Immune-related Progression-free Survival Research Articles

Intratumor tertiary lymphatic structure evaluation predicts the prognosis and immunotherapy response of patients with colorectal cancer.

Immune checkpoint therapy, involving the programmed cell death 1 (PD-1) monoclonal antibody, has revolutionized the treatment of cancer. Tertiary lymphatic structure (TLS) serves as an immune indicator to predict the efficacy of PD-1 antibody therapy. However, there is no clear result whether the distribution, quantity, and maturity of TLS can be effective indicators for predicting the clinical efficacy of anti-PD1 immunotherapy in patients with colorectal cancer (CRC). Fifty-seven patients who underwent surgical resection and thirty-nine patients who received anti-PD-1 immunotherapy were enrolled in this retrospective study. Immunohistochemical staining and multiple fluorescence immunohistochemistry were used to evaluate the mismatch repair (MMR) subtypes and TLS distribution, quantity, and maturity, respectively. A comprehensive patient score system was built based on TLS quantity and maturity. We found that the proportion of patients with score >1 was much higher in the deficient mismatch repair(dMMR) group than in the proficient mismatch repair(pMMR) group, and this difference was mainly due to intratumoral TLS. Patient score, based on the TLS evaluation of whole tumor, peritumor, or intratumor, was used to evaluate the efficacy of anti-PD1 immunotherapy. Based only on the intratumor TLS evaluation, the proportion of patients with a score >1 was higher in the response (PR + CR) group than in the non-response (PD) group. Multivariate analysis revealed that patient scores were positively correlated with the clinical efficacy of immunotherapy. Further analysis of immune-related progression-free survival was performed in patients with CRC who received anti-PD-1 immunotherapy. Patients with score >1 based on the intratumor TLS evaluation had significantly better survival. These results suggest that the patient score based on intratumor TLS evaluation may be a good immune predictive indicator for PD-1 antibody therapy in patients with CRC.

Primary resistance to nivolumab plus ipilimumab therapy in patients with metastatic renal cell carcinoma.

Nivolumab plus ipilimumab (NIVO+IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Approximately 40% of patients achieve a durable response; however, 20% develop primary resistant disease (PRD) to NIVO+IPI, about which little is known in patients with mRCC. Therefore, this investigation aimed to evaluate the clinical implication of PRD in patients with mRCC to select better candidates in whom NIVO+IPI can be initiated as first-line therapy. This multi-institutional retrospective cohort study used data collected between August 2015 and January 2023. In total, 120 patients with mRCC treated with NIVO+IPI were eligible. Associations between immune-related adverse events and progression-free survival, overall survival (OS), and objective response rate were analyzed. The relationship between other clinical factors and outcomes was also evaluated. The median observation period was 16 months (interquartile range, 5-27). The median age at NIVO+IPI initiation was 68 years in the male-dominant population (n = 86, 71.7%), and most patients had clear cell histology (n = 104, 86.7%). PRD was recorded in 26 (23.4%) of 111 investigated patients during NIVO+IPI therapy. Patients who experienced PRD showed worse OS (hazard ratio: 4.525, 95% confidence interval [CI]: 2.315-8.850, p < 0.001). Multivariable analysis showed that lymph node metastasis (LNM) (odds ratio: 4.274, 95% CI: 1.075-16.949, p = 0.039) was an independent risk factor for PRD. PRD was strongly correlated with worse survival rates. LNM was independently associated with PRD in patients with mRCC receiving NIVO+IPI as first-line therapy and might indicate that a candidate will not benefit from NIVO+IPI.

Prognostic value of pretreatment immune inflammation indices in patients with immune-related tumors

Background Pretreatment high levels of lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), modified Glasgow prognostic scores (mGPS), prognostic nutritional index (PNI), and other prognostic biomarkers have been associated with poor overall survival (OS) in immune-related tumor types. Therefore, we explored a simple, inexpensive and effective method for cancer prognosis. Methods Between March 2017 and June 2022, 111 individuals who had immunotherapy were retrospectively examined. Oncologic outcomes of patients with immune-related tumor types, include OS and progression-free survival (PFS), and response rates (RR). Results Pretreatment ECOG (Eastern Cooperative Oncology Group) performance quality was independently linked with poor OS ECOG ≥2 (HR 4.80, 95% CI 2.57–8.96, p < .001) and inferior PFS (HR 3.31, 95% CI 2.023–5.445, p < .001). Additionally, a high LDH status prior to therapy was independently linked to an inferior OS (HR 1.004, 95% CI 1.001–1.007, p = .003) and inferior PFS (HR 1.004, 95% CI 1.002–1.006, p < .001). Higher MLR at baseline was a prognostic factor for both shorter PFS (HR = 3.691, 95% CI 1.582–8.610, p = .003) and OS (HR = 2.876, 95% CI 1.127–7.342, p = .027). Conclusions In our cohort, elevated pre-treatment MLR, LDH and ECOG ≥2 were associated with poor OS and PFS. Prospective studies need to determine the utility of them.

Comparison of the Impact of Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Dual Combination Therapy and Immune Checkpoint Inhibitor Plus Tyrosine Kinase Inhibitor Combination Therapy in Patients with Advanced Renal Cell Carcinoma.

The prognostic impact of immune-related adverse events during immune checkpoint inhibitor-based combination therapy for advanced renal cell carcinoma remains unclear, especially in terms of differences between regimens. We aimed to clarify the prognostic impact of immune-related adverse events in patients with advanced renal cell carcinoma receiving immune checkpoint inhibitor dual combination therapy (IO-IO) or immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy (IO-TKI). We retrospectively evaluated the data of 148 patients who received immune checkpoint inhibitor-based combination therapy as first-line therapy. Patients were divided into two groups based on regimens, namely IO-IO and IO-TKI. The associations between immune-related adverse event development and outcomes, such as progression-free survival, overall survival, and objective response rate, were compared between the two groups. In the IO-IO and IO-TKI groups, 67 of 91 (74%) and 31 of 57 (54%) patients, respectively, experienced at least one immune-related adverse event and the rate was significantly higher in the IO-IO group (p = 0.0204), where immune-related adverse events development was significantly associated with longer progression-free survival (p < 0.0001) and overall survival (p = 0.0102), and a higher objective response rate (p = 0.0028). A multivariate analysis revealed immune-related adverse event development as an independent factor for longer progression-free survival (hazard ratio, 0.25; p < 0.0001) and overall survival (hazard ratio, 0.42; p = 0.0287). There were no significant associations between immune-related adverse events and progression-free survival, overall survival, or objective response rate in the IO-TKI group. The development of immune-related adverse events was positively associated with the outcome of patients with advanced renal cell carcinoma treated with IO-IO combination therapy; no such correlation was observed for IO-TKI combination therapy.

Safety and efficacy of immune checkpoint inhibitors in advanced cancer patients with autoimmune disease: A meta-analysis

ABSTRACT Cancer patients with autoimmune disease (AID) are usually excluded from clinical trials involving immune checkpoint inhibitors (ICIs). The available electronic databases were systematically searched from inception until July 3, 2022. We recorded the incidence of immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS) data of included studies. This meta-analysis included 14 studies comprising 11511 participants; however, only 8716 participants were treated with ICI. Therefore, the analysis was conducted on 8716 patients (769 patients with AID compared to 7947 patients without AID). The pooled risk ratio (RR) for any grade and grade ≥3 irAEs was 1.74 (95% confidence interval [CI]: 1.27-2.37) and 1.43 (95% CI: 1.10-1.88), respectively. The irAEs in the same system as that of the AID were referred to as AID-homogeneous irAEs; in the other cases, there were referred to as AID-heterogeneous irAEs. Subgroup analysis found that the higher risk of AID-homogeneous irAEs contributed to the higher risk of overall irAEs among patients with AID. The pooled hazard ratio (HR) for PFS and OS was 1.09 (95% CI: 0.96–1.24) and 1.07 (95% CI: 0.94-1.22), respectively. The results of PFS and OS subgroup analyses matched the overall results. Patients with AID had a significantly higher risk of developing any grade and ≥3 grade irAEs under ICI therapy, specifically AID-homogeneous irAEs; however, the frequency of AID-heterogeneous irAEs in patients with AID was similar to irAEs in patients without AID. No statistically significant differences in PFS and OS were observed between the two groups.

Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study

BackgroundIntratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death...

522 Associations between influenza vaccine and immunotherapy outcomes in metastatic melanoma patients

Immune checkpoint inhibitors (ICI) elicit antitumor response in 30-50% of metastatic melanoma (MM) patients. Prior studies have implicated a decreased melanoma risk and enhanced immune response with influenza vaccination. However, associations between this vaccine and patient outcomes on ICI, including immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS) are unclear. We performed a single institution, retrospective cohort analysis characterizing influenza vaccination patterns in MM patients receiving ICI. Inclusion criteria included newly diagnosed stage IV or unresectable stage III MM patients who received ICI as first-line systemic treatment from 2013-2018 and had vaccination records. With a vaccinated cohort of 90 patients and unvaccinated cohort of 86 patients, median age of vaccinated patients was significantly higher compared to unvaccinated at the initiation of ICI (70 vs 59 years; p<0.0001). Vaccinated patients were more likely to receive single agent anti-PD1 therapy (68% vs 38%; p=0.0003). IrAEs were more prevalent in the vaccinated cohort compared to the unvaccinated cohort (67% vs 40%; p=0.0005), predominantly due to cutaneous irAEs (61% vs 34%; p=0.0002). Both cohorts stopped ICI most often due to disease progression, but this was less common for the vaccinated cohort (46% vs 64%; p=0.03). Vaccinated patients had longer PFS than unvaccinated (HR=0.67; 95% CI, 0.47-0.97), but not OS (HR=0.95; 95% CI, 0.62-1.46). Overall, 51% of patients received the recommended flu vaccination prior to ICI. Vaccinated patients experienced a higher rate of irAEs yet had a higher PFS compared to unvaccinated patients. Larger cohorts are necessary to explore further associations between this simple, universally recommended preventative health adjunct and potentially improved ICI outcomes in MM patients.

Phase II open-label study of S-588410 as maintenance monotherapy after first-line platinum-containing chemotherapy in patients with advanced or metastatic urothelial carcinoma.

440 Background: S-588410 is a cancer peptide vaccine composed of 5 human leukocyte antigen (HLA)-A*24:02-restricted epitope peptides derived from 5 cancer-testis antigens: DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1; all of which are highly expressed in urothelial carcinoma. This study aimed to evaluate the effect of S-588410 maintenance therapy on peptide-specific cytotoxic T-lymphocyte (CTL) induction in patients with advanced or metastatic urothelial carcinoma after first-line platinum-based chemotherapy. Methods: An open-label, multicenter phase II trial was performed across 62 sites in Japan, the United Kingdom, France and Bulgaria (EudraCT 2013-005274-22). Eligible patients had completed ≥4 cycles of first-line platinum-based chemotherapy without disease progression. HLA-A*24:02-positive patients received S-588410 (1 mg of each of 5 peptides mixed with Montanide ISA 51 VG) subcutaneously weekly for 12 weeks, then every 2 weeks for up to 2 years. HLA-A*24:02-negative patients were enrolled in an observation group and did not receive study drug. The primary endpoint for the S-588410 group was the CTL induction rate at 12 weeks, defined as the proportion of patients who showed increased CTL activity for ≥1 peptide. Secondary endpoints included CTL induction rate after 1 year, antitumor effect defined by immune-related response criteria, progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 81 patients with platinum-sensitive advanced or metastatic urothelial carcinoma were enrolled (S-588410 group, n=45; observation group, n=36) between April 2014 and November 2017. Most patients were male and Asian with a mean age of 67 years. CTLs were induced in 42 (93.3%) patients who received S-588410 for 12 weeks (P&lt;0.0001, one-sided binomial test where the CTL induction rate is ≤50% as the null hypothesis). The CTL induction rate steadily increased to 95.6% within 48 weeks. CTL activity was high for the DEPDC1, MPHOSPH1 and URLC10 peptides. The response rate (immune-related complete response [CR] or partial response [PR]) was 8.9% (4/45 patients) in the S-588410 group and 0% in the observation group. Tumor imaging showed gradual (PR, n=3) and durable (CR, n=1) tumor shrinkage after ≥36 weeks in the S-588410 group. Median PFS was 18.1 weeks in the S-588410 group and 12.5 weeks in the observation group. Median OS was 71 and 99 weeks, respectively. The most frequent treatment-emergent adverse event was injection site reaction (42/45 patients [93.3%]; Grades 1–3). Pyrexia, rash and pruritus were also observed in the S-588410 group, but not the observation group. Conclusions: S-588410 showed a potent immune response and acceptable safety profile in patients with advanced or metastatic urothelial carcinoma, potentially offering a clinical benefit as post-chemotherapy maintenance therapy. Clinical trial information: EudraCT 2013-005274-22.

Significance of Glasgow Prognostic Scores in NSCLC Patients Treated With Immunotherapy After Platinum-based Cytotoxic Chemotherapy.

Little is known about the prognostic role of the Glasgow prognostic score (GPS) in non-small cell lung cancer (NSCLC) patients treated with immunotherapy after platinum-based cytotoxic chemotherapy. This study used a lung cancer cohort of the Catholic Medical Center of Korea between January 2018 and September 2020. A total of 78 patients with NSCLC treated with immunotherapy as second or further-line therapy were included. Higher GPS values were significant predictors of shorter immune-related progression-free survival (irPFS) and overall survival (OS). The hazard ratios for irPFS were 0.249 for programmed death-ligand 1 (PD-L1) expression ≥50% and 9.73 for a GPS of 2. Older age, lower PD-L1 expression and higher GPS values were independently associated with shorter OS. Higher GPS values were identified as a poor prognostic factor for OS and irPFS in NSCLC patients who received immunotherapy as second or further-line therapy.

Impact of systemic corticosteroids on survival outcomes in patients with immune-checkpoint inhibitor enterocolitis.

e15065 Background: Current guidelines for immune-checkpoint inhibitor enterocolitis (ICI-EC) recommend systemic corticosteroids (SCS) for moderate to severe cases, but whether these therapies have an impact on survival outcomes remains unclear. Prior work has been limited, considering only select cancer types, ICI regimens, and indications for immunosuppression. We therefore sought to examine the relationship between SCS for ICI-EC and survival outcomes, accounting for all other steroid exposures. Methods: We retrospectively reviewed the medical records of patients with biopsy-confirmed ICI-EC seen at our institution between August 2011 and April 2019, collecting patient demographics, cancer features, anti-neoplastic therapies, other immune-related adverse events (irAEs), SCS exposures, progression-free survival (PFS), and overall survival (OS). We further categorized SCS exposures by indication (ICI-EC, other irAE, other medical reason) and previously established dose thresholds (“high” ≥1mg/kg for ≥1 week; “moderate” ≥7.5mg for ≥2 months, or “none”). We assessed the relationship between SCS use for ICI-EC and PFS/OS using Cox proportional hazards models adjusted for age, sex, cancer type and stage, baseline brain metastases, functional status (Eastern Cooperative Oncology Group score), anti-neoplastic therapies, and other SCS exposures. Results: 90 patients (mean age 62.5 years, 37.8% female) had biopsy-confirmed ICI-EC, most commonly precipitated by CTLA-4 monotherapy (43.3%). Nearly all (80.0%) required SCS for their first episode of ICI-EC, with half (46.7%) requiring doses exceeding the highest threshold. Patients who received high-dose SCS for first ICI-EC episode had reduced PFS (HR = 2.50, p = 0.028) compared to those who did not receive SCS for this indication. OS was not affected by SCS therapy for ICI-EC at any dose. Conclusions: In cancer patients with biopsy-proven ICI-EC, receipt of high-dose SCS for first ICI-EC episode was associated with decreased PFS, but not OS. These findings suggest a nuanced and potentially dose-dependent relationship between SCS and survival outcomes meriting further investigation for a larger array of immunotoxicities.

Efficacy and predictive factors of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis.

Background:Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for metastatic breast cancer in several clinical trials. However, response only occurred in a small population. Evidence predicting response and survival of patients with metastatic breast cancer following ICI treatment with existing biomarkers has not been well summarized. This review aimed to summarize the efficacy and predictive factors of immune checkpoint therapy in metastatic breast cancer, which is critical for clinical practice.Methods:PubMed, Embase, Cochrane Library, Web of Science, www.clinicaltrials.gov, and meeting abstracts were comprehensively searched to identify clinical trials. The outcomes were objective response rate (ORR), treatment-related adverse events (trAEs), immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS).Results:In this review, 27 studies with 1746 patients were included for quantitative synthesis. The pooled ORR was 19% [95% confidence interval (CI) = 12–27%]. Programmed death-ligand 1 (PD-L1)-positive patients had a higher response rate [odds ratio (OR) = 1.44, p = 0.01]. First-line immunotherapy had a better ORR than second-line immunotherapy (OR = 2.00, p = 0.02). Tumor-infiltrating lymphocytes (TILs) ⩾5% (OR = 2.53, p = 0.002) and high infiltrated CD8+ T-cell level (OR = 4.33, p = 0.006) were ideal predictors of immune checkpoint therapy response. Liver metastasis indicated poor response (OR = 0.19, p = 0.009). However, the difference was non-significant in ORR based on age, performance status score, lymph node metastasis, and lactate dehydrogenase (LDH) level. In addition, the PD-L1-positive subgroup had a better 1-year PFS (OR = 1.55, p = 0.04) and 2-year OS (OR = 2.28, p = 0.02) following ICI treatment. The pooled incidence during ICI therapy of grade 3–4 trAEs was 25% (95% CI = 16–34%), whereas for grade 3–4 irAEs it was 15% (95% CI = 11–19%).Conclusions:Metastatic breast cancer had modest response to ICI therapy. PD-L1-positive, first-line immunotherapy, non-liver metastasis, and high TIL and CD8+ T-cell infiltrating levels could predict better response to ICI treatment. Patients with PD-L1-positive tumor could gain more survival benefits from immune checkpoint therapy.

666TiP - A phase Ib/ II trial to assess the safety and efficacy of CXD101 in combination with the PD-1 inhibitor nivolumab in patients with metastatic, previously-treated, microsatellite-stable (MSS) colorectal carcinoma (short title CAROSELL)

BackgroundCXD101 is a histone–deacetylase inhibitor which reactivates the patient’s immune system by increasing tumour expression of MHC I & II, tumoural infiltration by CD8 lymphocytes and decreasing T Reg cells. CXD101 has been shown in a Phase I study conducted in the UK to have anti-tumour activity as monotherapy, and to be generally well tolerated.The anti-tumour efficacy of CXD101 has been investigated as monotherapy or in combination with the immune checkpoint inhibitors, anti-mouse PD-1 and anti-mouse CTLA4, respectively, in the syngeneic MSS Colon 26 model. The tumour Colon26 celles were implanted subcutaneously in immunocompetent BALB/c mice. The syngeneic tumour was seen to respond poorly to anti-PD1 and anti-CTLA4 immune therapeutics alone. As a single agent, CXD101 caused modest inhibition of tumour growth. In contrast, when administered in combination with anti-PD1 or anti-CTLA4, synergistic anti-tumour activity was observed at well tolerated doses.The CAROSELL clinical trial is testing the effect of CXD101 with nivolumab in MSS colorectal cancer, with the hypothesis that this combination will re-engage recognition of tumours by the immune system. Trial designThe selected study population were patients with advanced or metastatic MSS CRC, previously threated with at least two lines of therapy; and ECOG PS 0, 1, or 2. A total of 5 UK investigators are contributing subjects to the study, the first of which was treated in July 2018. The design began with a Phase Ib variable dose safety run-in (n=9). No dose-limiting toxicities were observed, and CXD101 20mg bid in combination with nivolumab 240mg was selected as the Phase II treatment.The primary objective of the Phase II element is to assess immune Disease Control Rate, as determined by CT scan tumour measurements (iRECIST), following a Simon 2-Stage statistical approach. Secondary objectives are to determine 20-week immune-related progression-free survival; overall survival; immune Objective Response Rate, and safety. The CAROSELL Study will recruit a total of 55 subjects. Legal entity responsible for the studyCelleron Therapeutics Ltd. FundingCelleron Therapeutics Ltd. DisclosureS. Cook: Shareholder / Stockholder / Stock options, Full / Part-time employment: Celleron therapeutics. N. la Thangue: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Celleron therapeutics. D.J. Kerr: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Celleron therapeutics. All other authors have declared no conflicts of interest.

Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study

Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma. In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients. From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines. The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration. Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.

Efficacy and Safety of Ipilimumab plus Chemotherapy for Advanced Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related deaths worldwide, with poor prognosis in advanced lung cancer patients. Platinum-based chemotherapy has always been a first-line treatment for the majority of advanced lung cancer patients, but its long-term survival benefit is limited. Ipilimumab is an immune drug that targets the CTLA-4 protein in T cells. Therefore, we evaluated the efficacy and safety of adding ipilimumab to simple chemotherapy for patients with advanced lung cancer. We searched literatures in PubMed, Web of Science, EMBASE, the Cochrane Library and cliniclatrials.gov. The primary end points of this assessment were overall survival (OS), progression-free survival (PFS) and immune-related PFS(irPFS) of lung cancer patients. Other end points were objective response rate (ORR), disease control rate (DCR) and safety. The results of this study will be presented by the risk ratio (RR) of the endpoints and the 95% confidence interval (CI) of the various effect sizes. And when the p value is less than 0.05, we think there is a statistical difference. Finally, 6 RCTs and 2,037 patients including 953 with advanced or recurrent non-small cell lung cancer (NSCLC) and 1084 with extensive-disease small-cell lung cancer (ED-SCLC) were identified. Among them, 1089 received immunochemotherapy, and 948 patients received chemotherapy alone. Immunochemotherapy can't improve OS (6months: risk ratio (RR)=0.97 P=0.11; 1year: RR=1.05 P=0.36), ORR (RR=1.00 P=0.95) and DCR (RR=0.92, 95%CI 0.85-1.00, P=0.04) of patients with lung cancer compared to pure chemotherapy, but it can improve the PFS (6months: RR=1.16 P=0.02; 1year: RR=1.39 P=0.02) and 6months-irPFS(RR=1.60 P=0.004). However, due to the addition of ipilimumab, the immune-related toxicities are more apparent in immunochemotherapy group.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.ResultsThe immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair–deficient tumors, as compared with 73 in mismatch repair–proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).ConclusionsThis study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.)

PD-1 blockade in tumors with mismatch repair deficiency.

LBA100 Background: Somatic mutations have the potential to be recognized as “non-self” immunogenic antigens. Tumors with genetic defects in mismatch repair (MMR) harbor many more mutations than tumors of the same type without such repair defects. We hypothesized that tumors with mismatch repair defects would therefore be particularly susceptible to immune checkpoint blockade. Methods: We conducted a phase II study to evaluate the clinical activity of anti-PD-1, pembrolizumab, in 41 patients with previously-treated, progressive metastatic disease with and without MMR-deficiency. Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to three cohorts of patients: those with MMR-deficient colorectal cancers (CRCs) (N = 11); those with MMR-proficient CRCs (N = 21), and those with MMR-deficient cancers of types other than colorectal (N = 9). The co-primary endpoints were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks. Results: The study met its primary endpoints for both MMR-deficient cohorts. The irORR and irPFS at 20 weeks for MMR-deficient CRC were 40% and 78%, respectively, and for MMR-deficient other cancers were 71% and 67%, respectively. In MMR-proficient CRC, irORR and irPFS at 20 weeks were 0% and 11%, respectively. Response rates and Disease Control Rates (CR+PR+SD) by RECIST criteria were 40% and 90% in MMR-deficient CRC, 0% and 11% in MMR-proficient CRC, and 71% and 71% in MMR-deficient other cancers, respectively. Median PFS and overall survival (OS) were not reached in the MMR-deficient CRC group but was 2.2 and 5.0 months in the MMR-proficient CRC cohort (HR for PFS = 0.103; 95% CI, 0.029 to 0.373; p &lt; 0.001 and HR for OS = 0.216; 95% CI, 0.047 to 1.000; p = 0.05). Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors (p = 0.0015), and high total somatic mutation loads were associated with PFS (p = 0.02). Conclusions: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab. Clinical trial information: NCT01876511.

Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study

In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in 'memory' but not in 'naïve' T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome. Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. 2010-019356-50. NCT01654692.

A Novel Phase Ii Trial of Ipilimumab, Carboplatin and Etoposide (Ice) for the First Line Treatment of Extensive Stage Small Cell Lung Cancer (Sclc)

ABSTRACT Background: Platinum etoposide doublet chemotherapy remains the standard of care for SCLC; newer combination regimens have failed to improve outcome. A subgroup of patients with apparently better long-term survival present with autoimmune paraneoplastic syndromes. These reflect cross reactivity of anti-tumour immune responses with self-antigens, most frequently neuronal antigens, and suggest that SCLC is susceptible to immune control. Our study examines for the first time, whether addition of the immune stimulating anti-CTLA4 antibody Ipilimumab to carboplatin/etoposide chemotherapy can increase anti-tumour activity and whether this might come at the cost of extra immune related neurological toxicity. Methods: This phase II study examines the efficacy and toxicity of Ipilimumab (10 mg/kg) together with Carboplatin (AUC=6) and Etoposide (120 mg/m2 IV day1, 100mg BD PO days 2 and 3) chemotherapy in previously untreated patients with extensive stage (ES) SCLC. Ipilimumab was introduced in responding patients at cycles 3-6 with planned 3-monthly maintenance Ipilimumab. Primary end point is progression free survival at 1 year; secondary endpoints include 1 year overall survival and Immune related progression free survival (irPFS). Results: 39 of a planned 40 patients have entered the study with a median age of 58 yrs (range 47-84); 64% are male. Patients received at least one cycle of Ipilimumab. In 61.1% [95% CI: 44.9-75..2] >grade 3 adverse events were seen, assessed by the investigators as possibly ipilimumab related in 41.7% [95% CI: 27.1, 57.8]. Two patients (6%) had ipilimumab related neurological events, of these one was fatal, presenting like an anti-Hu syndrome. Both events occurred in patients with positive baseline anti-neuronal antibodies. Conclusions: Our multi centre study has demonstrates for the first time that chemo-immunotherapy with ICE is deliverable in ES SCLC, but with an appreciable burden of immune related toxicity. Two significant neurological immune mediated events were seen, one fatal. The data reinforce the view that SCLC is immunogenic and that immunological visibility of the tumour can link to anti neuronal immune events. Disclosure: C. Ottensmeier: Funding for this study was by an educational grant from BMS and Cancer Research UK. The trial uses the BMS proprietary compound Ipilimumab; J. Cave: Conference attendance support from BMS; M. Wheater: Conference attendance support from BMS; C. Mulatero: I have undertaken consultancy/advisory work for BMS (ipilimumab) and for Pfizer (although not about tremelimumab), and have received honoraria to attend meetings from BMS; V. Potter: I have received honoraria and consultancy fees from Roche, GSK and Lilly, but nothing from BMS; S. Danson: I sat on an advisory board and received travel expenses for a meeting from BMS - this was about 4 years ago; R. Griffiths: I have received honoraria and consultancy fees from Pfizer, Pierre-Fabre, GSK and Novartis, but nil from BMS. All other authors have declared no conflicts of interest.

Calm Study: Secondary Endpoints of a Phase Ii Study of a Novel Oncolytic Immunotherapeutic Agent, Coxsackievirus A21, Delivered Intratumorally in Patients with Advanced Malignant Melanoma

ABSTRACT Aim: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21. Following intratumoral injection, CAVATAK preferentially infects ICAM-1 expressing tumor cells, resulting in cell lysis and a systemic anti-tumor immune response. We here report on the key secondary endpoints in the Phase II CALM study. Methods: The CALM study investigated the efficacy and safety of intratumoral CAVATAK in 57 patients with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Patients received up to 3 x 108 TCID50 CAVATAK intratumorally on study days 1,3,5 and 8 and then every three weeks for a further 6 injections. Patients displaying immune-related progression-free survival (irPFS) or better at 6 months were eligible for 9 additional injections. Key eligibility criteria were ECOG 0-1, and at least 1 injectable cutaneous, subcutaneous, or nodal melanoma metastasis >1.0 cm. The primary endpoint was to achieve >9 of 54 evaluable patients with irPFS at 6 months. Secondary endpoints included median irPFS, 1-year survival, median time to response, irRECIST 1.1 best overall response (BORR) and safety. Results: The primary endpoint of the study was achieved with 19 of 51 (37.3%) evaluable patients displaying irPFS at 6 months. Preliminary analysis of secondary endpoints showed: median irPFS of 4.2 months (95% CI 2.8, 8.3), 1-year survival 61.5% (16 of 26 pts), on-going BORR (irRECIST 1.1) 26.3% (15 of 57 pts) with responses seen in both injected and non-injected lesions, median time to response 2.8 months. To date 15 patients have received additional series of CAVATAK injections. The most common patient side effects observed were Grade 1 local injection site reactions, fatigue, chills and fever. There were no Grade 3 or 4 product-related AE's. Conclusions: Intralesional CAVATAK is a promising novel oncolytic immunotherapeutic agent with limited toxicity and robust responses in both injected and non-injected lesions in patients with advanced melanoma. The effectiveness of CAVATAK warrants additional investigation as monotherapy and in combination with other targeted immunotherapies such as immune checkpoint blockade. Disclosure: R.H. Andtbacka: Travel honorarium–Viralytics; K. Zhou: Salary - Viralytics J.I. Weisberg: Salary–Viralytics; D. Shafren: Stock, salary–Viralytics. All other authors have declared no conflicts of interest.

Sequential ipilimumab (Ipi) versus best supportive care (BSC) following first-line chemotherapy (Ctx) in patients (pts) with unresectable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer: A randomized, open-label, two-arm, phase II trial (CA184-162) of immunotherapy as a maintenance concept.

TPS4151 Background: First-line systemic CTX is standard-of-care for advanced gastric cancer. However, most pts relapse or have severe adverse events (AEs), creating a need for new therapies with better benefit/risk and toxicity profiles. Endogenous immune activity against tumor cells has been demonstrated in the human gastric cancer tumor microenvironment, supporting a role for immunotherapy. As a new maintenance concept, sequential administration of immunotherapy may prolong clinical benefit of first-line CTX before disease progression (PD). Ipi, a fully human monoclonal antibody which binds CTLA-4, augments the antitumor immune response. Ipi improved overall survival (OS) in patients with advanced melanoma with AEs managed using product-specific treatment guidelines.This global (32 sites among 10 countries), multicenter, randomized, open-label, phase II trial (ClinicalTrials.gov identifier NCT01585987) will compare the efficacy of Ipi and BSC after first-line CTX. Methods: Pts with good performance status (0 or 1) and histologically confirmed, unresectable locally advanced or metastatic gastric or GEJ cancer without PD after first-line CTX with a fluoropyrimidine (F) and platinum (P) doublet will be eligible. Pts with radiological evidence of brain metastases, autoimmune/immune-mediated disease, inadequate hematologic, renal, and hepatic function, or are HER2+ will be ineligible. Pts will be randomized to Ipi (4 doses [10 mg/kg, IV Q3W], followed by Q12W) until confirmed immune-related PD or unacceptable toxicity, or to BSC (continuing F used in lead-in CTX or no active systemic therapy). The primary objective is to compare immune-related progression-free survival (PFS): immune-related response criteria were derived from World Health Organization (WHO) criteria to better capture Ipi response patterns. Secondary objectives are to compare PFS per mWHO criteria and OS, and estimate immune-related best overall response rate. The study is planned to randomize 114 pts. Clinical trial information: NCT01585987.