Efficacy of nivolumab in patients treated by corticosteroid due to immune-related adverse events.

163 Background: Nivolumab is a standard treatment for metastatic or refractory non-small cell lung cancer (NSCLC). Because immune-related adverse events (irAEs) are common and can be severe, a number of these patients require systemic corticosteroids. irAEs are reportedly associated with improved survival in melanoma patients treated with nivolumab. To date, little information is available regarding the effect of corticosteroid on the efficacy of nivolumab in terms of progression-free survival (PFS) and overall survival (OS). Methods: We reviewed consecutive patients who received nivolumab for metastatic or refractory NSCLC between December 2015 and August 2017. Nivolumab was administered at the standard dose of 3 mg/kg every two weeks. We recorded the patient demographics, efficacy and safety of nivolumab, previous and subsequent treatments, information about irAEs, corticosteroid usage, and survival. PFS and OS were calculated from the start of nivolumab treatment. A Cox proportional hazards regression model was applied using variables with the potential to influence the PFS: sex, age, performance status (PS), smoking history, driver gene alterations, histology, line of nivolumab treatment, and irAEs. Results: A total of 184 patients received nivolumab. Among them, 117 (64%) were male, the median age was 64 years (range, 34-83 years), 23 (13%) had a PS of 2 or more, 125 (68%) were ex-smokers, 37 (20%) had squamous NSCLC, and 37 (20%) had some kind of driver gene alteration, mainly EGFR mutation. Fifty patients (27%) experienced some grade of irAEs, and 37 (20%) patients required corticosteroid treatment. A multivariate analysis identified the occurrence of irAEs (hazard ratio [HR], 0.55; 95% confidence interval [CI] 0.33-0.91) and smoking (HR, 0.60;95% CI, 0.36-0.99) as independent predictors of a favorable PFS. There were no apparent differences in the proportions of patients who survived with or without the use of corticosteroid for irAEs: 73% vs. 71% at 6 months and 46% vs. 45% at 18 months. Conclusions: The occurrence of irAEs was positively associated with the PFS, and corticosteroid treatment did not have an adverse effect on OS in patients with NSCLC who were treated with nivolumab.

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Impact of systemic corticosteroids for cutaneous immune-related adverse events on survival outcomes in patients with advanced cancer: A retrospective cohort study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14523 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14523-e14523

Author(s):

Jaewon Yoon ◽

Leah L. Thompson ◽

Nira A. Krasnow ◽

Michael Chang ◽

Edward Li ◽

...

Keyword(s):

Adverse Events ◽

Proportional Hazards ◽

Progression Free Survival ◽

Cox Proportional Hazards ◽

Survival Outcomes ◽

Infection Rates ◽

Medical Reason ◽

Systemic Corticosteroids ◽

Impact On Survival ◽

The Impact

e14523 Background: Cutaneous immune-related adverse events (cirAE) may disrupt immune-checkpoint inhibitor (ICI) therapy. Current guidelines recommend systemic corticosteroids (SCS) for moderate to severe cirAE, but SCS-associated complications and their impact on survival remain poorly understood. We therefore investigated the impact of SCS exposures on infectious complications and survival outcomes among patients with cirAE. Methods: We retrospectively reviewed the medical records of patients who initiated anti-programmed death-1/ligand-1 (PD-1/PDL-1) and/or anti-cytotoxic-T-lymphocyte-4 (CTLA-4) ICI therapy between 1/1/16-3/8/19 with confirmed cirAE, obtaining oncologic history, clinical features, SCS exposures, infection rates, and survival outcomes. SCS exposures were categorized by indication (cirAE, other immune-related adverse event, other medical reason) and dosage in prednisone equivalents (low, ≤7.5mg/day for ≥2 months; moderate, > 7.5mg/day for ≥2 months; high, ≥1mg/kg/day for ≥1 week). Infection rates were compared among patients treated with SCS for initial cirAE and those with no SCS exposures for any indication. Cox proportional hazards (CPH) models adjusted for age, sex, and covariates with P <0.05 were used to assess relationships between SCS for first cirAE episode, progression-free survival (PFS) and overall survival (OS). Results: 358 patients developed cirAE (median age 64 years, 40.5% female, 41.9% melanoma). 50 (14.0%) patients received SCS for initial cirAE, 192 (53.6%) received SCS for another indication, and 116 (32.4%) had no SCS exposures. Patients who received SCS for initial cirAE had higher median rash severity (Common Terminology Criteria for Adverse Events grade 3 vs. 1, P< 0.001) and were more likely to be hospitalized for cirAE management (20.0% vs. 1.9%, P< 0.001) than those who did not receive SCS. SCS delivery for initial cirAE was predominantly at low doses (n = 42, 84.0%). Infection rates were higher in patients who received SCS for initial cirAE than those with no SCS exposures for any indication (34.0% vs. 19.8%). Most infections in both groups required systemic therapy (88.2% vs. 95.7%). In multivariate models adjusted for age, sex, and SCS exposures by indication and dosage, patients who received SCS for initial cirAE and those who did not had similar PFS (HR 0.7, CI 0.4-1.3, P= 0.287) and OS (HR 3.0, CI 0.3-35.3, P =0.380). Conclusions: We observed higher rates of infection than previously reported among both patients who did and did not receive SCS for initial cirAE. Despite the theoretical risk of SCS impeding the anti-tumor response, we found no relationship between SCS for initial cirAE and PFS/OS. Collectively, these findings suggest that with appropriate management, low-dose SCS may be safely administered for cirAE without significant impact on survival outcomes.

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Differential response rates in early-phase cancer clinical trials (EPCCT).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3133 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3133-3133

Author(s):

Rozana Abdul Rahman ◽

Neethu Billy Graham Mariam ◽

Hitesh Mistry ◽

Sreeja Aruketty ◽

Matt Church ◽

...

Keyword(s):

Proportional Hazards ◽

Performance Status ◽

Objective Response ◽

Progression Free Survival ◽

Response Rates ◽

Primary Objective ◽

Cox Proportional Hazards ◽

Sustained Response ◽

Phase Ii Trials ◽

Significant Difference

3133 Background: The primary objective of EPCCT (phase I and non-randomised phase II trials) is to determine the safety and tolerability of new therapeutic agents. Response rates (RR) in these trials have typically been reported at around 10-15%. Increasingly RR and survival outcomes are now investigated in EPCCT as primary or secondary objectives. Methods: Retrospective data analysis was performed on patients (pts) enrolled onto an EPCCT between January 2018 and December 2019 at The Christie NHS Foundation Trust, UK. Data on demographics, prior systemic treatment, sites of disease, performance status, comorbidities, types of therapy, RR, progression free survival (PFS), and overall survival (OS) were collected. Statistical analyses were performed with univariable and multivariable models. Objective response rate (ORR) was defined as the proportion of pts with complete response (CR) and partial response (PR). Duration of response (DOR) was from initial response to progressive disease (PD). Disease control rate (DCR) was defined as CR+PR+ stable disease (SD). Results: A total of 247 pts were treated across 46 EPCCTs. Median age 61 years; 57% female. Sixty-six percent of pts had ≥2 lines of treatment and the majority were ECOG PS 0/1 (98%). Eighty-one percent of pts had ≥2 sites of metastatic disease, and 13 major tumour types were included. Monotherapy trials (159 pts) were predominantly targeted therapies (TT; 60%), or immunotherapies (IO; 20%). Combination therapy trials (88 pts) were TT-based (68%) or IO-based (32%). Data for RR analyses was available for 231 pts. ORR across all trials was 15% (CR 2%) and DCR was 63%. The median DOR was 8.3 months (mos) (95% CI: 7.0 – 9.7) with 28% of pts responding for >6 mos and 7% for >12 mos. ORR in pooled IO treated pts was 27%, DCR was 65% with sustained response >6 mos seen in 37% of these pts. ORR in pooled TT treated pts was 9.4%, DCR was 60% and sustained response > 6 mos seen in 25% of pts. ORR for IO v TT treated pts was significantly different, p=0.007 (pearson chi square), but no significant difference was seen for DCR. Median PFS for all patients was 5.0 mos (95% CI: 4.1 – 6.0) and OS was 10.4 mos (95% CI: 8.4 – 13.0). OS for those with a PR is not reached (HR for PR v PD, 0.006 (95% CI: 0.002 – 0.18). Pts with SD appear to have significantly better OS compared to those with PD (14.6 v 4.2 mos, HR 0.2 (95% CI: 0.1 – 0.3). Multivariable Cox proportional hazards analysis for OS was significant for male gender (HR 1.9, p=0.002), presence of liver metastasis (HR 2.0, p=0.001), low Hb (HR 0.8, p=0.03) and log (LDH) (HR 1.9, p<0.001). Conclusions: Two-thirds of pts enrolled on EPCCTs benefitted in terms of DCR with significant OS improvement in those with PR and SD. Higher ORR were seen in pts receiving IO-based treatments however DCR was similar in IO and TT pts. Gender, presence of liver metastases, Hb count and LDH level contributed significantly to survival differences.

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Circulating mir-21 and mir-378 are predictive of progression-free survival (PFS) in patients treated with everolimus in metastatic renal cell cancer (mRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4617 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4617-4617

Author(s):

James Lin Chen ◽

Kimryn Rathmell ◽

David F. McDermott ◽

Walter Michael Stadler

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Clear Cell ◽

Standard Dose ◽

Cell Cancer ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Negative Control ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model

4617 Background: The oral mTOR inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and modestly delays RCC progression. We hypothesized that circulating microRNAs, which have been associated with renal cancer and inflammation, may serve as predictive biomarkers to help better define a population more sensitive to treatment. Methods: Plasma from mRCC pts refractory to VEGF inhibition were obtained prior to treatment with standard dose everolimus as part of a clinical trial examining FDG-PET as a potential predictive biomarker. As we were specifically interested in tumor response to drug, only pts who died, remained on trial, or had radiographic progression by RECIST criteria were profiled. Pts who were unable to tolerate drug were excluded. MicroRNAs were extracted and profiled without pre-amplification using Exiqon LNA PCR panels. Crossing point (Cp) values within 5 of the negative control were removed. MicroRNAs must have been present in >90% of samples and varied at least p > 0.10 from mean to be further analyzed. Cox-proportional hazards model and Kaplan-Meier analyses were performed. Results: 28 patients had available plasma and met criteria for profiling. Pt characteristics included: 20 (71%) clear cell histology, median age 57.7 (43 – 76), median number of prior systemic therapies 2 (1 – 3). 103 microRNAs were expressed in at least 90% of all samples. Mir-21 and mir-378 were independently correlated with PFS (FDR: 0.02 and 0.06, respectively). Low circulating plasma mir-21 and mir-378 levels resulted in a median PFS prolongation of 370d vs. 101d (p=0.027) and 368d vs. 106d (p=0.001). Analysis of the clear cell cohort for mir-21 and mir-378 also demonstrated a significant median PFS difference of 350d vs. 173d (p=0.045) and 345d vs. 147d (p=0.004). Conclusions: Elevated levels of circulating mir-21 and mir-378 have been associated with systemic inflammatory states, and in our study are correlated with decreased PFS in mRCC pts undergoing everolimus therapy. Further prospective studies will be required to validate these exploratory results for their potential role as prognostic or predictive biomarkers.

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Retrospective multicenter cohort of nab-paclitaxel plus gemcitabine (NG) after FOLFIRINOX failure in advanced pancreatic cancer (APC): Effectiveness, tolerability, and response markers.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15743 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15743-e15743

Author(s):

Ines Vendrell ◽

Arlindo Rebelo Ferreira ◽

Catarina Pulido ◽

Anuraj Parmanande ◽

Filipa Ferreira Da Silva ◽

...

Keyword(s):

Multivariate Analysis ◽

Proportional Hazards ◽

Performance Status ◽

Advanced Pancreatic Cancer ◽

Stage Iv ◽

Progression Free Survival ◽

Cox Proportional Hazards ◽

Line Treatment ◽

Ecog Performance Status ◽

Ca 19.9

e15743 Background: NG is a standard 1st line treatment for APC. Although recommended in 2nd line after FOLFIRINOX, there is little evidence of its efficacy, tolerability and of markers of efficacy. Methods: We performed a multicenter retrospective cohort study, including patients (pts) with APC from 5 centers in Portugal treated with 2nd line NG after 1st line FOLFIRINOX from 01/2013-12/2016. We collected demographic, clinicopathological characteristics and treatment data. We used descriptive statistics, Kaplan-Meier methods and Cox proportional hazards analysis. Results: 30 pts were included; median age was 64 years (range 45–78); the majority had stage IV (90%) disease, an ECOG Performance Status of 0 (76.7%) and had received a median of 8.5 cycles of FOLFIRINOX (range 1–18). A median of 6 cycles of NG were administered (range 1–13). Median progression free survival (PFS) and overall survival (OS) were 6.4 months (CI 95% 3.0-8.5) and 11.4 months (CI 95% 8.4–16.5), respectively, and did not differ by age < 65 or ≥65 (p = 0.87; p = 0.57 respectively). The most frequent toxicity was fatigue (66.6%, any grade). Grade 3-4 events occurred in 40% of pts – thrombocytopenia in 16.7%, neutropenia in 10.0%; anemia, sensorial neuropathy, fatigue and diarrhea each occurred in 3.3% of patients. No febrile neutropenia events or toxic deaths occurred. Median CA 19.9 at the beginning of NG was 1254U/mL (IQR: 207–6775); the median decrease of CA19.9 at 3 months was 45U/mL (IQR:-1373– +174). CA 19.9 variation at 3 months did not correlate with PFS (p = 0.53) or OS (p = 0.09) in multivariate analysis (adjusted for age and stage at diagnosis). Neutrophil to Lymphocyte ratio (NLR) was high ( > 3.0) in 37.5% of patients before 1st line treatment and in 27.6% at the beginning of NG. In multivariate analysis NLR before 1st or 2nd chemotherapy lines were not associated with PFS (p = 0.39; p = 0.14 respectively) or OS (p = 0.44; p = 0.12, respectively). Conclusions: In this cohort of pts with APC, NG was an effective and well tolerated 2nd line regimen after FOLFIRINOX failure, even in pts ≥65 years. Neither CA19.9 variation at 3 months nor NLR were markers of NG clinical benefit.

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Does Very Poor Performance Status Systematically Preclude Single Agent Anti-PD-1 Immunotherapy? A Multicenter Study of 35 Consecutive Patients

Cancers ◽

10.3390/cancers13051040 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1040

Author(s):

Valérie Gounant ◽

Michael Duruisseaux ◽

Ghassen Soussi ◽

Sylvie Van Hulst ◽

Olivier Bylicki ◽

...

Keyword(s):

Proportional Hazards ◽

Performance Status ◽

Single Agent ◽

Progression Free Survival ◽

Poor Performance ◽

Cox Proportional Hazards ◽

Poor Performance Status ◽

Low Grade ◽

Kaplan Meier ◽

Cox Proportional Hazards Models

Anti-PD-1 antibodies prolong survival of performance status (PS) 0–1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3–4 patients is unknown. Conse- cutive PS 3–4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3–4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1–7) as first- (n = 6) or second-line (n = 29) therapy. At a median of 52-month follow-up (95%CI, 41–63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1–3.2). Median OS was 4.4 months (95%CI, 0.5–8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2; 95%CI, 9–14.3, p = 0.001) and <20 pack-years (HR = 4.8; 95%CI, 1.7–13.8, p = 0.003) predicted worse survival. PS improvement from 3–4 to 0–1 (n = 9) led to a median 43-month (95%CI, 0–102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.

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Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center

Journal of Clinical Oncology ◽

10.1200/jco.2015.60.8448 ◽

2015 ◽

Vol 33 (28) ◽

pp. 3193-3198 ◽

Cited By ~ 503

Author(s):

Troy Z. Horvat ◽

Nelly G. Adel ◽

Thu-Oanh Dang ◽

Parisa Momtaz ◽

Michael A. Postow ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Treatment Failure ◽

Systemic Corticosteroid ◽

Standard Dose ◽

Corticosteroid Treatment ◽

Cancer Center ◽

Time To Treatment ◽

Systemic Corticosteroids ◽

Time To Treatment Failure

Purpose Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF). Patients and Methods We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival. Results Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids. Conclusion IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.

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The influence of institutional head and neck cancer (HNC) clinical trial accrual on overall survival (OS): An analysis of RTOG 0129.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.5530 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 5530-5530

Author(s):

Evan John Wuthrick ◽

Qiang Zhang ◽

Mitchell Machtay ◽

K. Kian Ang ◽

David Ira Rosenthal ◽

...

Keyword(s):

Proportional Hazards ◽

Smoking Status ◽

Performance Status ◽

Progression Free Survival ◽

Cox Proportional Hazards ◽

Independent Effect ◽

Locoregional Failure ◽

Risk Of Death ◽

Hpv Status ◽

N Stage

5530 Background: NCCN recommends HNC patients (pts) be treated by providers with experience in HNC management. Whether treatment by experienced providers (measured by no. of pts treated) is associated with HNC survival outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 with stage III-IVa HNC with known tumor HPV and smoking status randomized to cisplatin concurrent with standard or accelerated fractionation radiotherapy (RT). Participating centers were stratified into pt accrual tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for experience, we investigated the independent effect of AT on OS and progression-free survival (PFS) in multivariable cox proportional hazards models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT (low accruing centers [LAC]) were similar and compared to the upper AT (high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N stage, comorbidities and study arm assignment (SAA), but pts at LAC had better performance status (PS)(Zubrod 0; 62% vs 52%; p=0.04), fewer T4 tumors (27% vs. 35%; p=0.05) and were more likely uninsured (12% vs 4%; p=0.009). Compared to HAC, LAC pts had significantly worse OS, (5 yr 51.0% vs 69.1%; p = 0.002), and PFS (5 yr 42.7% vs 61.8%; p = 0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p <0.001). Treatment at LAC was associated with ~90% increase in risk of death (OS HR 1.91, 95%CI 1.37-2.65) and progression (PFS HR 1.89, 95%CI 1.39-2.56) when compared to pts treated at HAC, after adjustment for age, PS, pack-years, T and N stage, SAA and HPV status. Acute and chronic toxicities, RT dose, fractions, and treatment duration did not differ for pts at LAC vs HAC. RT at LAC was more likely than HAC to differ from protocol (18% [16.8% acceptable variation {AV}, 1.2% unacceptable deviation {UD}] vs 6% [4.7% AV, 1.3% UD]; p<0.001). Conclusions: Pts with HNC treated at LAC in RTOG trials were associated with significantly worse survival outcomes compared to pts treated at HAC.

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Analysis of the GERCOR index in KRAS Exon2 WT patients with mCRC treated with salvage-line cetuximab-based chemotherapy: HGCSG0901.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.781 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 781-781

Author(s):

Ayumu Hosokawa ◽

Satoshi Yuki ◽

Hiroshi Nakatsumi ◽

Kazuteru Hatanaka ◽

Yasushi Tsuji ◽

...

Keyword(s):

Multivariate Analysis ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Performance Status ◽

Progression Free Survival ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Rank Test ◽

Prognostic Impact ◽

Significant Difference

781 Background: The GERCOR index (GI) based on performance status and serum LDH was reported to be useful to predict survival for patients with previously untreated mCRC. However, in the salvage setting, the validity of the GI has not been reported in patients treated with cetuximab (Cmab)-based chemotherapy. Methods: 269 patients with mCRC treated with Cmab contained chemotherapy were retrospectively registered from 27 centers in Japan. This analysis was included in the KRAS Exon2 wild type patients who were refractory to or intolerant of 5-FU / irinotecan/ oxaliplatin and were never administered anti-EGFR-antibody. Univariate and multivariate analysis for overall survival (OS) were performed using patient characteristics. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox proportional hazards model. The analysis was also designed to determine whether the GERCOR index could be extended to progression-free survival (PFS). Results: All data were available for prognostic categorization in 132 patients. Median OS and PFS were 9.8 and 4.3 months. The distribution and median OS / PFS for GI were as follows: low risk (L)(n = 28; 17.9/3.8 months), intermediate risk (I)(n = 52; 12.2/5.0 months), and high risk (H)(n = 52; 7.5/4.1 months). For OS, there was significant difference between L and H (p < 0.001) and between I and H (p < 0.001), but not between L and I (p = 0.076). For PFS, there was significant difference between I and H (p = 0.017), but not between L and I (p = 0.407), and between L and H (p = 0.222). In the Cox multivariate analysis, GI showed an independent prognostic impact (L vs. I ; HR 2.195, p=0.003 / L vs. H ; HR 4.028, p<0.001), but not predictive impact (L vs. I ; HR 0.987, p=0.958 / L vs. H ; HR 1.314, p=0.268). Conclusions: In this analysis, GI might be a prognostic factor in salvage treatment with Cmab-based chemotherapy.

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The association of tissue tumor mutational burden (tTMB) using the Foundation Medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (pts) with gastric cancer (GC) from KEYNOTE-061.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4537 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4537-4537 ◽

Cited By ~ 5

Author(s):

Kohei Shitara ◽

Mustafa Özgüroğlu ◽

Yung-Jue Bang ◽

Maria Di Bartolomeo ◽

Mario Mandalà ◽

...

Keyword(s):

Proportional Hazards ◽

Performance Status ◽

Gastroesophageal Junction ◽

Objective Response ◽

Positive Association ◽

Progression Free Survival ◽

Wald Test ◽

Cox Proportional Hazards ◽

Open Label ◽

Ecog Performance Status

4537 Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in pts with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma with tumor progression after first-line therapy (N = 592). In this analysis, we evaluated tTMB using FoundationOne CDx (F1CDx; Foundation Medicine) in pts with gastric or GEJ cancer in KEYNOTE-061. Methods: In pts with evaluable F1CDx tTMB data (n = 204), we analyzed the association of tTMB with confirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) within each treatment arm using one-sided (pembrolizumab) and two-sided (paclitaxel) Wald test nominal P for logistic regression (ORR) and Cox proportional hazards regression (PFS; OS) adjusted for ECOG performance status; significance was prespecified at 0.05. The clinical utility of tTMB was assessed using the prespecified cutoff of 10 mut/Mb for F1CDx. Clinical data cutoff: Oct 26, 2017. Results: tTMB was positively associated with ORR ( P < 0.001; AUROC, 0.68), PFS ( P < 0.001), and OS ( P = 0.003) with pembrolizumab but not paclitaxel (ORR, P = 0.047; AUROC, 0.30; PFS, P = 0.605; OS, P = 0.084). Pt outcomes by tTMB cutoff are reported in the Table; prevalence of TMB ≥10 mut/Mb was 17%. In pts with microsatellite stable disease-only, HRs (95% CI) by treatment arm for OS by F1CDx cutoff were 0.40 (0.14-1.17) for tTMB ≥10 mut/Mb (n = 21) vs 0.97 (0.70-1.34) for tTMB <10 mut/Mb (n = 168). Conclusions: In this exploratory analysis from KEYNOTE-061, tTMB as determined by F1CDx demonstrated a positive association with clinical outcomes with pembrolizumab, but not paclitaxel, in pts with GC; these findings are consistent with those reported with whole exome sequencing. Pembrolizumab demonstrated an OS benefit vs paclitaxel in the subgroup with tTMB ≥10 mut/Mb, which remained when pts with microsatellite instability-high disease were excluded. Clinical trial information: NCT02370498 . [Table: see text]

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Prognostic value of KRAS and PI3K pathway mutations for advanced pancreatic ductal adenocarcinoma (PDAC) patients (pts).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.424 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 424-424

Author(s):

Adam Diehl ◽

Lindsay Marie Hannan ◽

Elena Gabriela Chiorean

Keyword(s):

Proportional Hazards ◽

Performance Status ◽

Progression Free Survival ◽

Pi3k Pathway ◽

Cox Proportional Hazards ◽

Ductal Adenocarcinoma ◽

Free Survival ◽

Exact Test ◽

Uptake Process ◽

Next Generation Sequencing Ngs

424 Background: KRAS mutation (MUT) variants (var) have been associated with differential clinical outcomes in advanced PDAC pts (Hendifar, 2020). Recent data from PDAC cell lines suggests that, unlike KRAS G12D/V, the KRAS G12R var is unable to interact with p110α PI3Kα and relies on KRAS-independent p110γ PI3K activity to support macropinocytosis, a nutrient uptake process necessary for tumor growth (Hobbs, 2020). Methods: We retrospectively reviewed advanced PDAC pts who received at least first-line (1L) systemic therapy and underwent next generation sequencing (NGS) at University of Washington between 2013 and 2020. We analyzed, using Fisher’s exact test, whether KRAS var were associated with PI3K pathway mutations (PI3K MUT). Using multivariate (Cox proportional hazards) analysis, we compared overall survival (OS) and progression-free survival (PFS) from start of 1L therapy for pts whose tumors harbored any KRAS var with and without stratification by PI3K MUT status. Results: 127 pts had NGS (96% tissue, 4% ctDNA). Median OS (mOS) and PFS were 16.8 months (mos) and 8.6 mos, respectively. 111 PDAC were KRAS MUT (87%): 43 (39%) G12D, 35 (32%) G12V, 23 (21%) G12R, 1 (0.9%) G12C, 6 (5%) Q61. 15 PDAC (12%) had 16 PI3K MUT, including 7 PIK3CA, 3 AKT2, 3 RICTOR, 1 PTEN, 1 PIK3C2B, and 1 PIK3R1. PI3K MUT occurred in 26% of tumors with KRAS G12R vs 8% in other KRAS var (p=0.0265). In multivariate analysis controlling for age, performance status, stage at diagnosis, type of 1L chemotherapy, TP53 MUT and GATA6 amplification status, pts with KRAS G12R var PDAC vs other variants had longer mOS (20.4 vs 14.5 mos, HR 0.67 (95% CI 0.47 – 0.93), p=0.0215) and mPFS on 1L therapy (12.2 vs 6.8mos, HR 0.60 (95% CI 0.40 – 0.85), p=0.0040). In pts with KRAS G12R var PDAC, concurrent PI3K MUT vs PI3K WT associated with shorter mOS (19.4 vs 24.2mos, HR 2.79 (95% CI 0.97 – 10.6), p=0.0570). In pts with non-G12R KRAS var tumors, PI3K MUT vs WT did not confer shorter OS (mOS 17.6 vs 14.5 mos, HR 1.20 (95% CI 0.72 – 2.0), p=0.55). Conclusions: KRAS G12R PDAC have a higher incidence of PI3K MUT than other KRAS var. KRAS G12R status may confer improved prognosis vs other KRAS variants, albeit this benefit is offset by the presence of concurrent PI3K MUT.

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