Tissue and plasma tumor mutation burden (TMB) as predictive biomarkers in the CO.26 trial of durvalumab + tremelimumab (D+T) versus best supportive care (BSC) in metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 61-61
Author(s):  
Jonathan M. Loree ◽  
James T. Topham ◽  
Hagen F. Kennecke ◽  
Harriet Feilotter ◽  
Faeze Keshavarz-Rahaghi ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
High Plasma ◽  
Best Supportive Care ◽  
P Value ◽  
Archival Tissue ◽  
Cut Point ◽  
Phase 2 Trial ◽  
Median Plasma ◽  
Pre Treatment

61 Background: Pembrolizumab was recently granted tissue agnostic FDA accelerated approval for metastatic cancers with TMB≥10 mut/Mb. However, limited data supports immunotherapy in microsatellite stable (MSS) mCRC with TMB≥10 mut/Mb. We assessed tissue TMB and contrasted it to plasma derived TMB in the CO.26 trial. Methods: CO.26 was a phase 2 trial (2-sided ⍺ = 0.1 and 80% power) that randomized 180 patients (pts) 2:1 to D+T or BSC in refractory mCRC. Pre-treatment plasma was sequenced with the GuardantOMNI assay and archival tissue underwent exome sequencing with TMB assessed per the TMB harmonization project. MSI-H cases were excluded. For plasma TMB, we used a previously published cut point (≥28). Results: Overall survival (OS) but not progression free survival (PFS) was improved with D+T in the entire population. Of 180 pts, 163 were evaluable for plasma and 110 for tissue TMB. Median time between archival tissue and plasma collection was 3.1 yrs (IQR 1.9-5.1). Median tissue TMB was 6.6 muts/Mb (IQR 4.1-12.0), while median plasma TMB was 16.3 muts/Mb (IQR 9.4-25.9). Tissue and plasma TMB (r = -0.039, P = 0.69) were not correlated. Tissue TMB≥10 was not prognostic in the BSC arm (HR 1.01, 90%CI 0.52-1.92, P = 0.99) and OS was not improved in pts with tissue TMB≥10 (32/110 pts) following D+T vs BSC. A test of interaction suggested this threshold was not predictive (P = 0.85). Using a minimum P-value approach, no threshold supported high tissue TMB as predictive in MSS mCRC. In fact, the optimal cut point suggested low tissue TMB ( < 4.1 muts/Mb) had the greatest benefit from D+T (P-interaction = 0.048) and pts with TMB ≥4.1 mut/Mb (HR 0.50, 90%CI 0.26-0.96, P = 0.083) trended to better OS in the BSC arm. In contrast, 35/163 pts (21%) were identified in a high plasma TMB group associated with worse OS (HR 2.56, 90%CI 1.45-4.54, P = 0.007) in the BSC arm but improved OS following D+T compared to BSC with P-interaction = 0.082. Only 1 response was noted following D+T in a pt with tissue TMB = 16 mut/Mb and plasma TMB = 13 mut/Mb. Conclusions: Archival tissue TMB≥10 mut/Mb does not appear predictive of D+T benefit in MSS mCRC. Plasma derived TMB may better reflect evolutionary changes following intervening therapy than archival tissue. Clinical trial information: NCT02870920. [Table: see text]

Early predictors of benefit to dual anti-PD1/HER2 inhibition: Biomarker analysis from phase 2 trial of pembrolizumab/trastuzumab in HER2-positive metastatic esophagogastric (mEG) cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4058-4058
Author(s):  
Steven Brad Maron ◽  
Walid Khaled Chatila ◽  
Henry S. Walch ◽  
Ryan Ptashkin ◽  
Shalom Sabwa ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Ct Scans ◽  
Her2 Positive ◽  
Phase 2 Trial ◽  
Biomarker Analysis ◽  
Pre Treatment ◽  
Pet Scans

4058 Background: Pembrolizumab and trastuzumab (P&T) and chemotherapy demonstrated 27 month mOS, 13 month mPFS, and 91% response rate in first-line HER2-positive mEG cancer irrespective of PD-L1 status (Janjigian Lancet Oncology 2020). Biomarkers including 89Zr-trastuzumab PET, blood, and tumor analysis were correlated with progression-free survival. Methods: Twenty-five patients received P&T once 3 weeks prior to addition of chemotherapy to P&T. Pre-treatment tumor biopsies, 89Zr-trastuzumab PET scans, serial plasma ctDNA (Guardant360, Redwood City, CA) and CT scans were performed. Tumor-matched DNA alterations were identified by correlating ctDNA and tissue-NGS variant calls. Pre-, on-, and post-treatment biopsies were analyzed using WES and IHC (HER2, PD-L1). Biomarkers were correlated with mPFS and 6-month PFS, the primary endpoint. Results: Of patients with tumor-matched mutations ctDNA at baseline, 12 of 16 had a decline in their maxVAF by week 3, corresponding to a mPFS of 14.7 (11.0-NR) vs 5.9 (95% CI 4.1-NR) months (p=0.009) and a mOS of 29.7 (95% CI 27.2-NR) vs 7.71 (95% CI 6.6-NR) months (p=0.006). 9 of 12 (75%) patients with decline in ctDNA at 3 weeks post-P&T achieved the 6-month PFS primary endpoint while the 4 patients with no decline in ctDNA all progressed in under 6-months. Similarly, 7 of 9 (78%) patients who had a decline in CT-measurements in all disease sites achieved the 6 month PFS primary endpoint, versus 10 of 16 (62.5%) of patients who did not respond in all sites (p=0.66), suggesting that ctDNA is superior to CT as an early predictive biomarker of response. Lack of ERBB2 amplification (amp) by NGS in ctDNA and/or tumor was associated with lack of response to P&T alone prior to addition of chemotherapy. Interestingly, no lesions from patients lacking ERBB2 ctDNA amp (n=3) responded to induction P&T by CT, while lesions from 3/9 patients lacking ERBB2 tissue amp responded to P&T by 3-week CT, suggesting intrapatient HER2 heterogeneity. Eight patients also underwent 89Zr-Trastuzumab PET scans prior to P&T and up to 5 lesions per disease site were measured on serial CT scans. All 15 lesions with intense uptake (SUVmax>10) responded to P&T, but only 9/24 lesions with SUVmax<10. All 4 patients who had at least 1 intense lesion achieved a post-P&T CT response and later 6+ month PFS. All 3 of 3 evaluable patients with intense uptake had baseline ctDNA ERBB2 amp. Conclusions: Patients with a decline in tumor-matched maxVAF after one dose of P&T were more likely to achieve durable PFS. Pre-treatment ctDNA ERBB2 amp and/or intense 89Zr-trastuzumab PET avidity are non-invasive predictive biomarkers of response to HER2-directed therapy. Evaluation of tumor immune environment digital spatial profiling is underway. Clinical trial information: NCT02954536.

High-Dose Imatinib Mesylate Treatment in Patients (Pts) with Previously Untreated Early Chronic Phase (CP) Chronic Myeloid Leukemia (CML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 999-999 ◽  
Author(s):  
Jorge Cortes ◽  
Moshe Talpaz ◽  
Susan O’Brien ◽  
Francis Giles ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Standard Dose ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
P Value ◽  
High Dose ◽  
Free Survival ◽  
Clinical Observations ◽  
Pre Treatment ◽  
Grade 3

Abstract Imatinib has become the treatment of choice for most with CML. The standard dose (SD) for CP CML is 400 mg daily, but pre-clinical and clinical observations suggest that higher doses (HD) may be more effective. We have treated 222 with previously untreated CML in early CP with imatinib in 3 consecutive trials: one using SD imatinib (400 mg/day) (n=50; all entered in April 2001) and 2 subsequent trials using 400 mg twice daily (total dose 800 mg/day) (n= 172; from June 2001 until present). The 2 HD trials had identical inclusion criteria and will be considered together for this analysis. Pts followed for at least 3 months (mo) are evaluable (n=210) for this report (n=49 at 400mg, 161 at 800 mg). The median age was 48 years (range, 15 to 84); platelets were >450 x109/L in 71 pts (34%), 78 (37%) had peripheral blood (PB) blasts, and 11 (5%) had clonal evolution. Sokal risk group classification was good in 128 (61%) pts, intermediate in 61 (29%) pts, and poor in 21 (10%) pts. There was no difference in pre-treatment characteristics between the standard SD and HD groups. The results at 18 months are as follows: Response % Response p value* 400 mg/day 800 mg/day CR=Complete remission, Molecular Major=BCR-ABL/ABL <0.05%, Molecular CR=BCR-ABL undetectable (confirmed by nested PCR), *p value by log-rank Median follow-up (months) 36 19 Cytogenetic CR 81 96 0.0002 Cytogenetic Major 99 93 0.15 Molecular Major 47 67 0.0007 Molecular CR 8 24 0.02 Four pts treated with SD have transformed (3 to BP, 1 to AP) and 3 (2 to BP, 1 to AP) in the HD groups (p=0.05) (median time to transformation 11 mo, range 3 to 27). Estimated progression-free survival at 12 mo is 92% in the SD group and 99% in the HD group (p=0.42) (p=0.12 for the estimated transformation-free-survival, 94% and 99% for SD and HD at 12 mo). 4 have died (1 in SD and 3 in HD). Extramedullary toxicity was similar in the 2 groups, but myelosuppression was more common with HD, with grade ≥3 anemia, neutropenia and thrombocytopenia occurring in 7%, 39%, and 27% of pts receiving HD, respectively, and 4%, 20% and 12% of pts receiving SD. At 12 mo, the median actual dose for the HD group is still 800mg, with 40/112 (36%) evaluable having required dose reduction. This compares with 7/43 (14%) of those treated with SD. We conclude that high-dose imatinib results in higher rates of complete cytogenetic and molecular remissions, with some increase in myelosuppression.

Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer (mCRC): Assessment as prognostic and predictive biomarkers of response to panitumumab (pmab).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3581-3581 ◽  
Author(s):  
Marc Peeters ◽  
Jean-Yves Douillard ◽  
Eric Van Cutsem ◽  
Salvatore Siena ◽  
Kathy Zhang ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Allele Distribution ◽  
Three Phase ◽  
Epidermal Growth ◽  
Codon 12 And 13 ◽  
Kras Codon

3581 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR). Significant improvement in progression-free survival (PFS) was demonstrated in pts with wild-type (WT) KRAS mCRC treated with pmab+FOLFOX4 (1st-line; study 20050203), pmab+FOLFIRI (2nd-line; study 20050181), and pmab monotherapy (study 20020408). In mCRC, mutations in KRAS codons 12 and 13 are established biomarkers for lack of clinical benefit to anti-EGFR therapies. We retrospectively examined individual MT KRAS codon 12 and 13 alleles as prognostic and predictive biomarkers of response in three phase 3 studies. Methods: Pts were randomized to receive FOLFOX4, FOLFIRI, or best supportive care +/- pmab 6.0 mg/kg Q2W in trials 20050203, 20050181, and 20020408, respectively. The MT KRAS codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D) were detected using the Therascreen K-RAS Mutation Kit (Qiagen). Results: MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096), 45% (486/1083), and 43% (184/427) of pts in trials 20050203, 20050181, and 20020408, respectively. MT KRAS allele distribution was conserved across studies and balanced between treatment arms. Baseline demographic and clinical features were comparable between all MT KRAS allele subgroups. There was no consistent evidence that any individual MT KRAS allele, compared to the remaining MT KRAS alleles or the entire MT KRAS group, differentially impacted PFS or overall survival (OS) in control arm-treated or pmab-treated pts. Only in the pmab+FOLFOX4 arm of study 20050203 were G13D (unfavorably) and G12V (favorably) significantly associated with OS. Response rates were similar between MT KRAS allele groups in the 1st- and 2nd-line mCRC treatment setting. Finally, in analyses of pts pooled from all 3 trials, only the G12A KRAS allele emerged as a significant negative predictive factor for OS. Conclusions: The lack of consistent results across three lines of therapy indicates pts whose tumors harbor MT KRAS codon 12 or 13 alleles are unlikely to respond to pmab therapy. Currently, only pts with WT KRAS mCRC should be treated with EGFR antibodies.

Panel of serum biomarkers to predict benefit from bevacizumab (BEV) in advanced NSCLC patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21069-e21069
Author(s):  
Eduardo Braun ◽  
Mary J. Fidler ◽  
Sanjib Basu ◽  
Anjali Gangaram ◽  
Kelly Kaiser Walters ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Progression Free Survival ◽  
Serum Levels ◽  
High Serum ◽  
Serum Biomarkers ◽  
Exploratory Analysis ◽  
P Value ◽  
Improved Outcomes ◽  
Pre Treatment ◽  
Nsclc Patients

e21069 Background: BEV has produced modest benefits in patients (PTS) with advanced NSCLC. Identification of positive predictors for BEV would have important implications for individual PTS and health care costs. Methods: We performed a prospective exploratory analysis to identify serum biomarkers as predictors of improved outcomes with BEV. Pre treatment sera were collected from 93 pts prior to initiation of first line treatment for advanced NSCLC. Treatment drugs, including BEV, were prescribed according to treating physician’s discretion. Seventy two serum biomarkers, relevant to angiogenesis and tumor progression, were recorded using Luminex immunobead platform. Serum levels were correlated with progression free survival (PFS) and overall survival (OS) and compared between patient treated with or without BEV containing regimens, BEV + and BEV- groups respectively. Log-rank and interaction p value tests were used to identify markers associated with longer PFS and OS in the BEV+ group but not in BEV- group. Results: Characteristics for each group were: BEV+ (n=43, median age 65 y/o, 72% smokers, 60% females, 100% non-squamous). BEV– (n=50, median age 64 y/o, 84% smokers, 50% female, 70 % non-squamous). The BEV+ group had longer PFS (5.8 vs. 3.0 mos, log-rank p= 0.039) and OS (13.1 vs. 8.5 mos, log-rank p =0.11) when compared to the BEV- group. High serum levels of these markers resulted in a differential decreased hazard in the BEV+ group: PDGF-AB/BB (interaction p <0.01 for PFS, p=0.04 for OS), FGF (interaction p=0.15 for PFS, p<0.04 for OS), tenascin-c (interaction p=0.18 for PFS, p=0.04 for OS), RANTES (interaction p=0.04 for PFS, p=0.6 for OS), epiregulin (interaction p=0.31 for PFS, p=0.04 for OS) and anti-HGF (interaction p=0.18 for PFS, p=0.03 for OS). In the BEV+ group higher levels of PDGF-AB/BB were associated with a better outcome (log-rank p=0.05 and p=0.01 for PFS and OS respectively). We did not find significant correlations between serum levels of VEGF, anti-VEGF or VEGFR and benefit from BEV. Conclusions: This exploratory analysis suggests that these biomarkers may have predictive value for BEV in NSCLC PTS and should be considered for further studies.

Tumor mutational burden (TMB) may be a promising predictive biomarker of response to PD-1/PD-L1 targeting in MSI-H colorectal cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 43-43 ◽  
Author(s):  
Marwan Fakih ◽  
Jaideep Singh Sandhu ◽  
Ching Ouyang ◽  
Ethan Sokol ◽  
Jeffrey S. Ross ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Large Data ◽  
Predictive Biomarker ◽  
Continuous Variable ◽  
Data Set ◽  
Cut Point ◽  
The Impact

43 Background: PD-1 targeting with pembrolizumab or nivolumab leads to durable clinical benefits in patients (pts) with microsatellite instability-high (MSI-H) tumors. However, 30-35% of mCRC pts with MSI-H tumors will experience progressive disease (PD) as a best response when treated with anti-PD1 agents, highlighting the need of additional predictive biomarkers. Methods: We performed a retrospective multi-center clinical investigation to evaluate the impact of TMB, age, gender, stage at initial presentation, pattern of metastatic disease, tumor grade, and RAS/RAF status on response to anti-PD1/PD-L1 in MSI-H mCRC. TMB and MSI status were determined by hybrid capture-based next-generation sequencing (Foundation Medicine [FM]). The TMB distribution in MSI-H CRC was estimated from a large data set from FM. Results: 22 eligible MSI-H mCRC pts were identified across 5 cancer centers: 19 pts received pembrolizumab, 1 pt received nivolumab, 1 pt received nivolumab + ipilimumab, and 1 pt received durvalumab + tremelimumab. Among tested variables, TMB (as a continuous variable) showed the strongest association with an objective response (OR; p < 0.001). Also, both univariate and multivariate analyses supported that TMB serves as an independent prognostic variable in predicting progression-free survival (PFS; p < 0.001 and p < 0.01, respectively). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37-41 mutations/Mb to dichotomize pts into TMBhigh and TMBlow groups. All 13 pts (100%) with TMBhigh had an OR, while only 2/9 (22%) pts with TMBlow had an OR and 6/9 had PD. The median PFS for TMBhigh pts has not been reached (no progressors, median follow-up > 18 mos), while the median PFS for TMBlow pts was 2 mos. Amongst 821 MSI-H CRC cases tested at FM, the 25th, 35th, 50th and 75th percentile TMB cutoffs were 33.1, 37.4, 46.1, and 61.8 mutations/Mb, respectively. Our optimal TMB cut-point range suggests that MSI-H mCRC with the lowest 35th percentile of TMB have a low likelihood of benefit from anti-PD1. Conclusions: These TMB findings require validation in prospective trials and may guide the sequencing of PD-1 inhibitor monotherapy in MSI-H mCRC.

Whole blood FOLH1 mRNA expression and treatment response in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 188-188
Author(s):  
Edmond Michael Kwan ◽  
Sarah Q To ◽  
Heidi C Fettke ◽  
Maria M Docanto ◽  
Patricia Bukczynska ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Whole Blood ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Response Rates ◽  
Predictive Biomarker ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Psa Response ◽  
Pre Treatment

188 Background: Identifying predictive biomarkers for mCRPC patients receiving androgen receptor signalling inhibitors (ARSI) or chemotherapy remains an unmet clinical need. FOLH1 encodes for Prostate-Specific Membrane Antigen (PSMA), a type II glycoprotein highly expressed on prostate cancer cells. We designed a whole blood assay to detect FOLH1 mRNA, and correlated expression with clinical outcomes in patients commencing ARSI (abiraterone or enzalutamide) or chemotherapy (docetaxel or cabazitaxel). Methods: mCRPC patients commencing ARSI or chemotherapy were prospectively recruited at three Australian centres from June 2016 to July 2018. A quantitative reverse transcription polymerase chain reaction assay was used to detect FOLH1 transcript from whole blood samples collected in PAXgene® RNA tubes. Pre-treatment FOLH1 expression was correlated with PSA response rate (Fisher’s exact test) and PSA progression-free survival (PSA-PFS) (log-rank test). Results: Median follow-up was 13.6 months (IQR 9.7–19.3). In total, 88 pre-treatment samples were analysed, of which 75 (85%) were FOLH1-positive. In patients receiving ARSI, outcomes favoured FOLH1-positive patients compared to FOLH1-negative patients, with higher PSA response rates (39/60, 65% vs. 2/7, 29%; p = 0.1) and longer PSA-PFS (median 9.0 months [95% CI, 7.2-10.8] vs. 2.8 months [95% CI, 2.3-3.3]; p = 0.03). Conversely, in chemotherapy-treated patients, inferior outcomes were observed in FOLH1-positive patients compared to FOLH1-negative patients, with lower PSA response rates (4/15, 27% vs. 5/6, 83%, p = 0.05) and shorter PSA-PFS (median 2.9 months [95% CI, 2.8-3.0] vs. 4.1 months [95% CI, 3.7-4.5]; p = 0.32). Conclusions: Pre-treatment FOLH1 expression may differentiate between outcomes on ARSI vs. chemotherapy in mCRPC patients. The utility of FOLH1 as a predictive biomarker in mCRPC warrants further evaluation in larger, independent cohorts. [Table: see text]

Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer (mCRC): Assessment as prognostic and predictive biomarkers of response to panitumumab (pmab).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 383-383 ◽  
Author(s):  
Marc Peeters ◽  
Jean-Yves Douillard ◽  
Eric Van Cutsem ◽  
Salvatore Siena ◽  
Kathy Zhang ◽  
...  
Keyword(s):  
Predictive Factor ◽  
Human Monoclonal Antibody ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Allele Distribution ◽  
Codon 12 And 13 ◽  
Kras Codon ◽  
Negative Predictive Factor

383 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR). Significant improvement in progression-free survival (PFS) was demonstrated in pts with wild-type (WT) KRAS mCRC treated with pmab+FOLFOX4 (1st-line; study 20050203), pmab+FOLFIRI (2nd-line; study 20050181), and pmab monotherapy (study 20020408). In mCRC, mutations in KRAS codons 12 and 13 are established biomarkers for lack of clinical benefit to anti-EGFR therapies. We retrospectively examined individual MT KRAS codon 12 and 13 alleles as prognostic and predictive biomarkers of response in three phase 3 studies. Methods: Pts were randomized to receive FOLFOX4, FOLFIRI, or best supportive care +/- pmab 6.0 mg/kg Q2W in studies 20050203, 20050181, and 20020408, respectively. The MT KRAS codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D) were detected using the Therascreen K-RAS Mutation Kit (Qiagen). Results: MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096), 45% (486/1083), and 43% (184/427) of pts in studies 20050203, 20050181, and 20020408, respectively. MT KRAS allele distribution was conserved across studies and balanced between treatment arms. Baseline demographic and clinical features were comparable between all MT KRAS allele subgroups. Across all studies, no single MT KRAS allele was consistently prognostic for PFS or overall survival (OS) in the control arm-treated pts. Similarly, no single MT KRAS allele was a consistent positive or negative predictive factor for PFS or OS in pmab-treated pts. Only in the pmab+FOLFOX4 arm of study 20050203 were G13D (unfavorably) and G12V (favorably) significantly associated with OS. Response rates were similar between MT KRAS allele groups in the 1st- and 2nd-line mCRC treatment setting. Finally, in analyses of pts pooled from all 3 trials, only the G12A KRAS allele emerged as a significant negative predictive factor for OS. Conclusions: The lack of consistent results across three lines of therapy indicates pts with MT KRAS codon 12 or 13 alleles are unlikely to respond to pmab therapy. Currently, only pts with WT KRAS mCRC should be treated with pmab.

CCTG CO.26: Updated analysis and impact of plasma-detected microsatellite stability (MSS) and tumor mutation burden (TMB) in a phase II trial of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with refractory metastatic colorectal carcinoma (rmCRC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3512-3512 ◽  
Author(s):  
Eric Xueyu Chen ◽  
Derek J. Jonker ◽  
Jonathan M. Loree ◽  
Hagen F. Kennecke ◽  
Scott R. Berry ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Best Supportive Care ◽  
P Value ◽  
Free Survival ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Microsatellite Stability ◽  
Worse Prognosis ◽  
Clinical Trial Information

3512 Background: Targeting both PD-L1 and CTLA-4 may be synergistic immunotherapy approaches. CO.26 evaluated if dual inhibition leads to improved pt survival vs BSC alone in rmCRC. Methods: rmCRC pts were randomized 2:1 to D+T vs BSC. Treatment consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and supportive measures. Primary endpoint was overall survival (OS). Two-sided p < 0.10 was considered statistically significant. Cell-free (cf)DNA sequencing for MSI and TMB used GuardantOMNI panel and baseline plasma. Results: From 08/2016-06/2017, 180 pts were enrolled. Pt characteristics were balanced between arms. At median follow-up of 15.2 months (mos), median OS was 6.6 mos for D+T and 4.1 mos for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 mos vs 1.9 mos, respectively (HR 1.01, 90% CI 0.76 – 1.34). Disease control rate (DCR) was 22.6% for D+T and 6.6% for BSC (p = 0.006). cfDNA analysis was successful in 168/169 pts (99.4%). Two pts were MSI-high. In 166 MSS pts, OS HR was 0.66 (p=0.024; 90% CI 0.49-0.89). Excluding the MSI-H cases (TMB of 74.7 and 247.1 mts/Mb), mean TMB was 20.4 ± 16.3 mts/Mb (range: 0.96 – 114.0). In MSS pts, a pre-specified cutpoint of 20 mts/Mb stratified pts into high and low TMB groups but was not predictive for OS , PFS, or DCR (interaction p-values > 0.7). Using a minimum p-value approach, pts with TMB >28 mts/Mb (21% of MSS pts) had the greatest OS benefit (HR 0.34, 90% CI 0.18-0.63) for D+T (interaction p = 0.07). High TMB was associated with a trend in worse prognosis for OS in the BSC arm using both 20 mts/Mb (HR 1.26, 90% CI 0.76-2.12) and 28 mts/Mb (HR 2.59 90% CI 1.46-4.62) cutpoints. Conclusions: D+T significantly prolonged OS in pts with rmCRC. High TMB may select a group of MSS pts who benefit from D+T. Plasma TMB appeared prognostic in the BSC arm. This is the first study showing combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with MSS rmCRC. Updated results based on deaths in more than 90% of pts will be presented. Clinical trial information: NCT02870920.

Predictive value of germline ATM mutations in the CCTG PA.7 trial: Gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D) and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4135-4135
Author(s):  
Daniel John Renouf ◽  
Jonathan M. Loree ◽  
Jennifer J. Knox ◽  
Petr Kavan ◽  
Derek J. Jonker ◽  
...  
Keyword(s):  
Predictive Value ◽  
Checkpoint Inhibitors ◽  
High Plasma ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Mutation Status ◽  
First Line Therapy ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Pre Treatment

4135 Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy. A previous analysis of the PA.7 data demonstrated high plasma based TMB (≥9 mut/Mb) was associated with improved OS in the Gem, Nab-P, D+T arm. DNA repair pathway aberrations beyond mismatch repair have been associated with potential immune sensitivity. We assessed the predictive value of germline ATM mutations in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the Predicine ATLAS next generation assay (600 gene, 2.4 Mb panel). 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B) There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma analysis was performed on 174/180 pts with available samples. 16/174 (9.2%) pts had germline ATM mutations, 12 in arm A and 4 in arm B. GEM, Nab-P, D+T was associated with improved OS in patients with ATM mutations (HR 0.10, 90% CI 0.03-0.37; median OS 13.9 months vs. 4.9 months) while no activity was seen in pts with ATM Wild Type (HR 0.99, 90% CI 0.73-1.33; median OS 9.79 months vs. 10.2 months); interaction p = 0.014. Germline ATM mutation status was independent of plasma TMB levels (Wilcoxon p = 0.76). Conclusions: Germline ATM mutation appeared predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. In addition to previous data from this trial regarding the predictive value of high plasma TMB (≥9 mut/Mb), this data further supports that there may be independent subgroups of PDAC, beyond MSI-H, that may benefit from immunotherapy, and trials evaluating immunotherapy in subgroups of PDAC with these profiles are warranted. Clinical trial information: NCT02879318.

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