Background

The prediction of outcome to ICPI in advanced NSCLC is of great clinical interest. We considered CGP, PD-L1 IHC, and real world data to investigate potential biomarkers for ICPI response.

Methods

CGP and IHC was performed on 1,619 FFPE NSCLC samples in the FoundationCORE database (FMI). The SP142 antibody was used to capture PD-L1 tumor expression (PD-L1 TE) for these 1,619 samples. NSCLC patients (n = 2139) in the Flatiron Health Analytic Database with FoundationOne testing CGP results and real world IHC results for PD-L1 TE were analyzed separately (FMI-FIH). CGP used ≥50 ng of DNA and a hybrid-capture, adaptor ligation-based assay (median coverage depth >600X). TMB (mut/Mb) was determined on 1.1 Mb of sequenced DNA.

Results

PD-L1 IHC TE correlated weakly with TMB (FMI samples) (Spearman’s ρ 0.085, p = 6.16e-4); mean TMB was 10.9 mut/Mb, median 8.1 mut/Mb and 14.5% had high TMB (≥20 mut/Mb). From FMI-FIH, high TMB but not PD-L1 status predicted longer mean duration on therapy (DOT) (p = 0.001). Analysis of the FMI and FMI-FIH datasets revealed relationships between GA, PD-L1 TE, TMB, and mean DOT. Inactivating STK11 GA were seen in 12.1% of FMI-FIH and 15.1% of FMI samples, most often adenocarcinomas (aCa). STK11 GA correlated with high TMB/low PD-L1 (FMI; p = 0.0014) and preliminary analyses suggest correlation with negative ICPI treatment outcome. Several genes were commonly co-altered with STK11 (FMI): KRAS (54.5%), TP53 (43%), CDKN2A (27.5%), CDKN2B (20.1%), KEAP1 (18.9%), and MYC (13.5%). BRAF GA, most often short variants (SV) in aCa, were associated with prolonged DOT on ICPI regardless of TMB score (FMI-FIH; p = 0.0073). MET SV also predicted prolonged DOT on ICPI, but insufficient events prevented calculation of statistical significance (FMI-FIH). Analysis of the TCGA lung aCa dataset revealed MET SV (2.8%) linked with immune activation gene expression profiles (p < 0.05) and STK11 mutations (14.2%) with immune evasion profiles (p < 0.05).

Conclusions

Although TMB powerfully predicts ICPI outcome independent of tumor cell PD-L1 expression, considering GA in STK11, BRAF or MET may significantly increase the precision and improve outcomes when using genomics with IHC to guide to ICPI selection.

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc., Flatiron Health

Disclosure

J.S. Ross, M.E. Goldberg, L.A. Albacker, L.M. Gay, J.A. Elvin, J-A. Vergilio, J. Suh, S. Ramkissoon, E. Severson, S. Daniel, S.M. Ali, A.B. Schrock, G.M. Frampton, D. Fabrizio, V.A. Miller, G. Singal, P.J. Stephens: Employee of and stockholder in Foundation Medicine, Inc. V. Agarwala: Employee of Flatiron Health. A. Abernethy: Employee of Flatiron Health.

Background

Highly discriminating biomarkers of response to cancer immunotherapies (CIT) remain elusive. Characterization of large real-world populations treated with CIT as part of routine care may enable better stratification.

Methods

Patients in the Flatiron Health Analytic Database with non-small cell lung cancer (NSCLC) who underwent comprehensive genomic profiling (CGP) by Foundation Medicine were included (n = 2139). CGP included >300 genes and tumor mutation burden (TMB), stratified into low (TMB-L; <6 mut/MB), intermediate (TMB-I; 6-20 mut/MB), and high (TMB-H; > =20 mut/MB) tertiles (Johnson, CIR 2016). PD-L1 expression was obtained from results reported to clinicians from multiple labs (using varying antibodies). Genomic data was linked to de-identified electronic health record (EHR) data, from which nivolumab response was measured as overall response rate (ORR = SD, PR, or CR), median duration of therapy (mDOT), and median overall survival (mOS) from advanced diagnosis and from nivolumab initiation.

Results

In patients treated with nivolumab (n = 444, 20.8%), TMB-H predicted longer mDOT than TMB-L/I (7.5 vs 4.6 months, p = 0.001), mOS from start of nivolumab treatment (median not reached vs 10 months, p < 0.01), and mOS from advanced diagnosis (65 vs 29 months, p = 0.10). In contrast, PD-L1 status (n = 282) was not associated with ORR, DOT, or OS. Among patients negative for PD-L1, TMB-H predicted longer DOT (mDOT 391 vs 166 days, p = 0.08) and higher ORR (100% in TMB-H [n = 5] vs 62% in TMB-I/L [n = 28], p = 0.03). TMB remained predictive of DOT and OS from nivolumab start when controlled for histology, age, stage, smoking, gender, and race in multivariate analysis. Multivariate analysis of TMB-L patients identified two additional genomic predictors of duration on nivolumab: BRAF (HR 0.12, p = 0.04), and BRCA 1/2 (HR 0.05, p = 0.01).

Conclusions

Real-world datasets combining clinical outcomes with genomic profiling may enable biomarker discovery in CIT. These data demonstrate the predictive power of TMB, which can augment and significantly improve on the currently approved PD-L1 expression as a predictor of CIT response. They may also enable discovery of novel biomarkers that can identify potential CIT responders among TMB-L populations.

Legal entity responsible for the study

Foundation Medicine, Inc. and Flatiron Health, Inc.

Funding

None

Disclosure

G. Singal: Employee of Foundation Medicine, Inc., with equity and salary. P.G. Miller: Consultant with Foundation Medicine, Inc. V. Agarwala: Employee and shareholder of Flatiron Health, Inc. G. Li, L.A. Albacker, M.E. Goldberg, J. He, D. Bourque, D. Fabrizio, A. Parker, A. Guria, V.A. Miller, J.A. Elvin, J.S. Ross, P.J. Stephens: Employee and shareholder of Foundation Medicine, Inc. A. Gossai, S. Frank, I. Ivanov, T. Caron, A. Abernethy: Employee and shareholder of Flatiron Health, Inc.

Background

Pseudo-progression associated with ICI has been well described. HP - characterized by paradoxically accelerated tumor growth rate (TGR) - while on ICI is increasingly being recognized. Preliminary data have reported murine double minute (MDM2/MDM4) amplification as a possible predictive biomarker for HP based on pre-treatment next generation sequencing (NGS) of tumor tissue. We sought to identify patients that hyper-progressed at our institution, characterize the SAs in those patients (pts) and conversely, estimate the incidence of HP in pts with such SAs.

Methods

HP was defined as: 1. progression at first restaging on ICI 2. Increase in tumor size > 50%, 3. >2-fold increase in TGR. Data were obtained by interrogating our institutional electronic medical record and molecular database (MDB). Next Generation Sequencing (NGS -Foundation Medicine, Cambridge MA) was performed on pre-treatment tumor tissue; DNA was extracted, NGS was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer.

Results

5 pts met criteria for HP, NGS data was available on 4 (80%) pts. Most frequently encountered SAs were MDM2/MDM4 amplifications (amp -50%), EGFR amp (25%) and amp of several genes located on chromosome 11q13 -CCND1, FGF3, FGF4, FGF19 (75%). Tumor mutational burden ranged from 4-13/Mb for all pts with HP. Review of our MDB (N = 696) identified MDM2/MDM4, EGFR and 11q13 amp in 26 (4%), 26 (4%) and 25 (4%) pts respectively. Of the 70 patients with these SAs, 10 received ICI. The incidence of HP in pts with MDM2/MDM4, EGFR and 11q13 amp was 2 (66%), 1 (50%) and 3 (43%) respectively. Patient details are summarized below.Table:

1140PD

Conclusions

A subset of pts treated with ICI develop HP. Copy number alterations in MDM2/MDM4, EGFR and several genes located on 11q13 are associated with HP. The role of these SAs as putative predictive biomarkers for HP needs further validation in larger cohorts of pts. Immune escape/editing, leading to HP needs mechanistic elucidation; prospective identification of pts at risk for HP is crucial and merits further investigation.

Legal entity responsible for the study

Arun K Singavi, MD and Ben George, MD

Funding

None

Disclosure

S. Ali: Employee - Foundation Medicine, Cambridge, MA. B. George: Consultant for Celgene, Cook Medical, Merrimack, Foundation Medicine, Ipsen. All other authors have declared no conflicts of interest.

Background

Programmed-death 1 (PD-1) and V-domain Ig suppressor of T-cell activation (VISTA) are independent immune checkpoints that inhibit T cell function. Preclinical studies demonstrated that dual blockade of these checkpoints can be synergistic. CA-170 is an oral small molecule antagonist of PD-L1 and VISTA, currently undergoing Phase (Ph) 1 clinical testing.

Methods

Pre-clinically, CA-170 inhibition of PD-L1 or VISTA-mediated suppression of T cell function was tested in vitro using human, monkey, or mouse cells. In vivo anti-tumor activity was examined in multiple syngeneic mouse models. Pts with advanced solid tumors or lymphomas, age ≥ 18, ECOG ≤1 and adequate organ function are treated with escalating doses of oral CA-170 daily during Ph 1a. Ph 1b dose expansion will enrich enrollment for selected pt population possibly responsive to this novel inhibitor. Primary objectives: safety, maximum tolerated dose and recommended Phase 2 dose. Secondary objectives: pharmacokinetics and anti-tumor activity. Exploratory endpoints: biomarkers and pharmacodynamic (PD) effects in periphery and tumor tissues.

Results

CA-170 rescues in vitro T cell effector function with activity comparable to that of PD-1 or VISTA blocking antibodies. Oral CA-170 inhibits the growth of mouse syngeneic tumors (B16 melanoma, CT26 and MC38 colon carcinoma), enhances peripheral T cell activation, and promotes the activation of tumor infiltrating CD8⁺ T cells in vivo. In humans, a total of 19 patients have been treated across 6 dose levels (50 - 800 mg). No dose limiting toxicity has been observed. CA-170 exhibits generally dose proportional plasma exposure with T_1/2 of ∼ 4-9.5 hours. Evidence of peripheral T cell activation was observed with an increased proportion of circulating CD8⁺ and CD4⁺ T cells expressing activation markers, CD69 and CD134, following oral dosing.

Conclusions

These pre-clinical and preliminary clinical PD data warrant the continued clinical development of CA-170, the first oral, small molecule immune checkpoint antagonist for the treatment of advanced cancers. Dose escalation is currently ongoing (NCT02812875).

Clinical trial identification

NCT02812875

Legal entity responsible for the study

Curis Inc

Funding

Curis Inc

Disclosure

J. Powderly: Employment BioCytics Consult Bristol-Myers Squibb; Genentech; AstraZeneca; Curis Stock BioCytics; Lion Biotech; Juno; Bluebird; Kite; Ziopharm; Carolina Funding Bristol-Myers Squibb; Genentech; AstraZeneca; EMD; Macrogeneics; Lilly; Incyte; TopAlliance; Seattle Genetics; Abbvie; Corvus; Curis. M.R. Patel: Honoraria and Speaker\'s Bureau Medivation, Genentech; Exelixis; Bristol-Myers Squibb; Gilead; Guardant Health. J.J. Lee: Consulting/Advisory role Genentech Research Funding Merck. J. Brody: Consulting/Advisory role Gilead; Teva; Pharmacyclics; Bristol-Myers Squibb; Corvus; Merck; Celledex; Novartis; Janssen Research funding Acerta; Merck; Celgene. E. Hamilton: Consulting Pfizer; Genentech; Flatiron health; Cascadian. H. Wang, A. Lazorchak, T. Wyant, A. Ma, S. Agarwal, D. Tuck: Employment/stock Curis. A. Daud: Consulting or Advisory Role Oncosec, Merck, GSK Stock/Ownership Oncosec Honoraria EMD Serono; Inovio Pharmaceuticals Research Funding Merck/Schering Plough; GSK; Pfizer; Genentech/Roche; Oncosec. All other authors have declared no conflicts of interest.

Background

PF-8600 and utomilumab are fully human IgG2 agonistic monoclonal antibodies directed at tumor necrosis factor receptor superfamily receptors OX40 and 4-1BB, respectively. In general, OX40 has a greater impact on CD4 T cell function, while 4-1BB has more impact on CD8 T cell function. Dual targeting of OX40 and 4-1BB synergistically induced CD8 and cytotoxic CD4 T cell clonal expansion in pre-clinical models. A Phase I study (NCT02315066), evaluated PF-8600 alone and in combination with utomilumab. As seen previously for utomilumab alone, PF-8600 monotherapy was tolerable at all dose levels, providing rationale to combine PF-8600 with utomilumab.

Methods

Non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma, bladder, gastric or cervical cancer patients (pts) unresponsive to available therapies or where no standard therapy is available are treated with PF-8600 at dose levels 0.1 mg/kg to 3 mg/kg q2w in combination with utomilumab at either 20 mg or 100 mg q4w intravenously. Blood was collected for PK/PD analysis.

Results

At time of data cut-off on 30-Jan 2017 (study ongoing), 28 pts had enrolled in 4/5 planned dose cohorts. No drug-related deaths, dose-limiting toxicities, or suspected unexpected serious adverse reactions have been confirmed to date. All drug-related adverse events (AEs) were grade (G) 1-2. The most common were nausea (10.7%), decreased appetite (7.1%) and fatigue (7.1%). Nine (32.1%) G3, 3 (10.7%) G4 and 2 (7.1%) G5 all-causality AEs were reported (G5 AEs in lowest dose cohort). Combination treatment resulted in greater increases in expression of activation and proliferation markers on CD8 memory T cells, in particular, and memory T cell subsets overall, than PF-8600 alone. Preliminary PK and efficacy data will be shown.

Conclusions

To date, dose escalation combining active monotherapy doses of PF-8600 and utomilumab has not demonstrated toxicity beyond that expected from either alone. Safety, efficacy, PK, and PD data from dose escalation will aid selection of optimal biologic doses for further evaluation and expansion.

Clinical trial identification

NCT02315066

Legal entity responsible for the study

Pfizer Inc

Funding

Pfizer Inc

Disclosure

O. Hamid: Consulting/Advising: Amgen, Novartis, Roche, Bristol-Myers Squibb, Merck; Speakers\' Bureau Bristol-Myers Squibb, GNE, Novartis, Amgen; Research Funding (Institution): AstraZeneca, Bristol-Myers Squibb, Celldex, GNE, Immunocore, Incyte, Merck, Merck Serono, MedImmune, Novartis, Pfizer, Rinat, Roche. J.A. Thompson: Honoraria: Celledex Consulting or advisory role: Celledex Research Funding (to institution): Bristol-Myers Squibb Agensys Seattle Genetics Pfizer Trillium Therapeutics Merck Inc. S. Hu-Lieskovan: Consulting: Amgen, Merck, Novartis, Vaccinex, Emergent BioSolutions Contracted Research: Pfizer, Plexxikon, Genentech, Neon Research Support: Bristol-Myers Squibb, Merck Travel Support: Amgen, Merck, Novartis, Vaccinex, Emergent BioSolutions, Neon. F.A.L.M. Eskens: Consulting or Advisory Role: Daiichi Sankyo Ipsen Pfizer Merck Inc. Novartis Pharma KK Travel, Accommodations, Expenses Daiichi Sankyo Ipsen Roche-Peru. A. Diab: Consulting/advisory: Nektar, CureVac, Celgene Travel/accomodations/expenses: Nektar Research funding (to institution): Nektar, Idera, Celgene, Pfizer. T. Doi: Advisory: Lilly, Chugai, Kyowa Hakko Kirin, Nippon BI, Novartis, MSD, Daiichi Sankyo, Amgen Funding to institution: Taiho, Novartis, Merck Serono, Astellas, MSD, Janssen, BI, Takeda, Pfizer, Lilly, Sumitomo, Chugai, Bayer, Kyowa, Daiichi Sankyo, Celgene. J. Wasser: Have received research support from Pfizer by means of a material transfer agreement. J-P. Spano: Adboard with Pfizer (Breast cancer). N.A. Rizvi: Advisory Board: Merck, AstraZeneca, Roche, Bristol-Myers Squibb, Novartis, Pfizer, Lilly, Novartis, Abbvie Co-founder and shareholder: Gritstone Oncology Scientific Advisory Board: Nilogen Oncosystems. A. Chiappori: Participated in advisory boards for Genentech, Novartis, Bristol-Myers Squibb, ARIAD and have also received honoraria from Genentech, Merck, Celgene, Boehringer Ingelheim. Received honoraria from Pfizer too, but not within the last year. P.A. Ott: Grants to the institution and personal fees from Bristol-Myers Squibb, CytomX, Celldex, Pfizer and Merck, personal fees from Neon Therapeutics, Amgen, Novartis, and Roche/Genentech, and grants from AstraZeneca/MedImmune, outside of the submitted work. B.J. Ganguly, K. Liao, T. Joh, J. Chou, C. Fleener: Employee and stockholder of Pfizer Inc. V. Dell: Contractor for Pfizer. A. El-Khoueiry: Advisory: CytomX, Bristol-Myers Squibb, AstraZeneca Speakers Bureau: Merrimack Honoraria: Merrimack, Bayer, Novartis, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Background

Platinum-resistant OC represents an unmet medical need with progression free survival (PFS) of 3.5 to 6 months. Niraparib, an oral PARP 1/2 inhibitor (PARPi), improved PFS in pts with recurrent OC following response to platinum (NEJM, 2016). Preclinical evidence suggests synergy between PARPis and PD-1 inhibitors in OC and TNBC. We report data from a phase 1 niraparib + pembrolizumab (pembro) combination study leading to recommended phase 2 dose (RP2D).

Methods

Primary objectives were to assess dose limiting toxicities (DLTs) in a 6 + 6 dose escalation design and determine RP2D. Eligible pts had metastatic TNBC treated with ≤4 prior lines of chemotherapy OR platinum-resistant recurrent OC treated with ≤5 prior lines of chemotherapy having responded with CR or PR for >6 months to 1^st line platinum based chemotherapy.

Results

The 14 pts (≥18 yrs) enrolled received pembro 200 mg IV on day 1 and niraparib 200 mg (dose level [DL] 1, n = 7; 2 TNBC, 5 OC) or 300 mg (DL2, n = 7; 3 TNBC, 4 OC) PO on days 1–21 of each 21-day cycle. In DL1, 1 pt had DLTs (neutropenia, anemia and thrombocytopenia) and discontinued niraparib but continued pembro. In DL2, 1 pt had DLT and 1 had DLT-equivalent (both thrombocytopenia); both resumed treatment with 200 mg niraparib and continued pembro. RP2D was determined as niraparib 200 mg PO daily + pembro 200 mg IV on day 1 of each 21-day cycle. Based on RECIST v1.1, 4/8 evaluable OC pts responded; the other 4 pts achieved SD (Table). 1/5 TNBC pts (BRCA wildtype) had SD for 10 cycles. BRCA & PD-L1 status will be presented.Table:

1143PD

Conclusions

This study established a RP2D, and showed preliminary efficacy of niraparib and pembro combination for treatment of heavily pretreated TNBC or platinum-resistant OC. No significant overlapping toxicity was noted. A phase 2 study is currently enrolling. Supporting translational work funded by SU2C.

Clinical trial identification

NCT02657889

Legal entity responsible for the study

TESARO, Inc.

Funding

TESARO, Inc. and Merck and Co.

Disclosure

P.A. Konstantinopoulos: Consulting/Advisory: Merck, Vertex. J.C. Sachdev: Consulting/Advisory: Celgene Honoraria: Celgene. L. Schwartzberg: Consulting/Advisory: Eisai, Teva, Amgen, Bristol-Myers Squibb, Helsinn Therapeutis, Tesaro, Spectrum Pharmaceuticals Speakers’ Bureau: Genentech, Bristol-Myers Squibb, Amgen. U.A. Matulonis: Consulting/Advisory: Merck KGaA, AstraZeneca, Immunogen, Tesaro, Genentech P. Sun, J.Y. Wang, W. Guo, B. Dezube: Employment: Tesaro Stock: Tesaro. D. Bobilev: Employment: Tesaro Stock: Tesaro Travel, Accommodations, Expenses: Tesaro G. Aktan: Employment: Merck Stock: Merck. V. Karantza: Employment: Merck Sharp & Dohme Stock: Merck Sharp & Dohme Patents, Royalties, IP: Merck Sharp & Dohme. S. Vinayak: Travel, Accommodations, Expenses: Tesaro.

Background

Metastatic ovarian cancer (OC) is often diagnosed at an advanced stage and treated with standard platinum-based chemotherapy after which the majority of patients will experience recurrent/progressive disease with a poor prognosis. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has shown impressive results in malignant melanoma, but has only been investigated scarcely in other cancers. This pilot study has tested TIL based ACT in patients with metastatic OC. Preliminary data has previously been presented at the European Society of Medical Oncology (ESMO), the Society of Immunotherapy of Cancer (SITC) and the Cancer Immunotherapy & Immunomonitoring (CITIM) conferences. In this abstract the final results of the study is presented.

Methods

Patients with platinum-resistant metastatic OC were treated with an infusion of TIL preceded by standard lymphodepleting chemotherapy (Cyclophosphamide 60 mg/kg for 2 days and Fludarabine 25 mg/m² for 5 days) and followed by stimulation with a continuous IL-2 infusion in accordance with the decrescendo regimen for up to 5 days. Stem cell harvest was performed before TIL therapy. Primarily, the feasibility and tolerability of the treatment was assessed. Secondarily, potential immune responses against tumor cells were monitored and objective response of the treatment was described.

Results

Only expected and manageable toxicities related to the treatment were observed. All patients had stable disease (SD) for a minimum of 3 months with 4 patients experiencing progressive disease (PD) at this time point. The last two patients had SD for 5 months. Modest antitumor reactivity was observed in expanded TIL, but not in peripheral blood lymphocytes (PBL) collected after treatment.

Conclusions

ACT with TIL in combination with decrescendo IL-2 is feasible and tolerable in patients with metastatic OC with only expected and manageable toxicities. Methods of altered TIL expansion or combining TIL therapy with checkpoint inhibitors in future studies could possible enhance the mainly transient clinical responses observed in this pilot study.

Clinical trial identification

NCT02482090

Legal entity responsible for the study

Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology, Herlev and Gentofte Hospital 2730 Herlev, Denmark

Funding

Center for Cancer Immune Therapy, Herlev and Gentofte Hospital Department of Oncology, Herlev Hospital and Gentofte Hospital University of Copenhagen The Danish Cancer Society OvaCure

Disclosure

All authors have declared no conflicts of interest.

Background

Interferon-alfa (IFN) is still a standard and most widely used adjuvant therapy for patients (Pts) with skin melanoma. Nevertheless, the efficacy of this approach is doubtful despite decades of clinical trials. CaTeVac is autologous DC, derived from peripheral mononuclear cells of the patient, loaded with lysate of allogenic melanoma cell lines with high expression of cancer-testis antigens. We compared cohort of Pts receiving adjuvant therapy with CaTeVac with a cohort of consecutive Pts in our center who received IFN in the adjuvant setting.

Methods

Pts with morphologically proven melanoma received CaTeVac or IFN. CaTeVac was injected subcutaneously in doses from 5 to 20*10⁶ cells per cycle (C.) in the following regimen: C.1 – 14 days, C.2-4 – 21 days, C.5-14 – 30 days. After a year of the therapy Pts were allowed to receive additional cycles: C.15-18 (3 mo each) and C.19-20 (6 mo each). Each C. consisted from cyclophosphamide 300 mg injection on day 1 and CaTeVac injection on day 4. Pts in control group received IFN until progression, toxicity or at least 1 year of therapy whatever comes first. Both groups of patients were followed with the same clinical and laboratory methods and in the same time intervals.

Results

Ninety Pts treated from 2009 to 2016 were included in the study: 48 received CaTeVac, 42 – IFN (2-high doses of IFN, 36 – low doses of IFN, 4 – IFN with dose escalation from 3 MIU until maximum tolerated dose achieved). Median of follow-up was 23 mo. Patients with stage III and IV were presented more often in CaTeVac group (79,2% and 20,8%) when compared to IFN group (68% and 4%, respectively). Stage I-II patients composed 28% of IFN group, none were in CaTevac group; X² test for stage p = 0,001. Median time to progression in CaTeVac was 11,4 mo, for IFN group - 6,9 mo (p = 0,097). Two-year progression-free survival was 42% and 17% for CaTeVac and IFN, respectively. Relative risk for progression in 2 years was 0,74 (95% CI 0,57-0,96) for CaTeVac. Median of overall survival was 79,8 mo in IFN group and was not reached in CaTeVac group (p = 0,352) with plateau at 58% after 41 months.

Conclusions

Rather promising results received in our study justify performing of randomized trials with CaTeVac versus IFN in adjuvant setting for patients with melanoma.

Legal entity responsible for the study

N.N. Petrov Research Institute of Oncology

Funding

None

Disclosure

A. Novik, S. Protsenko: Lector for MSD, Bristol-Myers Squib, Roche, Novartis. All other authors have declared no conflicts of interest.

Background

Single line or combination immune checkpoint inhibition (ICI) therapies in metastatic melanoma have shown high response rates and durable survival. However, while at least 50% of patients show positive response to ICI treatments, ∼60% of treated patients develop severe irAEs with high morbidity, substantially reducing treatment benefits. To date, no clinical or molecular indicators have been identified to predict irAEs.

Methods

Using data from our germline whole-exome sequencing scan of 69 anti-CTLA-4 (ipilimumab; IPI) treated patients, 30 with grade 3-5 irAEs and 39 with grade 0-2 irAEs, we assessed the association of exonic variants with irAEs by logistic regression analysis. Next, we cross-referenced the signification associations with irAEs against 1,140 risk variants previously found in GWAS on autoimmunity. Finally, pathway analyses of germline associations have been performed to identify biological networks involved in the susceptibility of IPI-related irAEs.

Results

We found most significant associations with increased risk of severe irAEs for two germline variants: rs504963 (OR = 2.57, p = 0.005697) in 3'UTR of FUT2, previously associated in GWAS with multiple autoimmune traits, including psoriasis, lupus, rheumatoid arthritis and celiac disease; and rs1738074 (OR = 2.209, p = 0.02528) in TAGAP found in GWAS for association with celiac disease and multiple sclerosis. While additional variants were also identified as significant, pathway analyses have found enrichment of associated variants in chemotaxis biological processes (p = 0.04).

Conclusions

Our approach provides the first evidence that germline variants previously associated with autoimmune risk modulate the susceptibility to irAEs in patients treated by ICI. This includes associations with severe irAEs for FUT2, a protein involved in H-antigen production and linked with multiple autoimmune diseases. We have also found enrichment of variants associated with irAEs in chemotaxis processes, critically important in migration of dendritic cells upon treatment with anti-CTLA4 ICI. Upon validation in larger patient subsets, these findings suggest novel personalized biomarkers predictive of IPI-related toxicty, potentially extending to other ICI treatments.

Legal entity responsible for the study

Tomas Kirchhoff

Funding

None

Disclosure

J.S. Weber: Consulting for Bristol-Myers Squibb, Merck, AstraZeneca and Genetech. All other authors have declared no conflicts of interest.

Background

Anti PD-1/L1 (PD1) agents are being used to treat various tumor types. Most trials have excluded patients (pts) who have had a solid organ transplant (SOT), HIV, or Hepatitis (Hep) B and Hepatitis C. The safety and efficacy of PD1 in this setting is unknown.

Methods

Pts treated at 16 centres that had a transplant, HIV, Hep B/C were included. Patient demographics, tumour characteristics, toxicity, response and survival data, and the effect on the underlying condition were collected.

Results

42 pts were identified; 29 with melanoma, 6 bladder carcinoma (BC), 2 hepatocellular carcinoma (HCC), 2 renal cell carcinoma (RCC), 2 mesothelioma (meso), and 1 each of gastric carcinoma, glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC). 5 pts with SOT (4 renal,1 liver) had melanoma received pembrolizumab; 3 had progressive disease (PD), 1 partial response (PR), and the pt with liver transplant had graft rejection and died from this after 1 dose. 11 pts had HIV; 2 with detectable viral load. 8 pts had pembrolizumab (7 melanoma, 1 HCC), 2 nivolumab (1 melanoma, 1 RCC) and 1 atezolizumab (BC). No pt had loss in viral control or immune reconstitution inflammatory syndrome. 2 had complete response (CR), 1 PR, 4 stable disease (SD) and 4 PD. 14 pts had Hep C; 9 with detectable viral load, 6 on anti-viral therapy and 5 with cirrhosis. 6 received pembrolizumab (5 melanoma, 1 meso), 7 nivolumab (4 melanoma, 1 each of NSCLC, BC, RCC) and 1 atezolizumab (BC). No pt had loss in viral control, 1 developed grade 3 colitis but no one developed hepatitis. 2 had CR, 9 SD and 3 PD. 12 pts with Hep B; 8 with detectable viral load, 6 on anti-viral therapy and none with cirrhosis. 8 had pembrolizumab (5 melanoma, 1 each of GBM, gastric carcinoma and meso), 4 nivolumab (2 melanoma, 1 BC, 1 HCC). No pt had loss in viral control.1 had CR, 1 PR, 8 SD and 2 PD. None of Hep B or Hep C pts developed immune related hepatits.

Conclusions

Immunotherapy appears to have activity in patients with SOT, HIV and Hep B and Hep C. It can be given to renal transplant pts without rejection, however this is not universal . PD1 does not appear to adversely affect the viral control in HIV and Hep B and Hep C pts.

Clinical trial identification

Not applicable

Legal entity responsible for the study

Human ethics approved protocol at Melanoma Institute Australia

Funding

None

Disclosure

L. Zimmer: Honoraria: Roche. S. Goldinger: Research funding from the Zurich University Hospital and received travel grant support from Novartis, Roche, MSD and Bristol-Myers Squibb. An intermittent advisory board relationship with Novartis, Roche, MSD and Bristol-Myers Squibb. M. Millward: grant support from GlaxoSmithKline during the conduct of the study and other support from GlaxoSmithKiline. V. Atkinson: advisory boards and received travel support and speaker\'s fees from Bristol-Myers Squibb, Novartis and MSD. GVL is a consultant advisor to Amgen, Merck MSD, Novartis and Roche received honoraria from Bristol-Myers Squibb, Novartis and Merck MSD. P.A. Ascierto: receiving consulting fees from Bristol-Myers Squibb, Roche, GSK, MSD, Ventana Medical Systems, Novartis, and Amgen, honoraria from Bristol-Myers Squibb, Roche, and GSK, and grant support to his institution from Bristol-Myers Squibb, Roche, and Ventana Medical Systems; C. Garbe: Advisory board: AMGEN, Bristol-Myers Squibb, GSK, MSD, Novartis and Roche Lecture honorarium: Bristol-Myers Squibb, MSD Consulting: Roche. R. Gutzmer: Received project support from Novartis Pharma and Pfizer Lecture honoraria from Novartis Pharma and Pfizer. D.B. Johnson: personal fees from Genoptix and Bristol-Myers Squibb. G.V. Long: personal fees from GlaxoSmithKline during the conduct of the study and personal fees from Roche, Novartis, Amgen, and Bristol Myers Squibb. A.M. Menzies: honoraria from Bristol-Myers Squibb and Novartis, and has sat on advisory boards for MSD and Chugai All other authors have declared no conflicts of interest.