PD-L1 Positive Patients Research Articles

The real-word evidence of first-line treatment of pembrolizumab in advanced NSCLC.

e18731 Background: For advanced non-small cell lung cancer (NSCLC), evidence from clinical trials indicates the superiority of pembrolizumab (P) than chemotherapy (C) in PD-L1 positive patients and superiority of P+C than C among PD-L1 unselected patients. Meta-analysis from different clinical trials stated P+C failed to improve overall survival (OS) or progression-free survival (PFS) compared with P alone. This study used real-world data of PD-L1+ patients with advanced NSCLC to compare treatment effect of P with P+C. Methods: A retrospective analysis of adult patients diagnosed between 2015-2020 with stage IV NSCLC with PD-L1+ and without EGFR/ALK mutation was examined using de-identified Syapse Learning Health Network(LHN). We compared the patients with first-line (1L) treatment of pembrolizumab + carboplatin + chemo (P+C) and patients with 1L treatment of P only (P). Patient characteristics and survival outcomes including real-world OS (rwOS) and real-world time to next treatment (rwTTNT) were collected. Results: 485 patients were included: 231 on P+C and 254 on P. The two groups are similar in race, primary tumor histology and ECOG, and P are older in age and have more female. The median rwOS for P+C is longer than P (13.2 vs 11.0 month), 1 year survival probability is higher (55% vs 49%), but 2 year survival probability is lower (34% vs 39%). Coxph model shows no significant difference between two groups (HR=0.89, 95% CI 0.69-1.14, p=0.34). Subgroup analysis of patients age≥75 shows median rwOS for P+C is shorter than P (8.7 vs 13.2 month), 1 year survival probability is lower (46% vs 51%). Coxph model shows no significant difference between two groups (HR=1.32, 95% CI 0.81-2.16, p=0.27). In each treatment group, the median rwOS for female is longer than male (13.2 vs 7.9 month in P, 15.8 vs 12.2 month in P+C), and 1 year survival probability is higher (52% vs 45% in P, 59% vs 53% in P+C). Coxph model shows no significant difference between female and male (HR=0.81, 95% CI 0.58-1.15, p=0.23 in P; HR=0.90, 95% CI 0.62-1.30, p=0.57 in P+C). Conclusions: Among patients with PD-L1+ advanced NSCLC, there is no significant difference in rwOS for patients with 1L treatment of P+C or P alone.[Table: see text]

RC48-ADC combined with toripalimab, an anti-PD-1 monoclonal antibody (Ab), in patients with locally advanced or metastatic urothelial carcinoma (UC): Preliminary results of a phase Ib/II study.

4534 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC), which showed promising data in HER2-positive and even negative patients (pts). Anti-PD-1 Abs have durable antitumor effect for mUC especially in PD-L1 positive patients. The combination may have synergistic antitumor effect. This phase 1b/II study evaluated the safety and activity of RC48-ADC combined with toripalimab in mUC. Methods: In dose-escalation cohort, pts received 1.5 or 2 mg/kg RC48-ADC + 3mg/kg toripalimab with the traditional 3+3 escalation design. In expansion cohort, patients received the recommended dose of RC48-ADC + toripalimab every 2 weeks. The primary endpoints were safety/tolerability and recommended RC48-ADC dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS stratified by HER2 and PD-L1 expression. HER2 positivity was determined by IHC and in situ hybridization (ISH). PD-L1 expression was tested with IHC 22C3 pharmDx assay. Results: As of 8 Jan 2021 (data cutoff), 14 mUC pts (9 males, median age 66 y [52-76]) were enrolled. Most pts were systemic treatment naïve (57%) in the locally advanced or metastatic setting. The primary site was in upper tract UC in 50%; 50% had visceral metastases (mets), including 36% with liver mets; HER2 expression was positive (IHC 3+ or 2+ ISH+) in 28%, and 43% PD-L1 CPS≥10. A total of 36 pts is anticipated to be enrolled by Apr 2021. No dose limiting toxicity was reported and the recommended dose for RC48-ADC was 2mg/kg. At data cutoff, 10/14 patients were evaluable for response, with 8 PR, 1 SD (tumor shrinking), and 1 PD. The objective response rate (ORR) was 80%, and disease control rate (DCR) was 90%. All responsive patients have durable efficacy and are still on treatment. Follow-up continues for PFS and OS. Most common treatment-related AEs were grade 1-2, including aminotransferase level increased (7/14, 50%), weight loss (6/14, 43%), alopecia (6/14, 43%), asthenia (4/14, 29%), anemia (3/14, 21%), leukopenia (21%), peripheral sensory neuropathy (21%), hypothyroidism (21%), blood triglycerides increased (21%), and creatine phosphokinase increase (21%). One pt had G3 intestinal obstruction attributed to study drug and went back to treatment after recovery. Conclusions: RC48-ADC in combination with toripalimab had a good tolerance and promising anti-tumor activity in pts with mUC. Further evaluation of safety and efficacy is ongoing. Clinical trial information: NCT04264936.

An investigation on biomarkers of hyperprogressive disease after PD-1/PDL-1 therapies in Chinese non-small cell lung cancer patients.

e21173 Background: Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, are becoming standard of care for lung cancer treatment. However, low response rates to ICI antibodies and even hyperprogressive disease (HPD) have limited the clinical application of ICIs. Considering HPD for patients means shorter survival times and worse prognoses, valid biomarkers are in urgent demand to predict the occurrence of HPD and the efficacy of ICI. Here, we explored the genomic biomarkers of HPD in Chinese non-small cell lung cancer (NSCLC) patients. Methods: 749 NSCLC patients with both genomic information and PD-L1 expression data were screened from HapLab database. HaploX 605-gene panel sequencing, covering 1.31 MB genome, was performed to analyze the genomic data of patients. PDL-1 expression was detected by immunochemistry. Results: 15 genes related to HPD were detected altered in NSCLC patients. Collectively, 511 out of 749 patients (68.22%) had at least one alteration of HPD related genes. The frequent alterations were EGFR mutation (46.86%), ALK fusion (7.49%), MDM2 amplification (6.54%), KEAP1 mutation (5.34%), STK11 mutation (4.27%), FGF3/4 amplification (4.14%), DNMT3A mutation (2.14%) and MDM4 amplification (2.00%). While in EGFR wild-type and ALK-negative patients, the top 5 frequent alterations were KEAP1 mutation (8.96%), FGF3/4 amplification (7.00%), STK11 mutation (6.16%), PTEN mutation (5.32%) and MDM2 amplification (4.20%). Notably, EGFR mutation (49.27%, 68/138), ALK fusion (9.42%, 13/138) and MDM2 amplification (4.35%, 6/138) were also observed in PDL-1 positive (TPS≥1%) patients. Conclusions: It is urgent to identify specific biomarkers that could predict HPD and to develop effective methods to prevent HPD. Our study investigated the genomic alterations associated with HPD in Chinese NSCLC patients.

PD-L1 Expression in Papillary Thyroid Cancer

Abstract There is limited data on prevalence of PD-L1 expression in papillary thyroid cancer (PTC). Anti- PD-L1 therapy is now being trialled for head and neck cancers including thyroid cancer. Whether presence of PD-L1 staining in PTC might result in a better response to anti-PD-L1 therapy is uncertain. We evaluated the frequency of tumoral PD-L1 expression using standard antibody (SP263) and clinicopathologic factors including mutation status - BRAF, NRAS, KRAS using OncoFocus Mass Array System in an Australian PTC cohort with low or high risk of recurrence /treatment response as per 2015 ATA guidelines. The cohort had 128 patients; 66% were females; 40% had both multifocal and bilateral PTC; 47% had low recurrence risk, of whom 92% had excellent treatment response; 34% had high recurrence risk, of whom 37% had structural incomplete treatment response. There was nil (0%) PD-L1 staining in 59%, 1% staining in 20%, 5-10% staining in 11%, >10% staining in rest of the cohort; 30%, 40% and 70% staining was seen in 2% each. PD-L1 in immune cells was positive in 62%. There was no significant association between PD-L1 tumour status and age, gender, size of tumour, multifocality, bilaterality, both multifocality and bilaterality, lymphovascular invasion, perineural invasion, extrathyroidal extension (ETE), histological variants, risk stratification, treatment response, metastases or mutation status. Among PD-L1 negative vs positive patients, BRAFV600E was present in 64.9% vs 67.5%, NRAS in 8.8% vs 0% and nil mutation in 26 % vs 33 % p=0.15. The staining thresholds were chosen according to existing literature. When analysed according to the percentage of PD-L1 staining (0%, 1-10% and >=10% thresholds), there was no significant association between PD-L1 staining category and other features, except for ETE (35% vs 65% vs 27%; p=0.007), a relationship that remained significant in a multivariable-adjusted model (OR 9.9, p=0.04). PD-L1 staining thresholds of <5% and >=5% were significantly associated with the size of tumour (24.7±15.4 vs 33.3±21.8; p=0.02) and histological variants (57 % vs 61% for classic variants and 27% vs 11% for follicular variants, p=0.03). This is the first study to our knowledge that analysed PD-L1 staining based on the risk stratification categories. The majority of PTC showed negative or low staining intensity for PD-L1 expression. There was no significant association between PD-L1 staining, clinicopathologic characteristics and mutation status of the PTC. Relatively less ETE was seen in the group that showed >=10% and also >=5% PD-L1 staining as compared to the group that showed 1% <10% and 1% to <5% staining which is an interesting observation and needs further investigation. The significant variation in reported PD-L1 staining in current literature reiterates that the method is yet to be optimised. Moreover the relationship between PD-L1 staining and PTC remains to be further investigated.

Correlation Between Dual-Time-Point FDG PET and Tumor Microenvironment Immune Types in Non-Small Cell Lung Cancer.

PurposeDual-time-point 18F-fluorodeoxyglucose positron emission tomography (DTP 18F-FDG PET), which reflects the dynamics of tumor glucose metabolism, may also provide a novel approach to the characterization of both cancer cells and immune cells within the tumor immune microenvironment (TIME). We investigated the correlations between the metabolic parameters (MPs) of DTP 18F-FDG PET images and the tumor microenvironment immune types (TMITs) in patients with non-small cell lung cancer (NSCLC).MethodsA retrospective analysis was performed in 91 patients with NSCLC who underwent preoperative DTP 18F-FDG PET/CT scans. MPs in the early scan (eSUVmax, eSUVmean, eMTV, eTLG) and delayed scan (dSUVmax, dSUVmean, dMTV, dTLG) were calculated, respectively. The change in MPs (ΔSUVmax, ΔSUVmean, ΔMTV, ΔTLG) between the two time points were calculated. Tumor specimens were analyzed by immunohistochemistry for PD-1/PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TILs). TIME was classified into four immune types (TMIT I ~ IV) according to the expression of PD-L1 and CD8+ TILs. Correlations between MPs with TMITs and the immune-related biomarkers were analyzed. A composite metabolic signature (Meta-Sig) and a combined model of Meta-Sig and clinical factors were constructed to predict patients with TMIT I tumors.ResultseSUVmax, eSUVmean, dSUVmax, dSUVmean, ΔSUVmax, ΔSUVmean, and ΔTLG were significantly higher in PD-L1 positive patients (p = 0.0007, 0.0006, < 0.0001, < 0.0001, 0.0002, 0.0002, 0.0247, respectively), and in TMIT-I tumors (p = 0.0001, < 0.0001, < 0.0001, < 0.0001, 0.0009, 0.0009, 0.0144, respectively). Compared to stand-alone MP, the Meta-Sig and combined model displayed better performance for assessing TMIT-I tumors (Meta-sig: AUC = 0.818, sensitivity = 86.36%, specificity = 73.91%; Model: AUC = 0.869, sensitivity = 77.27%, specificity = 82.61%).ConclusionHigh glucose metabolism on DTP 18F-FDG PET correlated with the TMIT-I tumors, and the Meta-Sig and combined model based on clinical and metabolic information could improve the performance of identifying the patients who may respond to immunotherapy.

PD-L1 expression with QR1 and E1L3N antibodies according to histological ovarian cancer subtype: A series of 232 cases.

Therapeutic strategies for epithelial ovarian cancers are evolving with the advent of immunotherapy, such as PD-L1 inhibitors, with encouraging results. However, little data are available on PDL-1 expression in ovarian cancers. Thus, we set out to determine the PD-L1 expression according to histological subtype. We evaluated the expression of two PD-L1 clones – QR1 and E1L3N – with two scores, one based on the percentage of labeled tumor cells (tumor proportion score, TPS) and the other on labeled immune cells (combined proportion score, CPS) in a consecutive retrospective series of 232 ovarian cancers. PD-L1 expression was more frequent in high grade serous carcinoma (27.5% with E1L3N clone and 41.5% with QR1 clone), grade 3 endometrioid carcinoma (25% with E1L3N clone and 50% with QR1 clone), and clear-cell carcinomas (27.3% with E1L3N clone and 29.6% with QR1 clone) than other histological subtypes with CPS score. Using the CPS score, 17% of cases were labeled with E1L3N vs 28% with QR1. Using the TPS score, 14% of cases were positive to E1L3N vs 17% for QR1. For TPS and CPS, respectively, 77% and 78% of the QR1 cases were concordant with E1L3N for the thresholds of 1%. Overall and progression-free survival between PD-L1 positive and PD-L1 negative patients were not different across all histological types, and each subtype in particular for serous carcinomas expressing PD-L1. Expression of PD-L1 is relatively uncommon in epithelium ovarian tumors. When positive, usually <10% of tumor cells are labeled. QR1 clone and CPS appear the best tools to evaluate PD-L1 expression.

Abstract SP086: Rationale for combination therapies

Abstract There has been a lot of emerging clinical data in the treatment of early and late stage breast cancer with PD-1/PD-L1 inhibitors in the last 12 months. We have learnt several important points relevant for future development in breast cancer patients. Most important of these is the observation that early-stage disease has a different immune context to advanced disease. This is evidenced by study results that in the neoadjuvant settings PD-(L)1 inhibitors have efficacy in both PD-L1 positive and negative populations, whereas in the advanced setting, efficacy has only been reported in PD-L1 positive patients. It has been hypothesized that chemotherapy, or certain types of chemotherapy, may be more “immunogenic” than others, but thus far, there is scant evidence to support this. Rather it is more likely that the immune context is important. In the early-stage setting, many primary breast cancers (triple negative and HER2-positive) are highly infiltrated with immune cells, the cancers has received no prior treatment, and cancer burden is low, confined to the breast and ultimately completely removed. In contrast, in the advanced setting, the immune infiltrate is low to non-existent, patients often have higher disease burden, hostile tumor microenvironments in multiple organs sites, and have received prior treatment, implying that the cancer has evolved to become treatment resistant, as well as more efficient at suppressing or evading host immune detection. Hence, in the setting of recurrent disease, and likely also in the locally advanced setting, despite chemotherapy usage and objective tumor shrinkage, it is the pre-existing immunity that ultimately dictates the chances of benefit from PD-(L)1 inhibitors. What combinations are likely therefore to be effective in the advanced setting where immunity does not exist? Targeted therapies such as MEK and AKT inhibitors are being evaluated in clinical trials, thus far have proven disappointing. New antibody drug conjugates (ADCs) such as Sacituzumab Govetecan and DS-8201a have shown impressive anti-tumor activity in the advanced setting. However, given their proven cytotoxic bystander effects on nearby cells, it will be essential to evaluate ADCs and immunotherapy sequencing approaches to ensure that the scant amount of pre-existing local TIL is also not destroyed. Interestingly a recent study in advanced HER2-positive breast cancer (KATE2) reported benefit of atezolizumab to trastuzumab emantasine also in only PD-L1 positive patients. Notably T-DM1 does not have prominent bystander effects. Other possibilities to create immunity in the advanced setting include radiotherapy, more potent anti-HER2 agents, as well as genetically engineered T cell receptor or chimeric antigen receptor T cells, and agents targeting T regulatory cells. This task is likely to be a very challenging as it will require more than making “cold” tumors “hot”, as is probable that we will need to find the means that can re-invigorate the whole host immune system in the context of advanced breast cancer. Citation Format: S Loi. Rationale for combination therapies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP086.

Abstract PS17-44: Pd-l1 expression among different subtypes of chinese breast cancer patients

Abstract Background Immunotherapies such as PD-L1 inhibitors have shown promising efficiency in breast cancer (BC) patients. However, treatment responses for immunotherapies are diverse since the immunogenicity of breast cancer is heterogeneous. Specific subtypes such as hormone receptor (HR)-positive, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown heterogeneity in immunogenicity. Therefore, precisely identification of patients potentially benefit from immunotherapy is important. Previous studies have proved PD-L1 expression and tumor mutational burden (TMB) as predictive biomarkers for immunotherapy. Here, we report the PD-L1 expression and TMB status in Chinese BC patients with different subtypes. Using comprehensive molecular analysis, we also characterized the genomic features related to these biomarkers. Methods Tumor samples from 112 Chinese patients with BC were collected and subjected to next-generation sequencing (NGS) and immunohistochemical (IHC) analysis. NGS were performed in a laboratory accredited by College of American Pathologists (CAP) and certified by Clinical Laboratory Improvement Amendments (CLIA) using validated panel targeting 450 cancer genes. Genomic alterations, included including single base substitution, short and long insertions/deletion (Indel), copy number variation, gene fusion, and rearrangement, were assessed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. Tumor tissues were analyzed for PD-L1 expression by IHC with 22C3 or 28-8 antibodies, respectively. Results The 112 Chinese BC patients consisted of 87 HR+ (77.7%), 19 TNBC (17.0%) and 6 HR-/ HER2 + (5.3%), with a median age of 47.5 years old (range 24-81). Of all patients, 42.0% were positive for PD-L1 expression (CPS≥1), including 30.4% PD-L1 (1≥CPS&amp;gt;10) and 11.6% PD-L1 (CPS≥10). PD-L1 expression were observed in HR+ BCs (41.4%) as well as in TNBC (47.4%) and HR-/ HER2+ (33.3%) subtypes, no significant difference were observed among the three subtypes. 8.9% patients were TMB-High (≥10 muts/Mb) with median TMB of 3.4 muts/Mb (range 0-80.8). TMB was slightly correlated with PD-L1 expression (Kendall tau = 0.241; P =0.01). 17.0% of PD-L1 positive patients and 3.1% of PD-L1 negative patients were TMB-High (p=0.016). Patients with PD-L1 CPS≥10 had significantly higher median TMB (7.1 vs. 3.1 muts/Mb, p&amp;lt;0.001). Moreover, patients with TMB-High were significantly elder than TMB-Low (median age, 57.5 vs. 47, p=0.012). In PD-L1 positive patients, the most frequently mutated genes were TP53 (66%), PIK3CA (36%) and ERBB2 (30%); In TMB-High patients, the most frequently mutated genes was PIK3CA (80%), followed by TP53 (60%) and ERBB2 (40%). Conclusion Our data shows that the PD-L1 expression has no significant difference among HR+, TNBC and HR-/ HER2+ subtypes. These data provide the hypothesis that PD-L1 expression positive in different subtype breast cancers may benefit from immune treatment, including HER2 and Luminal subtypes. Otherwise, there was a correlation between PD-L1 expression and TMB, High TMB was also observed in PD-L1 negative patients, which may enrich the subgroup of patients who could benefit from immunotherapy. The verification of integrated predictive biomarkers for immunotherapy in BC is further needed. Citation Format: Ning Liao, Cao Li, Jundong Wu, Bo Chen, Guochun Zhang, Xueri Li, Liping Guo, Guangnan Wei, Jiali Lin, Yingzi Li, Yuchen Zhang, Hsiaopei Mok, Chongyang Ren, Yulei Wang, Kai Li, Cheukfai Li, Lingzhu Wen, Minghan Jia, Tengjiao Lin, Chunyan Cheng. Pd-l1 expression among different subtypes of chinese breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-44.

PD-L1 - inhibitors in neuroendocrine neoplasia: Results from a real-life study.

Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN.

Efficacy and safety of immunological checkpoint inhibitors combined with anti-angiogenic drugs in first-line treatment of metastatic renal cell carcinoma: a systematic review and meta-analysis.

BackgroundImmune checkpoint inhibitors (ICIs) have shown promising results for the second-line treatment of metastatic renal cell carcinoma (mRCC). Several randomized controlled trials have so far also evaluated the efficacy of ICIs for first-line treatment of mRCC. In this study, we conducted a meta-analysis of relevant studies to further clarify the efficacy and safety of ICIs combined with anti-angiogenic drugs for the treatment of mRCC.MethodsWe searched the PubMed, Embase, and Cochrane libraries for RCT trials of ICIs combined with anti-angiogenic drugs for first-line treatment of mRCC published before November 20, 2019. A meta-analysis was conducted based on methodological recommendations by the Cochrane Collaboration.ResultsFour articles with a total of 2,967 patients met the inclusion criteria. Our meta-analysis revealed that progression-free survival (PFS) and objective response rate (ORR) were significantly improved in the experimental group while there was no significant difference in overall survival (OS) (HR 0.75, 95% CI: 0.67–0.84; HR 1.43, 95% CI: 1.07–1.91; HR 0.74, 95% CI: 0.53–1.03). After stratification for PD-L1 expression, OS, PFS, and ORR of PD-L1 positive patients were significantly increased in the experimental group (HR 0.74, 95% CI: 0.56–0.96; HR 1.66, 95% CI: 1.11–2.49; HR 0.65, 95% CI: 0.57–0.75).ConclusionsImmunological checkpoint inhibitors combined with anti-angiogenic drugs as a first-line treatment for mRCC improve PFS and ORR. This effect is more pronounced in PD-L1 positive patients, where ICIs also improve OS. ICIs do not increase the incidence of adverse events.

Prognostic and Predictive Significance of PD-L1 Expression in Non-Small Cell Lung Cancer Patients: A Single-Center Experience.

To investigate the prognostic and predictive value of PD-L1 expression in operated non-small cell lung cancer (NSCLC) patients and to analyze its relationship with clinicopathological factors. A total of 90 patients with operable NSCLC were included in this retrospective single center study. Tumor blocks of patients were stained immunohistochemically with PD-L1 polyclonal antibody. When evaluated immunohistochemically and statistically, patients with tumor staining percentage of ≥5%, those with +2 and +3 membranous staining intensity, and those with ≥50% H-Score were considered positive. The relationship between PD-L1 expression status and clinicopathological features in addition to the prognostic effect of PD-L1 on survival were statistically analyzed. The frequency of PD-L1 expression was 37%, 15% and 5% according to the staining percentage, staining intensity, and the H-Score, respectively. There was no significant relationship between PD-L1 expression and age, gender, smoking, tumor stage and histological subtype (p > 0.05). However, PD-L1 expression was relatively higher in patients < 65 years of age, men, smokers, patients with advanced tumor stage, and squamous cell subtype. Based on the analysis of the H-Score, no significant difference was noted regarding disease-free survival time between PD-L1 positive and PD-L1 negative patients (median 20 [95% CI 1.2-38.7] months vs. median 27 [95% CI 17.5-36] months, p=0.208). However, overall survival time was significantly shorter in PD-L1 positive compared to PD-L1 negative patients (median 24 months [95% CI 9.9-38] vs. median 48 months [95% CI 33.6-62.3], p=0.049). In patients with high PD-L1 expression, the biological behavior of the cancer was more aggressive, and the life expectancy was shorter. PD-L1 expression seems to be a poor prognostic marker in NSCLC patients.

Comparative Efficacy and Safety of Anti-PD-1/PD-L1 Immune Checkpoint Inhibitors for Refractory or Relapsed Advanced Non-Small-Cell Lung Cancer-A Systematic Review and Network Meta-Analysis.

Simple SummaryImproving treatment strategies for refractory or relapsed advanced non-small-cell lung cancer (NSCLC) remains a challenge. Efficacy and safety of the immune checkpoint inhibitors (ICIs), nivolumab (Niv) plus atezolizumab (Atz), were compared with those of ramucirumab (Ram) plus docetaxel (Doc), and the efficacy and safety of these two ICIs were compared with each other, using patient groups without programmed cell death ligand-1 (PD-L1) constraint. Additionally, efficacy and safety of, Niv, Atz, and pembrolizumab (Pem) were compared using a PD-L1 positive (≥1%) subgroup with refractory or relapsed advanced NSCLC. Niv or Atz was found to be more effective and safer than Ram plus Doc in groups without PD-L1 constraint. In the PD-L1 positive subgroup, Pem (10 mg/kg) showed the highest efficacy for ensuring overall survival, followed by Niv, Pem (2 mg/kg), Atz, and Doc. These results may help clinicians select and evaluate treatment options for relapsed or refractory advanced NSCLC.The efficacy and safety of immune checkpoint inhibitors (ICIs) in refractory or relapsed advanced non-small-cell lung cancer (NSCLC) have not yet been compared with those of ramucirumab (Ram) plus docetaxel (Doc). Furthermore, comprehensive comparisons between ICIs have not been conducted to date. In the current study, a Bayesian network meta-analysis of related phase III clinical trials was performed to compare the efficacy and safety of Ram+Doc, Niv, Atz, and Doc treatments in patient groups lacking the PD-L1 constraint. Surface under the cumulative ranking area (SUCRA) revealed that the overall survival (OS) of patients treated with Niv was the highest, followed by Atz, Ram+Doc, and Doc. Regarding grades 3–5 treatment-related adverse events (G3–5AEs), the use of Niv was ranked the safest, followed by Atz, Doc, and Ram+Doc. Significant differences in OS were observed between Niv and Ram+Doc, while significant differences in G3–5AEs were observed between Ram+Doc and Niv or Atz. In the PD-L1 positive (≥1%) patient subgroup, Pem (10 mg/kg) ranked the highest in efficacy for OS, followed by Niv, Pem (2 mg/kg), Atz, and Doc. These findings may expectedly provide oncologists with useful insights into therapeutic selection for refractory or relapsed advanced NSCLC.

CtDNA as a predictor of outcome in patients treated with neoadjuvant atezolizumab in muscle invasive urothelial cancer

To explore the clinical utility of circulating tumor DNA (ctDNA) with neoadjuvant atezolizumab and radical cystectomy (RC) in muscle invasive urothelial bladder cancer (MIUC). Forty patients from a phase II of neoadjuvant atezolizumab (2 cycles) and RC study in MIUC were included (NCT02662309). Whole-exome sequencing was performed on tumor and matched normal DNA to identify tumor-specific mutations and design a personalized multiplexed PCR Next Generation Sequencing (NGS) assay (bespoke, Signatera TM ) for ctDNA detection in plasma. Samples were taken at baseline, post-atezolizumab but pre-surgery, and 1-6 months post-surgery. Response (pathological complete response (pCR) and major pathological response (mPR)) and recurrence free survival (RFS) were correlated with ctDNA status (Pos/Neg) and level. Responders are pCR and mPR patients, whereas non-responders are SD and relapse patients. The pCR rate and 2 years RFS was 21.4% and 73.5%, respectively. ctDNA positivity at baseline, post-neoadjuvant pre-surgery (PreCx), and post-surgery (PostCx) were 25/40 (63%), 14/30 (47%), and 5/36 (14%), respectively. ctDNA status was highly prognostic at all timepoints, where PostCx had an HR of 78.11 (p<0.001), and zero events were observed for ctDNA negative patients at baseline and PreCx. An association between the change in ctDNA during neoadjuvant atezolizumab treatment and patient outcome was observed (mean of -90% ctDNA change in responders versus +27% in non-responders (p=0.04)). Patients who were PDL1 positive at baseline were more likely to be ctDNA positive at baseline (p=0.01), which was not the case for post-treatment time points. For patients who were ctDNA positive at baseline, PDL1-positive patients had better response rates than PDL1-negative (35% vs. 0%), as well as superior RFS (HR=0.11, p=0.0085). Pre-treatment ctDNA positivity was enriched in SCCL (Lund) and basal squamous (TCGA) patients. Tumors from ctDNA positive patients at baseline were enriched for immune signatures and the epithelial to mesenchymal transition (EMT) signature. ctDNA dynamics across timepoints correlates with clinical outcomes, including response rates and RFS in patients treated with neoadjuvant atezolizumab in MIUC. Immune biomarkers may be relevant in these responses. ctDNA may help the development of personalized therapy in this setting in the future.

A systematic review and meta-analysis of PD-1/PD-L1 inhibitors in specific patient subgroups with advanced gastro-oesophageal junction and gastric adenocarcinoma.

immune checkpoint inhibitors(ICIs) have shown contradictory results in patients with advanced gastro-oesophageal junction/gastric cancer(GOJ/GC). to identify specific patient subgroups that would derive survival benefit from ICIs. a subgroup meta-analysis of randomised clinical trials(RCTs) was carried out. four phase-III-RCTs were identified with data on the following variables: primary location(Gastric vs GOJ); age(≤ 65 vs >65); gender(male vs female); ECOG PS(0 vs 1); ethnicity (Asian vs non-Asian), histology(intestinal vs diffuse), PD-L1 expression(≥ 1% vs < 1%). PD-L1 positivity was significantly associated with survival benefit from ICIs (HR: 0.82, p 0.047), with a significant interaction between PD-L1 expression and ICI efficacy (interaction HR: 1.41, p 0.02). Numerically, the second most relevant interaction was ICI efficacy and gender, with ICI being more effective in males. The PD-L1 positive patient subgroup derives significant survival benefit from ICI in GOJ/GC, however other predictors are eagerly needed to further refine patient selection.

Safety and Tolerability Evaluation of Sintilimab in Combination with Low Dose Radiation and SBRT in Treatment Naive Stage IV PD-L1 Positive NSCLC Patients

Immunotherapy has been recommended as first-line standard of care in metastatic NSCLC. Radiotherapy coding with immunotherapy could enhance tumor responses via inducing a synergetic immunologic activity. Our preclinical research and retrospective analysis indicated low dose radiation (LDRT) combing with immunotherapy after SBRT had potential synergic anti-tumor effect. This study aims to explore the safety and tolerability of this new combination strategy. This is a phase I study includes a dose escalation phase (Ia) and a dose expansion phase (Ib) with at least 29 stage IV NSCLC patients. Eligible patients should be PD-L1 positive (TPS ≥ 1%), and has at least 3 extra-cranial tumor lesions. During phase Ia, patients will receive SBRT (30Gy/3f) to a small lesion, followed by LDRT to a large lesion at 3 dose levels (L1: 2Gy/1f, L2: 4Gy/2f, L3: 10Gy/5f) starting from the first day of SBRT. Sintilimab (200mg i.v., q3w) will start within 7 days after radiation completed until PD, unacceptable toxicities, withdrawal, or reaches a maximum of 24 months. If no DLT occurs with ≥ 1 PR in any dose level, will enroll 3 more patients. 20 patients receiving a recommended LDRT dose based on the result of phase Ia will then be enrolled in phase Ib to obtain additional safety and response data. Primary endpoint was safety and tolerability; secondary endpoints include ORR, PFS, and OS. From 4/2019 to 1/2020, the dose escalation phase was completed with no dose limiting toxicities observed. In total, 12 patients were enrolled. Most patients were male (91.7%) with adenocarcinoma (66.7%). 41.7%patients had PD-L1 expression≥50% (TPS, 22C3). 6patients were enrolled in L1, and 3 in both L2 and L3, separately. The most common toxicity was hypothyroidism (3/10, G1). One patient in L2 experienced G2 radiation-related pneumonitis and one patient in L1 experienced G2 immune-related pneumonitis. No≥ grade 3 AEs were observed. Until January 1th 2020, 10 patients received at least once tumor assessment. ORR was 70%, including 4/6 patients in L1 and 3/3 patients in L2. One patient in L3 achieved SD. Through immune related biomarkers analysis in peripheral blood samples, we found that the combination therapy increased the number of T-cell clones and TCR diversity, while at the same time decreased the PD-1 expression on CD8+T cell and ctDNA. The combination of SBRT + LDRT+ sintilimab is safe and tolerable. LDRT at 4Gy/2f seems to have better tumor response. This report is the first to document the use of SBRT + LDRT+ ICIs for the fist-line treatment of metastasis NSCLC. Clinical trial information: NCT03812549.

Abstract 2680: Exploration of tumor environment classification using mIHC in pan-cancer tissue samples

Abstract Background: Besides three major biomarkers (PD-L1, TMB and MSI), tumor immune microenvironment is also elemental to predict how patients respond to immunotherapy and their prognosis. According to PD-L1 expression and tumor infiltrating lymphocytes, the tumor environment was classified into four types by Chen L. The multiplex immunohistochemistry (mIHC) provides the possibility to characterize the infiltrating immune cells in a single tissue section and classified patients more precisely with multi-biomarkers. Methods: We collected FFPE tissues from 170 cancer patients and performed Tumor Immune Microenvironment tests using a validated commercial assay, which included PD-L1 test (22C3, DAKO) and 7-plex mIHC to quantify and locate CD8+ T cells, M1 macrophages, M2 macrophages, CD56dim NK cells and CD56bright NK cells. CD8+ T cell positive was defined as ≥median CD8+ T cells density (cells/mm2) in tumor. Positive PD-L1 expression was defined as ≥1% of tumor cells with membranous staining(TPS). Results:In our study, the tissues were collected from colorectum cancer(n=46), biliary tract cancer(n=40), liver cancer(n=38), lung cancer(n=18)and others (n=28). Of the 170 patients, 44.1% were identified as tumor environment Type I (PDL1- /CD8-),11.1% Type II (PDL1+ /CD8+),38.8% Type III (PDL1- /CD8+) and 5.9% Type IV (PDL1+ /CD8-). Type II patients were the most likely subgroup benefit from anti-PD1/PDL1 therapy, who make up 22.2%, 12.5%, 7.8% and 4.3% in Lung, biliary tract cancer, liver cancer, colorectum cancer, respectively. We used unsupervised clustering to cluster patients into 3 groups: immune hot, immune cold and intermediate immunosuppressed, according to the above five kinds of immune cells. The immune hot environment was rich in immune cells and the immune cold environment was lack of immune cells, between which was the intermediate immunosuppressed environment. The proportion of immune hot was 23.5% in 170 patients, 44.8% in PDL1 positive patients and 19.1% in PDL1 negative patients. In addition, no correlation between Immune cells density in tumor /stroma and PD-L1 expression was observed. In our cohort, there was one lung adenocarcinoma patient, female, 37 years old, had positive PDL1 expression (TPS=95%), low TMB, MSS, EGFR/ALK- and carried KRAS G12D mutation, but was identified as immune cold tumor environment, who also had lower immune cell density in tumor than in stroma. During three months of receiving pembrolizumab plus pemetrexed and carboplatin, she quickly had multiple sites metastases. Conclusions: In our study, PDL1 expression and Tumor immune microenvironment are independent. And tumor immune microenvironment varies between Cancer types. Taking multi-biomarkers into consideration might help to evaluate immunotherapy response and resistance comprehensively. Citation Format: Tianhang Luo, Bei Zhang, Yifan Zhou, Fei Wang, Hui Chen, Xiaochen Zhao, Yuezong Bai, Li Li. Exploration of tumor environment classification using mIHC in pan-cancer tissue samples [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2680.

Abstract 2160: Immune escape mutations in HLA Class I, B2M and CASP8 genes shape tumor evolution

Abstract The immune system has several mechanisms to recognize tumor cells as foreign and eliminate them. Somatically altered genes can create peptides, or neoantigens, that class I HLA (HLA-I) molecules can present to cytotoxic T-cells. As a result, people with suppressed immune systems commonly have a higher rate of cancer. PanCancer data of 9423 tumor exomes from the Cancer Genome Atlas project identified 299 frequently mutated cancer genes, 4 of which (HLA-A, HLA-B, beta-2-microglobulin (B2M), and caspase-8 (CASP8) are associated with the neoantigen presentation system. By mutating genes essential to immune recognition and cytotoxicity, tumors can escape the immune system. Tumors with a high mutation burden (MB) and thus more neoantigens experience even greater pressure to mutate HLA-I genes to escape detection. Therefore, the immune system shapes tumor evolution. Tumors with a higher mutation burden respond more effectively to immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-CTLA-4 drugs. However, there are many PD-L1 positive patients who fail to respond. These patients may have immune escape (IE) mutations inhibiting neoantigen presentation to T-cells, and a database of immune escape mutations would help inform cancer treatment and improve response to immunotherapy. From the TCGA Pan-Cancer dataset we identified samples with mutations in HLA-A, HLA-B, HLA-C and mutations or loss of B2M or CASP8. We also identified samples with microsatellite instability (MSI) and mutations in DNA Polymerase E (POLE), both of which are associated with high mutation burden. We predicted individual HLA genotypes using multiple programs and aligned tumor and normal reads to these alleles, and called mutations. We used the Integrative Genome Viewer, to validate the mutations and used multiple programs to identify potential functional effects of missense mutations. Finally, we used chi-squared tests to find associations between genes and phenotypes. There were substantially more mutations in HLA-A and HLA-B genes than in HLA-C. Loss-of-function (LoF) mutations accounted for over 50% of the mutations in HLA-A and 54% in HLA-B, but are significantly suppressed (25%) in HLA-C (X2=21; P=3 × 10-5). Since all HLA-C alleles are ligands for natural killer (NK) cell receptors (KIR) this indicates that NK cell recognition of tumor cells is important. Over 90% of HLA-I missense variants were predicted to be functional (likely to impact the stability, membrane localization, B2M binding, peptide binding of the protein, the signal peptide or T cell recognition). Cervical, head and neck, stomach, colon and lung cancer have the highest level of IE mutations (9-20%). Immune escape mutations were significantly higher in MSI (45%) and POLE mutated (72%) tumors as compared to MSI- and POLE wild type tumors (3.9%, X2=470 P&amp;lt;&amp;lt;0.0001). An increased knowledge of these IE mutations can be useful in identifying tumor or patient subsets that may respond better to ICI therapies. Citation Format: Megan Ren, Mathias Viard, Arman Bashirova, Meredith Yeager, Lisa Mirabello, Mary Carrington, Michael Dean. Immune escape mutations in HLA Class I, B2M and CASP8 genes shape tumor evolution [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2160.

Abstract 868: Prediction of clinical benefit to checkpoint blockade in advanced NSCLC patients using radiomics of PET/CT images

Abstract Immunotherapy has emerged as a one of the most successful treatment approach in advanced Non-small Cell Lung Cancer (NSCLC) patients. However, only 25-50% patients obtain durable clinical benefit (DCB), and 7-43% patient may suffer from immune-related severe adverse events. Therefore robust biomarkers that are predictive of response immune-checkpoint blockades at baseline are needed. Though PD-L1 expression by immunohistochemistry (IHC) is the only clinically-approved biomarker to trigger treatment decisions, sampling bias and the dynamic nature of PD-L1 expression can affect the final results. In this study, we investigated the value of PET/CT images in the predicting progression-free survival (PFS) and overall survival (OS) of immunotherapy in advanced NSCLC patients. The retrospective arm of this study included 400 patients with histologically-confirmed NSCLC, and these were split into training (N=284) and test (N=116) cohorts. A residual-convolutional-network model was developed to generate a deep learning score (PDL1-DLS) to predict the PD-L1 expression status with PET/CT images. Another 146 retrospective patients with histologically confirmed stage IIIB-IV NSCLC treated with immunotherapy (IO) were split into training (N=99) and test (N=47) cohorts, and a multiparametric radiomics signature (mpRS) generated from conventional PET and CT radiomics features was developed to predict DCB using an improved least absolute shrinkage and selection operator (LASSO) method. Subsequently, multivariable Cox regression models for PFS and OS prediction were trained with the mpRS, PDL1-DLS, and clinical characteristics, and these were further validated with 48 prospective IO-treated NSCLC patients. The PDL1-DLS significantly discriminated PD-L1 positive and negative patients with AUCs of 0.89 (95%CI:0.84-0.94) and 0.84 (95%CI:0.76-0.92) for training and test cohorts. The mpRS could predict DCB with AUCs of 0.86 (95%CI:0.79-0.94) and 0.83 (95%CI:0.71-0.94) in the training and test cohorts. In both retrospective and prospective IO-treated cohorts, the combination of binarized PDL1-DLS and binarized mpRS significantly improved the prediction of PFS and OS compared to single binarized PDL1-DLS (PFS: p&amp;lt;0.001, OS: p&amp;lt;0.001) or single binarized mpRS (PFS: p&amp;lt;0.040, OS: p&amp;lt;0.10). Subsequent multivariable Cox regression models identified binarized mpRS, binarized PDL1-DLS, ECOG, and histology as significant independent variables, and could achieve significant higher C-indices of 0.75 (95%CI:0.70-0.79) and 0.79 (95%CI:0.73-0.86) in prediction of PFS, 0.79 (95%CI:0.73-0.85) and 0.76 (95%CI:0.61-0.92) in prediction of OS in the retrospective and prospective IO-treated cohorts. We have therefore observed that, prior to therapy initiation, PET/CT fusion images can be used independently to predict PD-L1 status or DCB of immunotherapy in advanced NSCLC patients. Both of these models can be leveraged to improve more precise and individualized decision support in the treatment of patients with advanced NSCLC. Citation Format: Wei Mu, Ilke Tunali, Jhanelle E. Gray, Jin Qi, Matthew B. Schabath, Robert J. Gillies. Prediction of clinical benefit to checkpoint blockade in advanced NSCLC patients using radiomics of PET/CT images [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 868.

Pharmacoeconomic analysis of atezolizumab plus nab-paclitaxel in the treatment of the advanced or metastatic triple-negative breast cancer

Objective.To determine the pharmacoeconomical feasibility of using a combination of atezolizumab + nab-paclitaxel in the 1st line of therapy for locally advanced or metastatic triple negative breast cancer (TNBC) in adult PDL1 positive patients in the Russian healthcare system.Materials and methods.A decision analysis model was used followed by Markov modelling for the economic evaluation of the drugs in the treatment of metastatic TNBC. We used the «cost-effectiveness» analysis and the «impact on the budget» (BIA) analysis. Two therapeutic approaches were evaluated: the use of combined therapy with atezolizumab + nab-paclitaxel and monotherapy with nab-paclitaxel. The analysis included direct costs. Additionally, the obtained pharmacoeconomical indicators of the use of a combination of atezolizumab and nab-paclitaxel and other drugs for the treatment of locally advanced and metastatic breast cancer were compared.Results. The use of the estimated therapeutic approaches in the treatment of metastatic TNBC was characterized by the following costs: with a modelling horizon of 1 year, the cost of using atezolizumab in combination with nab-paclitaxel was 5,076,321 rubles per patient. The costs for the use of single agent nab-paclitaxel with was 60 % less than: — 2 020 038,78 RUB. At the same time, the effectiveness of therapy with a combination of atezolizumab and nab-paclitaxel clinically significantly exceeded that of nab-paclitaxel monotherapy: a 38 % reduction in the risk of death or progression, a 10-fold increase in the frequency of complete response to therapy (10 vs 1 %), and a 7-month increase in the median overall survival (25 vs 18 months). The economic evaluation of the combination of atezolizumab with nab-paclitaxel was carried out with the calculation of the incremental cost-effectiveness ratios (ICER) — the calculation of the additional cost for each additional year of life in comparison with standard therapy. Due to the fact that currently in Russia for patients with metastatic TNBC no similar performance modes of therapy ICER for the combination atezolizumab + nab-paclitaxel compared with the ICER for palbociclib in combination with fulvestrant (drugs, showed improved overall survival in clinical research and included in clinical guidelines for the treatment of diseases of the same class ICD-10 in locally advanced and metastatic breast cancer). The ICER for overall survival at the end of the first year of follow-up for atezolizumab + nab-paclitaxel and palbociclib + fulvestrant was 30.5 million rubles and 47.4 million rubles, respectively. For the combination of atezolizumab + nab-paclitaxel, ICER is lower than the similar ICER for the palbociclib + fulvestrant mode by 36 %. Analysis of trends in the weighted average cost of systemic pathogenetic treatment of breast cancer (breast cancer) shows the following: increased use of the combination of atezolizumab + nab-paclitaxel for the treatment of patients with metastatic TNBC doesn’t lead to a considerable growth in the cost of therapy in patients with breast cancer — providing therapy to 1400 patients that includes the entire target population of patients with TNBC and expression of PD-L1 in Russia changes in the costs of chemotherapy and immunotherapy of breast cancer will remain within 2.6 %.Conclusion. Pharmacoeconomic indicators of the use of atezolizumab in combination with nab-paclitaxel are more cost-effective in comparison with other expensive schemes for the treatment of breast cancer, and tumors of other localities that are actively used in current practice, which suggests the acceptability and feasibility of introducing and expanding the use of this therapeutic option in the target population.

Pembrolizumab versus paclitaxel for previously treated patients with PD-L1–positive advanced gastric or gastroesophageal junction cancer (GC): Update from the phase III KEYNOTE-061 trial.

4503 Background: KEYNOTE-061 ( NCT02370498) is a global phase 3 study of pembrolizumab vs paclitaxel as second-line therapy for GC. At the time of primary analysis (data cutoff: Oct 26, 2017), in patients with PD-L1–positive status (combined positive score [CPS] ≥1), pembrolizumab did not significantly prolong overall survival (OS) vs paclitaxel (9.1 months vs 8.3 months) but did elicit a longer duration of response (DOR) and a favorable safety profile vs paclitaxel. We present results of KEYNOTE-061 in patients with CPS ≥1, ≥5, and ≥10 after 2 additional years of follow-up (cutoff: Oct 7, 2019). Methods: Adult patients with GC that progressed after platinum + fluoropyrimidine chemotherapy were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for up to 35 cycles (~2 y) or standard-dose paclitaxel. OS and progression-free survival (PFS) in the CPS ≥1 population were the primary end points. Comparisons were made using stratified log-rank tests. Results: At the time of this analysis, 366/395 patients with CPS ≥1 had died (92.6%). Pembrolizumab prolonged OS vs paclitaxel in PD-L1–positive patients (Table). No significant differences appeared between groups in PFS (Table). Objective response rate (ORR) was higher for pembrolizumab in the CPS ≥10 group, and DOR was longer with pembrolizumab using all CPS cutoffs (Table). There were fewer drug-related adverse events (AEs) with pembrolizumab than paclitaxel in the overall population (53% vs 84%). Conclusions: This long-term analysis found that second-line pembrolizumab prolonged OS among patients with PD-L1–positive GC and led to fewer drug-related AEs vs paclitaxel. Clinical trial information: NCT02370498 . [Table: see text]