OS Analysis Research Articles

Efficacy of olaparib therapy in metastatic pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency (HRD).

e16266 Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T > C, gCHEK2 c.1461+1 G > A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease > 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.

ESCORT-1st: A randomized, double-blind, placebo-controlled, phase 3 trial of camrelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced or metastatic esophageal squamous cell carcinoma (ESCC).

4000 Background: The current standard first-line therapy for advanced or metastatic ESCC is doublet chemotherapy, and prognosis remains poor. Camrelizumab, a humanized anti-PD-1 monoclonal antibody, has shown promising antitumor activity in previously treated advanced or metastatic ESCC (Huang et al. Lancet Oncol 2019). Immunotherapy may work synergistically with chemotherapy, but lacking clinical evidences in ESCC. Here, we report the findings of the phase 3 ESCORT-1st study which evaluated the efficacy and safety of camrelizumab plus chemotherapy vs chemotherapy in patients with untreated advanced or metastatic ESCC. Methods: Eligible patients were randomized 1:1 to receive camrelizumab 200 mg or placebo, both combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All were given intravenously Q3W. Tumor response was assessed every 6 weeks according to RECIST v1.1. Co-primary endpoints were OS and independent review committee (IRC)-assessed PFS. Efficacy was assessed in all randomized patients and safety was assessed in all treated patients. Data cutoff date for the prespecified interim OS and final PFS analysis was Oct 30, 2020. Results: From Dec 3, 2018 to May 12, 2020, 596 patients were randomized. 298 patients were treated with camrelizumb-chemotherapy and 297 patients with placebo-chemotherapy. With a median follow-up of 10.8 months, camrelizumab plus chemotherapy significantly improved OS compared with placebo plus chemotherapy (median, 15.3 month [95% CI 12.8-17.3] vs 12.0 months [11.0-13.3]; HR, 0.70 [95% CI, 0.56-0.88]; one-sided P = 0.0010). Camrelizumab plus chemotherapy was also superior for PFS (per IRC) vs placebo plus chemotherapy (median, 6.9 months [95% CI, 5.8-7.4] vs 5.6 months [95% CI, 5.5-5.7]; HR, 0.56 [95% CI, 0.46-0.68]; one-sided P < 0.0001). ORR per investigator was 72.1% in camrelizumab-chemotherapy group vs 62.1% in placebo-chemotherapy group, and median DoR was 7.0 vs 4.6 months. Incidences of grade ≥3 treatment-related AEs were comparable between the two groups (63.4% vs 67.7%), with decreased neutrophil count (39.9% vs 43.4%) as the most common one. Serious treatment-related AEs occurred in 30.2% vs 23.2% of patients, and treatment-related deaths occurred in 3.0% vs 3.7% of patients, respectively. Conclusions: Addition of camrelizumab to chemotherapy provided superior OS and PFS vs placebo plus chemotherapy, with a manageable safety profile. Camrelizumab in combination with paclitaxel and cisplatin has the potential to become a new standard first-line therapy in patients with advanced or metastatic ESCC. Based on this trial, we are submitting NDA to seek the approval from China National Medical Products Administration for camrelizumab plus chemotherapy in the treatment of untreated advanced or metastatic ESCC. Clinical trial information: NCT03691090.

Update analysis of NEJ009: Gefitinib alone (G) versus gefitinib plus chemotherapy (GCP) for non-small cell lung cancer with mutated EGFR.

9081 Background: NEJ009 study is the first randomized phase III trial that compared gefitinib plus chemotherapy with gefitinib in patients with untreated NSCLC harboring EGFR mutations. We report an updated OS and long-term tolerability analysis, including subgroup analyses focusing on a type of EGFR mutation and metastatic sites. Methods: Patients were randomly assigned to gefitinib (gefitinib 250 mg PO, QD) and GCP regimen (gefitinib 250 mg PO, QD combined with carboplatin AUC 5 and pemetrexed 500 mg/m2 in a 3-week cycle for up to six cycles, followed by concurrent gefitinib and pemetrexed maintenance). This study tested multiple primary endpoints, PFS, PFS2, and OS, which were analyzed using a preplanned hierarchical sequential testing method. Results: Three hundred forty-five patients were randomly assigned (gefitinib, n = 172; GCP, n =170). At latest data cut-off (May 22, 2020), although there was no significant difference in OS between the groups (HR, 0.82; 95% CI, 0.64 to 1.06; P=0.13), GCP still demonstrated significantly better PFS and PFS2 compared to G. The updated median PFS, PFS2, and OS was 11.2 months, 18.0 months, and 38.5 months in the gefitinib group and 20.9 months, 20.9 months, and 49.0 months in the GCP group, respectively. No severe adverse events occurred in the period since the first report. Conclusions: This updated analysis confirmed that the GCP regimen achieved significantly better PFS and PFS2 with an acceptable safety profile compared with gefitinib alone. The efficacy outcome of GCP is more favorable than gefitinib monotherapy as first-line treatment of NSCLC with EGFR mutation. Clinical trial information: UMIN000006340. Clinical trial information: UMIN000006340. [Table: see text]

Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC).

4561 Background: In the phase 3 CM 9ER trial (NCT03141177), N+C significantly improved progression-free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p < 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p < 0.0001) vs S in 1L aRCC (Choueiri, 2020). N+C was generally well tolerated with low rates of treatment-related discontinuations, indicating successful adverse event (AE) management with dose modification to maintain tolerability. Here the impact of C exposure on efficacy and safety outcomes in CM 9ER was evaluated using ER analysis. Methods: Patients (pts, N = 320) with previously untreated aRCC received C 40 mg QD in combination with N 240 mg Q2W; dose reductions of C to 20 mg QD or 20 mg Q2D were allowed to manage AEs. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between predicted C exposure or apparent clearance (CL/F) and specified endpoints, including PFS, dose modification, and select AEs (palmar-plantar erythrodysesthesia [PPE; Gr ≥1], diarrhea [Gr ≥3], hypertension [Gr ≥3], fatigue/asthenia [Gr ≥3], and ALT/AST elevation [Gr ≥3]). C exposure was defined as the overall average concentration from time zero to the time of event or censoring (CAVG) and estimated by population pharmacokinetic modeling for a typical patient. ER analysis for OS was not done due to the low number of events at the database lock date (March 30, 2020). Results: In the ER analysis of PFS, predicted C exposure at 40-mg and 20-mg QD doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of AEs, lower predicted C exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation. Higher predicted C CL/F was associated with a lower rate of C dose modification; however, this association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr). Conclusions: In ER models of pts with 1L aRCC treated with the combination of N+C, C exposure was not significantly associated with PFS; however, higher C exposure was associated with higher rates of PPE and diarrhea. ER modeling predicts that a starting dose of 40 mg QD C in combination with N with appropriate dose modifications to manage C AEs will not adversely affect the efficacy of the combination in 1L aRCC. Clinical trial information: NCT03141177.

Investigation of prognostic factors for second-line treatment with nivolumab for unresectable or recurrent esophageal cancer.

e16055 Background: Nivolumab, an immune-checkpoint inhibitor for unresectable or recurrent esophageal cancer is used as second-line treatment. On the other hand, the relationship between indicators of cancer immunity (GPS, NLR, PLR), indicators of nutritional status (PNI, BMI), and prognosis of patients treated with nivolumab is unclear. Methods: We investigated the prognostic factors of nivolumab for unresectable or recurrent esophageal cancer. The subjects were 62 patients who received nivolumab as a second-line or later treatment for unresectable or recurrent esophageal cancer before January 2021. Of these 13 patients had previously been treated with taxan. We used GPS (Glasgow prognostic score), NLR (Neutrophil-Lymphocyte Ratio: cutoff value is 3.5), PLR (Platelet-Lymphocyte Ratio: cutoff value is 200), PNI (Prognostic nutrition index: cutoff value is 40), BMI (Body mass index: cutoff value is 18.5 for under 70 years old, and 20 for over 70 years old defined by Asian GLIM standard) as prognostic indicators. We examined the association between age, gender, PS, GPS, NLR, PLR, PNI, BMI and prognosis in patients treated with nivolumab. And we also examined the relationship between the history of taxan administration, the presence of adverse events and the prognosis. Results: Of the 62 cases, 48 cases were male and 14 cases were female. The median age was 70 years. Median OS was 359 days, and median PFS was 97 days. OS in patients with no prior taxan treatment group was significantly longer (P<0.05). AE appeared in 49 cases (79%), and irAE appeared in 22 cases (35.5%). OS in patients with irAE was significantly longer (P<0.01). PS (0/1/2) was 27 cases/33 cases/2 cases, and GPS (0 point/1 point/2 point) was 41 cases/11 cases/10 cases. NLR high was 35 cases, and NLR low was 27 cases. PLR high was 31 cases and PLR low was 31 cases. PNI high was 46 cases and PNI low was 16 cases. BMI normal or high was 27 cases and BMI low was 35 cases. In univariate analysis of OS, GPS (P<0.001), NLR (P<0.01), PS (P<0.05), PNI (P<0.001) showed a significant difference in survival, and in multivariate analysis, PS (p<0.05) and PNI (P<0.05) were significant prognostic factors. Conclusions: PS and PNI were good prognostic factors with nivolumab after second or later treatment for unresectable or recurrent esophageal cancer.

Prognostic role of clinical and biological factors and parameters of hormonal profile in patients with primary inoperable HER2-negative breast cancer

Relevance. Breast cancer (BC) is among the most common cancers and the leading causes of cancer death in women worldwide. Much attention is paid to the problem of its hormoneresistance; however, the issues of using prognostic markers and predictors in routine cancer clinical practice remain unresolved.
 Aim. Study and analysis of prognostic significance of clinical and biological factors and parameters of the hormonal profile in patients with primary inoperable HER2-negative breast cancer receiving neoadjuvant chemotherapy.
 Materials and methods. The study included 162 patients with locally advanced primary inoperable HER2-negative breast cancer. Patients were divided into 2 groups. Group 1 included 58 patients with early disease progression within 6 to 12 months after radical surgical treatment. Group 2 included 104 patients with no disease progression within 2 years after radical surgical treatment. In all cases, diagnosis was verified histologically and immunohistochemically. Levels of prolactine, progesterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone, testosterone and cortisol were measured by RIA. The blood plasma values in 20 healthy donors were used as reference one. The data were processed using the Statistica 7.0 and MedCalc (version 9.3.5.0) programs. All patients received combination antitumor treatment according to clinical guidance.
 Results. An analysis of the overall (OS) and event-free (EFS) survival in group 1 showed that the median EFS in patients with luminal B BC was 9 months, with triple-negative BC (TNBC) 8 months. 6-month EFS in luminal B subtype was 87.5%, in TNBC 79.4%, p=0.37985. 1-year EFS was 1.721.7% regardless of the biological subtype. The median OS in luminal B BC was 25 months, in TNBC 26 months. 1-year OS in luminal B BC 100%, in TNBC 93.9%, p=0.138. 2-year OS in luminal B BC 54.2%, in TNBC 55.9%, p=0.697. 3-year survival in luminal B BC 37.5%, in TNBC 41.2%, p=0.639. An analysis of OS and EFS in group 2 showed that the median EFS was not reached for all biological subtypes. 3-year survival in the group was 100% regardless of the biological subtype. The median OS was not reached for all biological subtypes. 3-year OS in the group was 100%. An analysis of the hormonal profile in the treatment dynamics showed decreased levels of estradiol in all groups of patients (by 1.6 times). In group 1, progesterone was decreased by 2.1 times, testosterone by 2.4 times and LH by 2.1 times in all BC subtypes (p0.05). Patients of group 2 showed 2 times reduced cortisol and 3 times reduced prolactin in all BC subtypes, while LH levels were elevated by 1.6 times in luminal A and B BC.
 Conclusion. Aggressive course was observed similarly in triple-negative cancer as well as in luminal cancer with primary hormone resistance. Studying of pituitary and sex hormones and cortisol have a great clinical significance in patients with all biological subtypes of BC. This should be taken into account when predicting the course of the disease and developing further treatment options.

Prognostic significance of survivin expression in pediatric ewing sarcoma

Survivin is an inhibitor of apoptosis protein that inhibits caspases and blocks cell death. It is undetectable in most normal adult tissues. High survivin expression has been detected in various tumors and has been correlated with therapy resistance and poor outcome. We conducted this study to examine survivin expression in pediatric Ewing sarcoma (ES) and evaluate its role in predicting clinical outcome. Formalin-fixed paraffin-embedded tumor tissues from 108 pediatric ES patients were examined by immunostaining with survivin rabbit monoclonal antibodies. Survivin was detected in tumor tissues of 72 (66.7%) patients. High expression (≥50%) was detected in 18 (16.7%) patients. High survivin expression was shown to be a significant univariate parameter for poorer overall (OS) and event free survival (EFS) with p value 0.033, and 0.037 respectively. It was confirmed as an independent factor in multivariate analysis for OS (p: 0.041; HR: 1.97 with 95% CI of 1.03-3.79) and EFS (p: 0.049; HR: 1.86 with 95% CI of 1.00-3.46). These results suggest that high survivin expression identifies a group of patients with poor prognosis and this may help to refine risk adapted treatment; however, this needs to be confirmed in prospective studies.

Gemcitabine/nab-Paclitaxel versus FOLFIRINOX for palliative first-line treatment of advanced pancreatic cancer: A propensity score analysis

BackgroundGemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed. MethodsWe conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX. ResultsIn unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329). ConclusionThis real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.

Gene expression and immune infiltration in melanoma patients with different mutation burden

BackgroundImmunotherapy is a vital component in cancer treatment. However, due to the complex genetic bases of cancer, a clear prediction index for efficacy has not been established. Tumor mutation burden (TMB) is one of the essential factors that affect immunotherapeutic efficacies, but it has not been determined whether the mutation is associated with the survival of Skin Cutaneous Melanoma (SKCM) patients. This study aimed at evaluating the correlation between TMB and immune infiltration.MethodsSomatic mutation profiles (n = 467), transcriptome data (n = 471), and their clinical information (n = 447) of all SKCM samples were downloaded from The Cancer Genome Atlas (TCGA) database. For each sample, TMB was calculated as the number of variants per megabase. Based on K-M survival analysis, they were allocated into the high-TMB and low-TMB groups (the optimal cutoff was determined by the ‘surv_cutpoint’ algorithm of survival R package). Then, Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) were performed, with immune-associated biological pathways found to be significantly enriched in the low-TMB group. Therefore, immune genes that were differentially expressed between the two groups were evaluated in Cox regression to determine their prognostic values, and a four-gene TMB immune prognostic model (TMB-IP) was constructed.ResultsElevated TMB levels were associated with better survival outcomes in SKCM patients. Based on the cutoff value in OS analysis, they were divided into high-TMB and low-TMB groups. GSEA revealed that the low-TMB group was associated with immunity while intersection analysis revealed that there were 38 differentially expressed immune-related genes between the two groups. Four TMB-associated immune genes were used to construct a TMB-IP model. The AUC of the ROC curve of this model reached a maximum of 0.75 (95%CI, 0.66–0.85) for OS outcomes. Validation in each clinical subgroup confirmed the efficacy of the model to distinguish between high and low TMB-IP score patients.ConclusionsIn SKCM patients, low TMB was associated with worse survival outcomes and enriched immune-associated pathways. The four TMB-associated immune genes model can effectively distinguish between high and low-risk patients.

Allelic Expression Imbalance Analysis Identified YAP1 Amplification in p53- Dependent Osteosarcoma.

Simple SummaryOsteosarcoma (OS) is a highly heterogenous cancer, making the identification of genetic driving factors difficult. Genetic factors, such as heritable mutations of Rb1 and TP53, are associated with an increased risk of OS. We previously generated pigs carrying a mutated TP53 gene, which develop OS at high frequency. RNA sequencing and allelic expression imbalance analysis identified an amplification of YAP1 involved in p53- dependent OS progression. The inactivation of YAP1 inhibits proliferation, migration, and invasion, and leads to the silencing of TP63 and reconstruction of p16 expression in p53-deficient porcine OS cells. This study confirms the importance of p53/YAP1 network in cancer.Osteosarcoma (OS) is a primary bone malignancy that mainly occurs during adolescent growth, suggesting that bone growth plays an important role in the aetiology of the disease. Genetic factors, such as heritable mutations of Rb1 and TP53, are associated with an increased risk of OS. Identifying driver mutations for OS has been challenging due to the complexity of bone growth-related pathways and the extensive intra-tumoral heterogeneity of this cancer. We previously generated pigs carrying a mutated TP53 gene, which develop OS at high frequency. RNA sequencing and allele expression imbalance (AEI) analysis of OS and matched healthy control samples revealed a highly significant AEI (p = 2.14 × 10−39) for SNPs in the BIRC3-YAP1 locus on pig chromosome 9. Analysis of copy number variation showed that YAP1 amplification is associated with the AEI and the progression of OS. Accordingly, the inactivation of YAP1 inhibits proliferation, migration, and invasion, and leads to the silencing of TP63 and reconstruction of p16 expression in p53-deficient porcine OS cells. Increased p16 mRNA expression correlated with lower methylation of its promoter. Altogether, our study provides molecular evidence for the role of YAP1 amplification in the progression of p53-dependent OS.

FP13.03 IMpower110: Updated OS Analysis of Atezolizumab vs Platinum-Based Chemotherapy as First-Line Treatment in PD-L1–Selected NSCLC

FP13.03 IMpower110: Updated OS Analysis of Atezolizumab vs Platinum-Based Chemotherapy as First-Line Treatment in PD-L1–Selected NSCLC

Age and comorbidity are determining factors in the overall and relative survival of patients with follicular lymphoma.

Frailty and concurrent medical conditions are crucial factors in the management of follicular lymphoma (FL). We evaluated the impact of age and comorbidity on survival, causes of death, histological transformation (HT), and second malignancies (SM) in a large single-center series of grade 1-3A FL. We studied 414 patients diagnosed in the rituximab era, categorized into three age groups (≤60, 61-70, >70 years) and two comorbidity groups (Charlson Comorbidity Index, CCI, 0-1 and ≥2). Despite a similar cumulative incidence of relapse, older and comorbid patients had a lower 10-year overall survival (OS, 88, 65, and 41% for patients ≤60 years, 61-70 years, and >70 years, P<0.0001; and 76 vs. 51% for CCI 0-1 and ≥2, P<0.0001). In a multivariate analysis for OS, comorbidity retained its prognostic impact (HR=2.5, P=0.0003). The proportion of patients dying due to FL was higher among those ≤60 years (74%) and those with a CCI 0-1 (67%). Furthermore, 10-year excess mortality (survival reduction) was more prominent for patients >70 years (30%) and those with a CCI ≥2 (32%). Patients with a CCI ≥2 also had a higher incidence of SM. These data encourage a comprehensive pre-treatment evaluation and a tailored therapeutic approach for all FL patients.

Post-hoc analysis of long-term outcomes in patients with CR, PR, or SD to pembrolizumab (pembro) or platinum-based chemotherapy (chemo) as 1L therapy for advanced urothelial carcinoma (UC) in KEYNOTE-361.

435 Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]

Impact of subsequent therapy on survival in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as first-line therapy for advanced urothelial carcinoma (UC).

439 Background: The phase III KEYNOTE-361 study examined the efficacy and safety of 1L pembro + chemo or pembro alone vs chemo for pts with advanced UC. The PFS and OS benefit of pembro + chemo vs chemo did not reach statistical significance; no further formal tesing was done. We present an exploratory analysis of OS by subsequent therapy in KEYNOTE-361 (NCT02853305) to assess how 1L and 2L therapy selection affected survival outcomes; no formal comparisons were conducted. Methods: OS was estimated for pts by whether they received subsequent therapy, and by whether subsequent therapy included an anti–PD-(L)1 agent. Results: 351 pts were randomized to pembro + chemo, 307 pts to pembro, and 352 pts to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. 124/351 pts (35%) in the pembro + chemo arm, 126/307 pts (41%) in the pembro arm, and 215/352 pts (61%) in the chemo arm received any subsequent therapy. Similar rates of subsequent therapy (pembro + chemo: 32%; pembro: 43%; chemo: 59%) were observed for pts who experienced progressive disease (PD) by blinded independent central review (BICR). A higher rate of pts (169/352 [48%]) in the chemo arm received subsequent anti–PD-(L)1 therapy than in either the pembro + chemo arm (23/351 [7%]) or pembro arm (14/307 [5%]). Due to the small pt numbers, pts in the pembro + chemo or pembro arms who received subsequent anti−PD-(L)1 were not considered further. This analysis included all pts who received 2L therapy (465/1010 pts [46%]); the rate of 2L therapy was similar in pts with PD by BICR (274/615 [45%]). Chemo agents alone or in combination, specifically carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, and paclitaxel, were the most commonly received subsequent therapies for pts who did not receive anti–PD-(L)1 in 2L. Pts who received 1L chemo followed by subsequent anti–PD-(L)1 had longer mOS (19.1 mo [95% CI 16.2-22.2]) than pts with 1L pembro followed by 2L therapy not including an anti−PD-(L)1 agent (16.0 mo [95% CI 11.8-19.2]) (Table). Conclusions: In this exploratory analysis, favorable survival outcomes were observed for pts who received 1L chemo followed by anti–PD-(L)1 compared with pts who received 1L pembro followed by 2L therapy not including an anti–PD-(L)1 agent. These data underline the continued importance of immunotherapy as 2L therapy for advanced UC. Clinical trial information: NCT02853305 . Research Sponsor: Merck &amp; Co., Inc[Table: see text]

Abstract PS10-41: PARP inhibitors for treatment of BRCA positive metastatic breast cancer: A systematic review and meta-analysis

Abstract Background: PARP Inhibitors (inh), Olaparib and Talazoparib, are approved for deleterious germline BRCA mutated (gBRCA+) metastatic breast cancer (MBC). This approval was based on a progression-free survival (PFS) benefit seen in two randomized controlled trials (RCTs). Other PARP inh such as Veliparib and Niraparib have also been studied. We conducted this meta-analysis of RCTs aiming to assess PFS and OS of PARP inh in gBRCA+ MBC. Methods: We performed a systematic search for RCTs using Cochrane Library, PubMed, Embase, and Web of Science up to June 2020. Only phase II and III RCTs evaluating PFS for PARP inh alone or in combination with chemotherapy (CT) to standard CT were eligible for this meta-analysis. The pooled analysis of hazard ratio (HR) was performed with RevMan 5.4 software using random effect model. Results: A total of 5 RCTs including 1563 patients were included in this meta-analysis. Baseline study characteristics are listed in Table 1. The pooled HR for PFS was 0.77 (95%CI 0.55-1.09) and the pooled HR for OS was 0.96 (95%CI 0.80-1.16). The only statistically significant adverse event more common in PARP inh group was anemia (Odds Ratio, 3.01; CI95%, 1.14-7.93, P=0.03). (Table 2) Conclusion: The results of our meta-analysis confirmed the previously reported PFS benefit of PARP inh either alone or with standard CT when compared to standard CT alone in gBRCA+ MBC. PARP inh when combined with temozolomide did not show PFS benefit. OS benefit is not seen with PARP inh alone or with standard CT. Ongoing trials are evaluating the benefit of PARP inh in early stage gBRCA+ BC. Table 1: Baseline study characteristics as experimental group vs. control groupVCP: veliparib with carboplatin/paclitaxelVT: veliparib with temozolomidePCP: placebo plus carboplatin/paclitaxelNA: Not available** Subgroup germline BRCA+ pts (n=37, 13 vs 24) is used for PFS and OS analysis in this study.TrialsSample sizeExperimental groupControl groupECOG PS % (0/1/2)Previous CT no. (%)Previous platinum no. (%)Median PFS (mo)Median OS (mo)OlympiAD302 (205 Vs 97)OlaparibStandard CT (Capecitabine or Eribulin orVinorelbine)72.2/28.8/0 Vs 63.9/36.1/0146 (71.2) Vs 69 (71.1)60 (29.3) Vs 26 (26.8)7.0 Vs 4.219.3 Vs 17.1EMBRACA431 (287 Vs 144)TalazoparibStandard therapy53.3/44.3/2.1 Vs 58.3/39.6/1.4176(61.4) Vs 90(62.5)46 (16.0) Vs 30 (20.8)8.6 Vs 5.619.3 Vs 19.5BROCADE284 (97 Vs 99)VCPPCP92/5 Vs 93/623(23.7) Vs 37(37.4)NA14.1 Vs 12.328.3 Vs 25.9(94 Vs 99)VTPCP91/3 Vs 93/628(30.6) Vs 37 (37.4)NA7.4 Vs 12.319.1 Vs 25.9BROCADE-3509 (337 Vs 172)VCPPCPNA19%8%14.5 Vs 12.633.5 Vs 28.2SWOG S1416 **321Veliparib + CisplatinPlacebo + Cisplatin69/41Vs 57/4351(32) Vs 49(31)14(9) Vs 18(11)6.2 Vs 6.414.2 Vs 14.6BRAVO-NiraparibPhysician choice CTStudy was prematurely closed after an interim analysis showed too many patients were not completing the necessary assessments in the control arm, and it was no longer suitable as a registration trial. Table 2: Side effect profile of PARP inh arm vs. CT armNA: Not available**side effect includes all 154 pts in experimental arm and 149 in control armAdverse Events (%)OlympiAD EMBRACABROCADE(VCP &amp; VT Vs PCP)BROCADE-3SWOG S1416**Odds Ratio for Adverse EventsAnemia Grade ≥333 (16.1) Vs 4 (4.4)112 (39.2) Vs 6 (4.8)16 (17.2) &amp;7 (7.5) Vs 17 (17.7)91(27) Vs 29(17)35(23) vs 11(7)3.01 (1.14,7.93) P=0.03Neutropenia Grade ≥319 (9.3) Vs 24 (26.4)60 (20.9) Vs 44 (34.9)52(55.9) &amp;34(36.6) Vs 53 (55.2)175(52) Vs 86 (50)71(46) vs 29(19)0.80 (0.40, 1.62) P=0.53Leukopenia Grade ≥37(3.4) Vs 9 (9.9)19 (6.6) Vs 11(8.7)15(16.1) &amp;11(11.8) Vs 11 (11.5)NA42 (27) Vs 11 (7)1.19 (0.42,3.38) P=0.74Nausea/Vomiting Grade ≥30 Vs 1 (1.1)8 (2.7) Vs 4(3.2)2(2.2) &amp;5(5.4) Vs 3 (3.1)NA28(18) Vs 16(10)1.45 (0.85,2.46) P=0.17Diarrhea Grade ≥31 (0.5) Vs 02 (0.7) Vs 7 (5.6)4(4.3) &amp; 2(2.2) Vs 7(7.3)NANA0.33 (0.13, 0.85) P=0.02Fatigue Grade ≥36 (2.9) vs 1 (1.1)5 (1.7) Vs 4 (3.2)5(5.4) &amp;3(3.2) Vs 8(8.3)NA8(5) Vs 9(6)0.73 (0.40,1.33) P=0.30Treatment discontinuation due to any AE10 (4.9) Vs 7(7.7)17 (5.9) Vs 11 (8.7)NANA0.72 (0.39,1.34) P=0.30 Citation Format: Ranju Kunwor, Daniel P Silver, Saveri Bhattacharya, Rebecca Jaslow, Frederick Fellin, Ana Maria Lopez, Maysa M Abu-Khalaf. PARP inhibitors for treatment of BRCA positive metastatic breast cancer: A systematic review and meta-analysis [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 PS10-41.

Abstract PS5-09: Tumour infiltrating lymphocytes of prognostic value in different molecular breast cancer subgroups and as a suggestive predictive factor for adjuvant tamoxifen benefit in premenopausal patients after 30 years follow-up

Abstract BACKGROUND The molecular breast cancer subgroups comprise diverse immune biology; for human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) and triple-negative breast cancer (TNBC) abundance of tumour infiltrating lymphocytes (TILs) have been shown to indicate good prognosis and could predict pathological complete response after neoadjuvant chemotherapy. In contrast, the clinical relevance of TILs in estrogen receptor-positive/HER2-negative (ER+/HER2-) tumours is not settled. We primary aimed to analyse the prognostic effect of TILs on BC-free interval (BCFi) in premenopausal patients, stratified by molecular subgroups. The secondary aim was to investigate the predictive value of TILs on tamoxifen benefit. METHODS Archival tissue from primary tumours was collected from patients included in the SBII:2pre trial. In this study, 564 premenopausal women were randomised between two years of adjuvant tamoxifen or no systemic treatment regardless of hormone-receptor status. TILs were scored on whole tissue sections and the tumours were divided into ER+/HER2- (n = 255), HER2+ (n = 65) and TNBC (n = 95) molecular subgroups by immunohistochemistry and in situ hybridisation (ISH). The prognostic value of TILs was evaluated in patients allocated to no systemic therapy, whose tumours were successfully scored for TILs and had IHC/ISH data for generating molecular subgroups (n = 221). All patients with ER+ tumours and successfully annotated TILs were considered for prediction of tamoxifen benefit (n = 321). The median follow-up was 28 years and the prognostic and predictive analyses were performed by cumulative incidence curves and Cox regression analyses. RESULTS TILs were successfully scored in 477 tumours with available ER status and the proportion of low (&amp;lt;10%), intermediate (10-49%) and high (≥50%) TILs were 52% (n = 248), 33% (n = 157) and 15% (n = 72), respectively. High infiltration of TILs was a favourable prognostic factor (univariable analysis: hazard ratioBCFi (HRBCFi) 0.40; 95% confidence interval (CI) 0.22-0.71; P = 0.002) (Table 1). The results were essentially the same in the ER+/HER2- molecular subgroup (HRBCFi 0.40; 95% CI 0.14-1.09; P = 0.07). Adjuvant tamoxifen improved prognosis in patients with ER+ tumours and TILs levels &amp;lt;50%, (univariable analysis HRBCFi 0.63; 95% CI 0.47-0.84; P = 0.002), which was not observed in patients displaying high immune infiltration (≥50%) (HRBCFi 0.84; 95% CI (0.24-2.86); P = 0.77). However, evidence for differential effect of tamoxifen in categories of TILs, i.e. interaction, was weak. CONCLUSIONS We demonstrate a long-term favorable prognostic value of levels of TILs in a cohort of premenopausal BC patients. This effect seems to be extended to the ER+/HER2- subgroup. A beneficial effect of tamoxifen in ER+ patients was observed in patients with tumours of low TILs infiltration as compared to patients with tumours of high immune infiltration, but we could not confirm a treatment predictive effect. Table 1. Uni- and multivariable Cox regression analyses of BCFi and OS (control arm)Univariable*MultivariableEndpointBCFiOSBCFiOSHR (95% CI); P valueTILs, category***All molecular subgroups(n = 221)(n = 213)Low (Ref.)1.001.001.001.00Intermediate1.10 (0.78-1.54); 0.611.26 (0.88-1.80); 0.210.61 (0.40-0.93); 0.020.65 (0.41-1.02); 0.06High0.40 (0.22-0.71); 0.0020.52 (0.29-0.95); 0.030.22 (0.11-0.43); &amp;lt;0.0010.23 (0.11-0.48); &amp;lt;0.001ER+/HER2-(n = 136)(n = 135)Low (Ref.)1.001.001.001.00Intermediate1.02 (0.63-1.64); 0.941.02 (0.61-1.71); 0.950.69 (0.42-1.15); 0.160.65 (0.37-1.15); 0.14High0.40 (0.14-1.09); 0.070.55 (0.20-1.52); 0.250.20 (0.06-0.60); 0.0040.30 (0.10-0.96); 0.04HER2+(n = 38)(n = 35)Low (Ref.)1.001.001.001.00Intermediate1.47 (0.62-3.49); 0.391.07 (0.45-2.56); 0.880.47 (0.14-1.60); 0.230.38 (0.11-1.31); 0.13High0.28 (0.08-0.97); 0.050.27 (0.08-0.96); 0.040.06 (0.01-0.56); 0.010.05 (0.01-0.39); 0.005TNBC(n = 47)(n = 43)Low (Ref.)1.001.001.001.00Intermediate0.76 (0.31-1.87); 0.551.24 (0.49-3.14); 0.650.59 (0.21-1.67); 0.321.02 (0.34-3.11); 0.97High0.27 (0.08-0.88); 0.030.44 (0.14-1.36); 0.160.38 (0.11-1.39); 0.150.59 (0.16-2.26); 0.44*Stratified by Region**The following variables were included in multivariable analysis: age (≥40 vs.&amp;lt;40 years), nodal status (0 vs.1-3 vs. ≥4), tumour size (&amp;gt;20 mm vs. ≤20), NHG (1 vs. 2 vs. 3), ER (positive vs. negative), PR (positive vs. negative), HER2 (positive vs. negative), LVI (present vs. absent) and TILs (high vs. intermediate vs. low). Stratified by Region.*** TILs were categorised as low: &amp;lt;10%, intermediate: 10-49% and high: ≥50%Abbreviations: BCFi breast cancer free-interval, OS overall survival, TILs tumour infiltrating lymphocytes, HER2 human epidermal growth factor receptor 2, TNBC triple-negative breast cancer, NHG nottingham histological grade, ER estrogen receptor, PR progesterone receptor, HR hazard ratio, CI confidence interval Citation Format: Christine Lundgren, Pär-Ola Bendahl, Maria Ekholm, Mårten Fernö, Carina Forsare, Ute Krüger, Bo Nordenskjöld, Olle Stål, Lisa Rydén. Tumour infiltrating lymphocytes of prognostic value in different molecular breast cancer subgroups and as a suggestive predictive factor for adjuvant tamoxifen benefit in premenopausal patients after 30 years follow-up [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 PS5-09.

KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer.

6 Background: KEYNOTE-177 (NCT02563002) evaluated the antitumor activity of pembrolizumab (pembro) vs chemotherapy ± bevacizumab or cetuximab (chemo) as first-line therapy for patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). We present results of the final PFS analysis and analysis of PFS2. Methods: Patients with locally-determined MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chosen before randomization). Treatment continued until progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles (pembro only). Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were PFS (RECIST v1.1, central review) and OS. Secondary end points included ORR (RECIST v1.1, central review) and safety. Exploratory endpoints included duration of response (DOR), PFS2 (time from randomization to progression on next line of therapy or any cause death), and health-related quality of life (HRQoL). Data cutoff was Feb 19, 2020. Results: At data cutoff a total of 307 patients were randomized (153 to pembro, 154 to chemo). Median (range) study follow-up was 32.4 mo (24.0-48.3). Pembro was superior to chemo for PFS (median 16.5 mo vs 8.2 mo; HR 0.60; 95% CI, 0.45-0.80; P= 0.0002). The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Confirmed ORR was 43.8% vs 33.1%; median (range) DOR was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo. PFS2 was longer with pembro vs chemo (median not reached vs 23.5 mo [HR 0.63; 95% CI, 0.45-0.88]). OS analysis is ongoing. Grade ≥3 treatment related adverse event (TRAE) rates were 22% vs 66% for pembro vs chemo. There were no grade 5 TRAEs in the pembro arm and 1 grade 5 intestinal perforation in the chemo arm. HRQoL scores were improved with pembro vs chemo. Conclusions: Pembro provided a statistically significant improvement in PFS vs chemo as first-line therapy for patients with MSI-H/dMMR mCRC, with fewer TRAEs observed. Furthermore, pembro provided a clinically meaningful improvement in PFS2 for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02563002.

Post hoc analysis in patients (pts) with unresectable hepatocellular carcinoma (uHCC) who progressed to Child-Pugh B (CPB) liver function in the phase III REFLECT study of lenvatinib (LEN).

298 Background: The treatment landscape for pts with uHCC has recently expanded. However, there is an unmet need for effective treatment options in CPB pts. LEN is approved first-line in uHCC based on the REFLECT study (Child-Pugh A [CPA] pts were allowed, per inclusion criteria). In a prior analysis of REFLECT, pts treated with LEN benefited irrespective of baseline liver function (ALBI grade 1 or 2; Child-Pugh score 5 or 6). To determine outcomes in pts with reduced liver function, we report a post hoc analysis of key efficacy and safety results in LEN-treated pts from REFLECT who progressed to CPB and those who did not within the first 8 weeks of treatment. Methods: In REFLECT, pts with uHCC were randomized 1:1 to LEN (per bodyweight: 12 mg/day for ≥60 kg; 8 mg/day for &lt; 60 kg) or sorafenib (400 mg twice daily) in 28-day cycles. This analysis assessed ORR. Landmark analyses (starting at week 8) of PFS, time-to-progression (TTP), and OS in CPB pts and in pts who remained CPA at 8 weeks post-randomization were also conducted. Tumors were assessed by mRECIST by independent imaging review. Safety was also assessed from baseline. Results: This subgroup analysis included LEN-treated pts (n = 60) who progressed to CPB within the first 8 weeks of treatment (CPB pts) and 413 pts who did not (CPA pts). At baseline, 26.7% and 73.1% of pts had an ALBI grade of 1 and 73.3% and 26.9% of pts had an ALBI grade of 2 in CPB and CPA pts, respectively. ORR was 28.3% (95% CI 16.9–39.7) for CPB pts and 42.9% (95% CI 38.1–47.6) for CPA pts. A landmark analysis showed a median PFS of 3.7 mos (95% CI 1.8–7.4) for CPB pts and 6.5 mos (95% CI 5.6–7.4) for CPA pts from the week 8 timepoint. Landmark analyses at week 8 also showed that the median TTP was 5.6 mos (95% CI 3.5–9.3) for CPB pts and 7.3 mos (95% CI 5.6–7.4) for CPA pts; the median OS was 6.8 mos (95% CI 2.6–10.3) for CPB pts and 13.3 mos (95% CI 11.6–16.1) for CPA pts per week 8 landmark analyses. As expected, efficacy appeared to be greater in CPA pts versus CPB pts; however, OS of 6.8 months in CPB pts after the week 8 landmark is notable. Moreover, median duration of treatment was 3.2 mos for CPB pts and 6.9 mos for CPA pts, thereby suggesting CPB pts can remain on LEN. The incidence of grade ≥3 treatment-related AEs (TRAEs) was 71.7% in CPB pts and 54.7% in CPA pts. TRAEs leading to discontinuation occurred in 18.3% of CPB pts and 7.5% of CPA pts. Conclusions: In this post hoc analysis of pts in REFLECT, we examine the key efficacy and safety results for LEN-treated pts who progressed to CPB by week 8. This post hoc analysis is limited by its descriptive nature; however, the results indicate that further study of LEN in CPB pts with uHCC is warranted. Clinical trial information: NCT01761266.

A multi-institutional phase Ib/II trial of first-line triplet regimen (Pembrolizumab, Trastuzumab, Chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): Molecular profiling and clinical update.

218 Background: We report the updated clinical data and molecular profiling results of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive advanced gastric and gastroesophageal junction (AGC/GEJ) cancer. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DOR, safety, and predictive biomarker analysis by targeted NGS. Results: At the time of data lock on Aug 31, 2020, total of 43 patients were treated with median follow up of 18.2 months, and 3 patients remained on the treatment, and 6 patients finished 2-year treatment without progression. ORR was 76.7% (CR 16.3%, PR 60.5%, conversion surgery 4.6%) with 26 pts (56.6%) showing more than 50% of tumor burden reduction. Median PFS was 8.6 months (95% CI 7.2-16.5) and median OS was 19.3 months (95% CI 16.5-NR). There were no MSI-H/dMMR or EBV-positive pts. No patient discontinued pembrolizumab because of immune-related adverse events. Clinical features including PD-L1 status (55.3% of pts ≥ CPS 1 and 13.2% of pts ≥ CPS 10 among available 38 pts), metastatic organ or baseline tumor burden was not related to the survival. Ninety-eight tumor tissues from 39 pts (paired tumor tissues from 22 pts) were analyzed with targeted NGS. Although every pts were HER2 IHC-positive, baseline HER2 amplification by NGS was related to the survival ( HER2 amp (n=8) vs HER2 non-amp (n=23); mPFS, not reached vs 7.7 months, P=0.0178; mOS, not reached vs 17.9 months, P=0.044) but no other signaling pathways predicted pts’ survival. HER2 mutations including L869R or D769H were related to the acquired resistance. High TMB showed a tendency toward better survival (mPFS; High (n=7) vs Low (n=24) TMB, 22.0 vs 8.2, P=0.2835) due to small number of patients. Updated immune markers and serial NGS analyses will be presented. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in AGC/GEJ cancer. Correlative biomarkers found from NGS study need to be validated through on-going phase III Keynote-811 study. Clinical trial information: NCT02901301. [Table: see text]

Changes in treatment and outcomes of stage II/III rectal cancer patients treated with trimodality therapy (TT) between 2006-2016: An NCDB analysis.

32 Background: Trimodality therapy (TT) remains standard for stage 2/3 rectal cancer and emerging evidence supports better outcomes with total neoadjuvant therapy (TNT) than similar therapy given post-operatively (Post-op). Real-world practice patterns and sequence of TT have significant implications on rectal cancer quality of care, outcomes and clinical trial design, and are not well described. Methods: The National Cancer Database was used to identify patients with clinical (c) stage 2/3 rectal adenocarcinoma diagnosed between 2006-2016, while pathologic (p) stage 2/3 was used when c stage was missing. Patients were included if they received Chemo/Radiation (C/RT), single or multiagent (SA or MA) chemotherapy (CT) and surgery. TNT was defined as receipt of pre-op C/RT and MA CT and no post-op therapy. Survival analyses were performed using Kaplan-Meier (KM) estimates and Cox univariate and multivariate hazard ratios (HRs) adjusted for TNT group, sex, race, year of diagnosis, stage, facility type, and age of diagnosis. Five-year KM survival proportions were limited to years 2006-2012, while Cox HRs were estimated from 2006 to 2015. Results: Of 32,467 patients who received TT, 8883 (27%) received TNT and 23,584 were classified no-TNT. TNT and no-TNT cohorts were numerically similar in age, race and gender. A significantly higher proportion of pStages 0-2 patients were observed in the TNT vs the no-TNT cohorts (61% vs. 48%, p &lt; .001). In analysis of annual treatment patterns of the whole cohort, a gradual reduction in Post-op C/RT was observed between 2006 (28%) and 2016 (8%, p &lt; .001), while use of TNT and MA CT did not increase. A migration to lower pStages 0/1/2/3 was seen between 2006 (1/10/31/57%, respectively) and 2016 (3/22/29/45%) (2016) (p &lt; .001). Five-year OS analysis showed superior OS for Pre-op vs Post-op C/RT (74 vs 69%, HR = .81, p &lt; .001), and MA CT vs. SA CT (76 vs 71%, HR = 0.79, p &lt; .001) but inferior 5-y OS for the TNT vs. no-TNT cohorts (74 vs 78%, HR = 1.17, p &lt; .001). Conclusions: Between 2006-16, a minority of patients treated with TT for stage 2/3 rectal cancer received TNT which did not increase over time. Significant annual shifts from Post-op C/RT to Pre-op C/RT, and migration to lower pStages were seen during this time period. Pre-op C/RT and MA CT were associated with improved OS, while TNT patients experienced inferior OS vs. the no-TNT cohort, possibly related to confounding factors in this observational cohort; multivariate sub-group analysis to be presented. Emerging evidence in support of TNT may further change treatment patterns and outcomes. [Table: see text]