terms of progression-free survival (PFS, Hazard ratio [HR] = 0.66, P = 0.002), objective response rate (ORR, 40.9% vs 20.3%, P < 0.001), durable clinical benefit (DCB, 48.3% vs 29.8%, P = 0.001) and overall survival (OS, HR = 0.70, P = 0.033). Furthermore, we validated the predictive potential of KMT2A/C mutations in an expanded ICI-treated cohort (n = 1395). KMT2A/C-mutant patients achieved better OS compared with KMT2A/C-wildtype patients (HR = 0.68, P = 0.003); and the survival advantages appeared in the majority of cancer subtypes. Our study suggests that KMT2A/C mutations function as a novel and potential predictive biomarker for ICI treatment in multiple solid tumors and the underlying mechanism is worth investigating.

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Safety results from phase I/II study of the PI3Kβ inhibitor GSK2636771 (G) in combination with pembrolizumab (P) in patients (pts) with PD-1 refractory metastatic melanoma (MM) and PTEN loss.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e22000 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e22000-e22000 ◽

Cited By ~ 2

Author(s):

Hussein Abdul-Hassan Tawbi ◽

Weiyi Peng ◽

Suzanne Phillips ◽

Denai R. Milton ◽

Rodabe Navroze Amaria ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Dose Level ◽

Clinical Benefit ◽

Renal Toxicity ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Safety Data ◽

Pten Loss ◽

Higher Doses

e22000 Background: Checkpoint inhibitors (CPI) have improved survival and long-term disease control in 35-40% of pts with MM. Many pts derive no clinical benefit or progress after an initial response. Our group and others have shown that loss of the tumor suppressor protein PTEN occurs in multiple cancers, up to 30% of MM pts, activates the PI3K pathway, and correlates with decreased MM response rates to CPI and decreased T cell infiltrates. In PTEN-null MM preclinical models, inhibition of the PI3Kβ-subunit with GSK2636771 (G) was superior to pan-PI3K inhibitors, increased intratumoral T cell infiltration and the activity of CPI. To test our hypothesis that PI3Kβi reverses resistance to CPI, we are conducting a Phase I/II study (NCT03131908) combining G with P in PD-1 refractory pts with PTEN loss. Methods: The primary objective of Ph I portion is to determine the Maximum-Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of G with P in PD-1 refractory pts (including melanoma, endometrial, TNBC, and prostate cancers) with PTEN loss. Pts receive P at 200mg IV q 3 wks. G starting dose level (DL1) was 300 mg PO qd for 21 days and escalated to 400 mg PO qd (DL2) using a 3+3 design. A dose level -1 (DL-1) (200 mg PO qd) was also included in the event of unacceptable toxicities at higher doses. Ph II will accrue 35 pts at the RP2D. This study is continuously monitored for toxicity and futility. The primary objectives of Ph II are safety, tolerability, and efficacy of the combination as defined by Objective Response Rate (ORR) by RECIST 1.1. Secondary Objectives include the PKs of G and PD effects in tumor tissue as measured by pathway inhibition and T cell trafficking into tumors. Results: 13 pts have been treated, 6 at the 300mg (DL1), 5 at 400mg (DL2), and 2 at 200 mg (DL-1). One DLT (grade 3 hypocalcemia) was observed at the 300mg dose. Two DLTs were observed in the 400mg cohort, one of which was AKI requiring dialysis and the other was a Gr 3 rash. Based on this experience and additional safety data from GSK regarding renal toxicity, DL-1 was declared RP2D at 200mg. 2 pts at the RP2D have passed the DLT evaluation period without toxicities. Conclusions: The combination of G and P is being explored at the RP2D of 200 mg. Renal toxicity precluded higher doses. No objective responses have been observed although 2 pts have experienced prolonged clinical benefit including a MM pt with 27% decrease in tumor burden. Through longitudinal biopsies, we aim to better understand the role PTEN loss plays when targeted in combination with CPI. Clinical trial information: NCT03131908.

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Correlation Between Immune-Related Adverse Events and Prognosis in Hepatocellular Carcinoma Patients Treated With Immune Checkpoint Inhibitors

Frontiers in Immunology ◽

10.3389/fimmu.2021.794099 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shuo Xu ◽

Ruixue Lai ◽

Qian Zhao ◽

Pandong Zhao ◽

Ruili Zhao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Immune Checkpoint ◽

Clinical Benefit ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Low Grade ◽

Better Than

BackgroundImmune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were associated with clinical benefit in cancer patients of melanoma, a lung cancer. In the present study, we investigated the correlation between irAE and ICI efficacy in hepatocellular carcinoma (HCC) patients.MethodsWe divided the HCC patients who received the anti-PD-1 antibody into two groups as irAE group and non-irAE group according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. The treatment efficacy of ICIs was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultOf the 65 HCC patients who received the anti-PD-1 antibody (monotherapy or combined with targeted medicine), median PFS in the irAE group was superior to that in the non-irAE group (302 days vs. 148 days, p = 0.004). Median OS in the irAE group was also better than that in the non-irAE group (374 days vs. 279 days, p = 0.038). Although the statistical difference for DCR in the irAE group and non-irAE group was not reached, the DCR of the irAE displayed a trend better than that of the non-irAE group (41.20% vs. 20.80%, p = 0.118). Multivariate analysis also demonstrated that the non-irAE group (HR = 6.410, 95% CI: 1.404 to 29.275) was associated independently with the poor prognosis.ConclusionsDevelopment of irAEs was associated with clinical benefit for HCC patients who were treated with immune checkpoint inhibitors; irAE, particularly low-grade irAE, was a predictable marker for better ICI treatment efficiency in HCC patients.

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A phase III study of nivolumab (NIVO), NIVO + ipilimumab (IPI), or chemotherapy (CT) for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): Checkmate 8HW.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.tps266 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. TPS266-TPS266 ◽

Cited By ~ 1

Author(s):

Sandzhar Abdullaev ◽

Thierry André ◽

Ming Lei ◽

Heinz-Josef Lenz ◽

James Novotny ◽

...

Keyword(s):

Clinical Benefit ◽

Low Dose ◽

Group Performance ◽

Checkpoint Inhibitors ◽

Performance Status ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Phase Iii ◽

Open Label ◽

Phase 3

TPS266 Background: Patients (pts) with MSI-H/dMMR mCRC treated with CT have poorer outcomes than pts with microsatellite stable/MMR proficient mCRC. NIVO (anti–programmed death [PD]-1) and IPI (anti–cytotoxic T lymphocyte antigen-4 [CTLA-4]) are immune checkpoint inhibitors that act synergistically and promote antitumor immune response by complementary mechanisms. NIVO±IPI received accelerated US FDA approval for MSI-H/dMMR mCRC that progressed after fluoropyrimidine, oxaliplatin, and irinotecan treatment based on the phase 2, non-randomized, multicohort CheckMate 142 study. Indirect comparisons suggest that NIVO (3 mg/kg) + low-dose IPI (1 mg/kg) provides improved clinical benefit vs NIVO (investigator-assessed [INV] objective response rate [ORR] 55% vs 31%; 12-month [mo] INV progression-free survival [PFS] rate 71% vs 50%; 12-mo overall survival [OS] rate 85% vs 73%) with a favorable benefit-risk profile for previously treated MSI-H/dMMR mCRC (Overman et al. JCO 2018). NIVO+low-dose IPI also demonstrated robust and durable clinical benefit in first-line MSI-H/dMMR mCRC (INV ORR 64%; 12-mo INV PFS rate 77%; 12-mo OS rate 84%; Lenz et al. ASCO 2019, #3521). To date, no prospective phase 3 studies have reported results for anti–PD-1, anti–PD-1 + anti–CTLA-4, or CT in MSI-H/dMMR mCRC; these treatments will be evaluated in the international, multicenter, open-label, randomized, phase 3 CheckMate 8HW (NCT04008030) study. Methods: Approximately 494 pts aged ≥18 years with histologically confirmed recurrent or mCRC, irrespective of prior treatment with CT and/or targeted agents, not amenable to surgery, and with known tumor MSI-H or dMMR status, and Eastern Cooperative Oncology Group performance status ≤1 will be randomized to receive NIVO, NIVO+IPI, or investigator’s choice CT (pts in the CT arm can receive NIVO+IPI upon progression). The primary endpoint is PFS, assessed by blinded independent central review (BICR). Secondary endpoints include PFS by INV, ORR and disease control rate by BICR and INV, OS, time to and duration of response. Exploratory endpoints include safety. Clinical trial information: NCT04008030.

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353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0353 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A378-A378

Author(s):

Antonio Jimeno ◽

Sophie Papa ◽

Missak Haigentz ◽

Juan Rodríguez-Moreno ◽

Julian Schardt ◽

...

Keyword(s):

Cell Therapy ◽

Checkpoint Inhibitors ◽

Adoptive Cell Therapy ◽

Single Agent ◽

Objective Response ◽

Tumor Resection ◽

Tumor Infiltrating Lymphocytes ◽

Open Label ◽

Safety And Efficacy ◽

Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

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Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

Journal of Translational Medicine ◽

10.1186/s12967-021-02712-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Paul Johannet ◽

Amelia Sawyers ◽

Nicholas Gulati ◽

Douglas Donnelly ◽

Samuel Kozloff ◽

...

Keyword(s):

Cancer Patients ◽

Advanced Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Coagulation Cascade ◽

Advanced Cancer Patients ◽

Clinical Endpoints

Abstract Background Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. Methods We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). Results Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). Conclusion AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

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