scholarly journals Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer

2018 ◽  
Vol 36 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Vivek Subbiah ◽  
Robert J. Kreitman ◽  
Zev A. Wainberg ◽  
Jae Yong Cho ◽  
Jan H.M. Schellens ◽  
...  
Keyword(s):  
Overall Survival ◽  
Thyroid Cancer ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Anaplastic Thyroid Cancer ◽  
Braf V600e ◽  
Free Survival ◽  
Overall Response ◽  
Duration Of Response

Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E–mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E–mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E–mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Efficacy of bevacizumab and temozolomide therapy in locally advanced, recurrent, and metastatic malignant solitary fibrous tumour: A population-based analysis

2018 ◽  
Vol 25 (6) ◽  
pp. 1301-1304 ◽  
Author(s):  
Mário L de Lemos ◽  
Isabell Kang ◽  
Kimberly Schaff
Keyword(s):  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Locally Advanced ◽  
Case Series ◽  
Progression Free Survival ◽  
Population Based ◽  
Solitary Fibrous Tumour ◽  
Free Survival ◽  
Overall Response

Background Patients with locally advanced, recurrent or metastatic solitary fibrous tumour are often treated with bevacizumab and temozolomide based on the clinical efficacy reported in a case series of 14 patients. Given the rarity of solitary fibrous tumour, large trials are not feasible. We report the efficacy of this regimen based on a population-based analysis. Methods This was a population-based retrospective, multi-centre analysis using patient data from a provincial cancer registry and treatment database. Cases from June 2006 through October 2016 were identified for patients receiving bevacizumab and temozolomide for locally advanced, recurrent or metastatic solitary fibrous tumour or hemangiopericytoma, which is sometimes used to describe tumours arising from the meninges. The primary outcome was overall response rate. Secondary outcomes included time to response, progression free survival and overall survival estimated using the Kaplan–Meier method. Results Fourteen patients were identified: median age 59 (range 44–70), male 78.6%. Diagnoses were solitary fibrous tumour in 10 (71.4%) and hemangiopericytoma in four (28.6%), with metastatic disease in 10 (72.7%) patients. The most common primary sites were meninges in four (28.6%) and pelvis in three (21.4%) patients. The median follow-up was 15.5 months, with median treatment of four months. Overall response rate was 21.4% (no complete response, 3 partial response), with median time to response of four months. Median progression free survival, six-month progression free survival and overall survival were 17 months, 65.0%, and 45 months, respectively. Conclusions Efficacy of bevacizumab and temozolomide in solitary fibrous tumour appeared to be similar to that previously reported. Our findings confirmed that bevacizumab and temozolomide is an effective and tolerated treatment for this patient population.

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

scholarly journals Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252665
Author(s):  
Christine S. Walsh ◽  
Mitchell Kamrava ◽  
Andre Rogatko ◽  
Sungjin Kim ◽  
Andrew Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Interim Analysis ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Free Survival ◽  
Platinum Resistant ◽  
Duration Of Response

Objective To evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. Methods Patients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3–6 and as maintenance monotherapy in cycles 7–34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival. Results An interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual. Conclusions The addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer.

The efficacy and safety of lenvatinib in the treatment of solid tumors: an up-to-date meta-analysis

2021 ◽  
Author(s):  
Wen jie Xie ◽  
Shuai Zhang ◽  
Lei Su ◽  
Yan hong Li ◽  
Xi Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Meta Analysis ◽  
Severe Infection ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Overall Response

Aim: We performed an updated meta-analysis to evaluate the efficacy and safety of lenvatinib in cancer patients. Materials & methods: Databases were searched to identify relevant trials. Data were extracted to evaluate overall survival, progression-free survival, overall response rate and grade ≥3 adverse events. Results: The pooled analysis demonstrated that lenvatinib significantly improved progression-free survival (hazard ratio: 0.43; 95% CI: 0.23–0.80; p = 0.008), overall survival (hazard ratio: 0.85; 95% CI: 0.75–0.97; p = 0.013) and overall response rate (relative risk: 6.89; 95% CI: 2.22–21.36; p = 0.001) compared with control therapy. However, the use of lenvatinib can increase the risk of severe infection. Conclusion: Lenvatinib-containing regimens are associated with better progression-free survival, overall survival and overall response rate, but can induce severe infection.

scholarly journals Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma

2021 ◽  
pp. JCO.20.03433 ◽  
Author(s):  
Nathan H. Fowler ◽  
Felipe Samaniego ◽  
Wojciech Jurczak ◽  
Nilanjan Ghosh ◽  
Enrico Derenzini ◽  
...  
Keyword(s):  
Adverse Event ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Dual Inhibitor ◽  
Free Survival ◽  
Pi3k Inhibitors ◽  
Overall Response ◽  
Duration Of Response ◽  
Grade 3

PURPOSE Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL. PATIENTS AND METHODS In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20–based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety. RESULTS The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients. CONCLUSION Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event–related discontinuations.

First Analysis of a Phase II Study of Rituximab-Gemcitabine, Cyclophosphamide, Vincristine and Prednisolone (R-GCVP) for Diffuse Large B Cell Lymphoma (DLBCL) Patients Considered Unsuitable for Anthracycline Containing Chemo-Immunotherapy. An NCRI Lymphoma Clinical Studies Group Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1634-1634
Author(s):  
Paul Fields ◽  
Andrew Webb ◽  
Christopher FE Pocock ◽  
William Townsend ◽  
Paul Smith ◽  
...  
Keyword(s):  
Overall Survival ◽  
Ejection Fraction ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Overall Response ◽  
End Of Treatment ◽  
Grade 3

Abstract Abstract 1634FN2 Introduction: The treatment of patients with DLBCL who are unsuitable for anthracycline containing chemotherapy remains a clinical challenge. Gemcitabine is a nucleoside analogue which has proven efficacy in the relapse setting in both non Hodgkin's and Hodgkin's lymphoma. We therefore developed a protocol incorporating Gemcitabine in a first line approach combined with CVP-R chemo-immunotherapy in DLBCL patients considered unfit for anthracycline containing chemotherapy. Methods: We performed a prospective, multicentre phase II trial in patients with DLCBL who were considered unfit for anthracycline containing chemo-immunotherapy. Eligibility criteria included ejection fraction < 50%, or ejection fraction ≥ 50% but with the presence of attendant significant co-morbidities (including: ischaemic heart disease, hypertension, diabetes mellitus), and ECOG PS 0–3. Patients received 6 cycles of Rituximab (375 mg/m2 IV D1), Cyclophosphamide (750mg/m2 IV D1), Vincristine (1.4 mg /m2 IV D1), Prednisolone (100mg, orally D1–5) and Gemcitabine IV D1 and D8. The Gemcitabine dose, if tolerated was sequentially escalated from 750mg/m2 in cycle 1 to 875mg/m2 in cycle 2 to 1000mg/m2 in cycle 3 with the dose maintained at 1000mg/m2 for cycles 4–6. Cycles were repeated every 21 days with growth factor support administered on day 9 of each cycle (pegfilgrastrim 6mg s/c).The primary endpoint was to achieve an overall response rate of > 40% assessed by CT scan at the end of treatment according to the Cheson criteria. Secondary endpoints were progression free survival and overall survival. Results: 62 patients were recruited from 32 UK sites over a 28 month period from April 2008 to July 2010. 66% were male. Median age was 76 years (range 52–90), 48 (77%) were > 70 years. 43 (69%) had stage III/IV disease and 46 (72%) had high – intermediate or high IPI (3–5) disease. ECOG performance status was ≥ 2 in 50% patients. Left ventricular ejection fraction (LVEF) was < 50% in 28 patients (45%). The 34 patients with LVEF ≥ 50% had significant co-morbidities, 22 (65%) had multiple co-morbidities. 44 (70%) received ≥ 3 cycles of treatment, reasons for early termination of treatment in the remaining 18 patients were progression (n=2), toxicity (n=5), death (n=6) patient choice (n=1) and other (n=4). 29 patients (47%) received the full 6 cycles. A total of 250 treatment cycles were delivered. Of the 44 patients who received ≥ 3 cycles of treatment, the dose of Gemcitabine was escalated to the full dose (1000mg/m2) in 67%. Day 8 Gemcitabine was delivered in 215/250 (86%) cycles of treatment. The overall response rate (CR/CRu/PR) at end of treatment for all 62 patients was 60%. For patients who received ≥ 3 cycles of treatment (n =44) the ORR was 79.5% at the end of treatment. There was no significant difference in ORR between those with LVEF <50% and those with LVEF ≥ 50% (71% vs 53%, p=0.155). At a median follow up of 18.2 months the 1 year progression free survival rate for all patients was 52.9% (95% CI 39.4–64.8). The 1 year overall survival (OS) rate is 62.4% (95% CI 48.5–73.6). For the group with LVEF <50% OS was 70.8% (95% CI: 48.4, 84.9) and LVEF group ≥ 50% OS was 55.9% (95% CI 37.1–71).Grade 3/4 haematological toxicity was observed in 54.1% patients. Grade 3/4 infection was observed in 24.6% of patients. The death rate observed related to infection for the whole cohort was 11%. Conclusion: This multicentre trial demonstrates that the R-GCVP regimen delivers excellent overall response rates with durable remissions in a group of patients where anthracycline use was precluded. The efficacy attained in this difficult group of patients provides a platform for testing the regimen in subsequent randomised phase II and phase III studies to confirm its efficacy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study

2019 ◽  
Vol 37 (17) ◽  
pp. 1460-1469 ◽  
Author(s):  
Eric Van Cutsem ◽  
Sanne Huijberts ◽  
Axel Grothey ◽  
Rona Yaeger ◽  
Pieter-Jan Cuyle ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Braf V600e ◽  
Phase Iii ◽  
Cancer Trial ◽  
Free Survival

PURPOSE To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35). PATIENTS AND METHODS Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E–mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E–mutant tumors (one patient had a non– BRAF V600E–mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E–mutant mCRC.

scholarly journals Statystyka w praktyce hematologicznej

2018 ◽  
Vol 49 (3) ◽  
pp. 121-127
Author(s):  
Iga Andrasiak ◽  
Tomasz Wróbel
Keyword(s):  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Patient Reported Outcome ◽  
Free Survival ◽  
Overall Response ◽  
Patient Reported

StreszczenieWraz ze stale rosnącą liczbą badań w dziedzinie hematologii, znajomość metod statystycznych wykorzystywanych w analizie i interpretacji wyników stała się niezbędnym narzędziem pracy klinicystów. W artykule omówiono najczęściej stosowane testy statystyczne oraz zdefiniowano punkty końcowe stosowane podczas raportowania rezultatów badań klinicznych. Testy statystyczne funkcjonują na zasadzie testowania hipotez. Odrzucenie lub nieodrzucenie danej hipotezy zależy od wybranego poziomu istotności oraz wyliczonej wartości p. Z kolei otrzymany przedział ufności wskazuje na wielkość efektu i precyzję oszacowania. W hematologii głównie raportowanymi punktami końcowymi są: całkowite przeżycie (ang. overall survival – OS), przeżycie wolne od progresji (ang. progression-free survival – PFS), odpowiedź na leczenie (ang. overall response rate – ORR) oraz coraz częściej spotykana, ocena terapii raportowana przez pacjenta (patient reported outcome – PRO). Biorąc pod uwagę kierunek rozwoju medycyny, znajomość biostatystyki jest niezbędna w podejmowaniu decyzji terapeutycznych, a także ocenianiu, interpretowaniu i raportowaniu wyników przeprowadzonych badań.

246 Clinicopathologic and genomic correlates of tumor mutational burden and its impact on PD-(L)1 inhibition efficacy in non-small cell lung cancer according to different PD-L1 expression subgroups

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A266-A267
Author(s):  
Biagio Ricciuti ◽  
Navin Mahadevan ◽  
Renato Umeton ◽  
Joao Alessi ◽  
Andrew Polio ◽  
...  
Keyword(s):  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Recursive Partitioning ◽  
Progression Free Survival ◽  
Small Cell Lung ◽  
Free Survival ◽  
Overall Response ◽  
Mutational Burden ◽  
Tumor Mutational Burden

BackgroundHigh tumor mutational burden (TMB) and PD-L1 expression are associated with improved clinical outcomes in patients (pts) with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). However, how TMB performs as a predictive biomarker to ICIs in different PD-L1 expression subgroups is not well characterized.MethodsWe collected clinicopathologic and genomic data from NSCLCs which underwent targeted NGS and TMB assessment at DFCI. An unbiased recursive partitioning (URP) algorithm was used to investigate an optimal TMB cut-off with respect to objective response rate (ORR) in the subset of pts treated with ICIs. This TMB cut-off was then validated in the prospective POPLAR/OAK cohort.ResultsAmong 3560 NSCLCs identified, median TMB was significantly higher among current smokers compared to former (P<0.0001) and never smokers (P<0.0001), and there was a significant correlation between TMB and pack-years (figure 1A-B). Pts with BRAF or KRAS mutations had the highest median TMB (10.9 and 9.8 mutations/Megabase [mut/Mb], respectively), while tumors with RET and ALK alterations had the lowest median TMB of 5.3 mut/Mb (figure 2A-B). Tumors with PD-L1 expression of ≥50% had significantly higher median TMB compared to those with a PD-L1 expression of 1–49% (P=0.002) and <1% (P<00001). Among pts treated with ICIs (N=690), URP identified an optimal grouping TMB cut-off for ORR of 19.0 mut/Mb, which corresponded to the 90th percentile. Pts with a TMB of ≥19.0 mut/Mb had a significantly higher ORR (45.2% vs 20.1%, P<0.0001) and longer median PFS (11.0 vs. 2.9 months, HR:0.49, P<0.0001) and OS (20.8 vs. 11.2 months, HR:0.59, P=0.001) compared to those with a TMB of <19.0 mut/Mb (figure 3A-C). A TMB of ≥19.0 mut/Mb was an independent predictor of improved PFS and OS at multivariable analysis (table 1). A TMB within the top 10th percentile was confirmed to correlate with improved ORR and PFS in atezolizumab arm but not in the docetaxel arm of the POPLAR/OAK trials (figure 4A-B). When TMB and PD-L1 where integrated in the URP, we identified an optimal cut-off of 19 mut/Mb among cases with a PD-L1 expression of ≤25%, and of 8.4 mut/Mb among those with a PD-L1 expression of >25%, suggesting that TMB differentially impacts response to immunotherapy among PD-L1 high versus low NSCLCs (figure 5).Abstract 246 Figure 1(A) Correlation between TMB and smoking status. (B) Linear correlation between TMB and pack-years on a continuous scaleAbstract 246 Figure 2(A) TMB distribution across genomically defined subsets of NSCLC. (B) Pairwise comparison in TMB distribution among genomically defined subsets of NSCLC. Reported in each box are the Q-values for each comparison (FDR method of Benjamini and Hochberg)Abstract 246 Figure 3(A) Overall response rate, (B) progression-free survival and (C) overall survival to PD-(L)1 inhibition in patients with NSCLC and a TMB of ≥19.0 vs <19.0 mut/Mb, as determined by unbiased recursive partitioningAbstract 246 Figure 4(A) Overall response rate, progression-free survival and overall survival to atezolizumab in patients enrolled in the POPLAR/OAK trials and a bTMB of ≥25 (top 10th percentile) vs <25.0 (lower 90th percentile) mut/Mb. (B) Overall response rate, progression-free survival and overall survival to docetaxel in patients enrolled in the POPLAR/OAK trials and a bTMB of ≥25 (top 10th percentile) vs <25.0 (lower 90th percentile) mut/Mb. bTMB, blood tumor mutational burdenAbstract 246 Figure 5Unbiased regression tree algorithm recursively identifies that different TMB cut-offs impact response to immunotherapy in PD-L1 TPS high (≥25) vs low (<25%) NSCLCs. TPS, tumor proportion scoreAbstract 246 Table 1Multivariable Cox regression for PFS and OS among patients with NSCLC treated with PD-(L)1 blockade.ConclusionsThe impact of TMB may vary across PD-L1 expression subgroups. Rational integration of TMB and PD-L1 expression may identify NSCLCs with the greatest likelihood of response or resistance to ICIs.Ethics ApprovalClinicopathologic data were collected from patients with advanced NSCLC who had consented to a correlative research study (DF/HCC protocol #02-180).

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