Outcome of KRAS mutated (m) non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (immuneCI).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20526-e20526
Author(s):  
Nuria Pardo Aranda ◽  
Cristina Viaplana ◽  
Jordi Remon ◽  
Alex Martinez Marti ◽  
Susana Cedres Perez ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Current Smoker ◽  
Rank Test ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Smoking Pattern ◽  
Third Line ◽  
Metastatic Sites ◽  
Nsclc Patients

e20526 Background: The most frequent genetic alteration in advanced NSCLC is KRASm in ~25% of tumors. This event associates with smoking pattern and high mutational burden, which correlate with the efficacy of CI in NSCLC. There is in silico evidence that coexisting KRASm and TP53m positively impact immuneCI benefit , but this association needs clinical validation. Methods: We retrospectively assess the efficacy of PD-1/PDL-1 CI (atezolizumab, pembrolizumab, nivolumab or durvalumab) in a cohort of NSCLC patients whose tumors were KRASm (with or without coexisting TP53m) as assessed by a next-generation sequencing test. Endpoints were clinical benefit rate (CBR), defined as partial response or stable disease > 4 months (m), and time to progression (TTP) on immuneCI. Fisher-exact test and log-rank test P values are described. Results: 25 pacients were identified, 68% female, median age 54 y (33-75), 95% former/current smoker; 95% adenocarcinoma; 59% with 2 or more metastatic sites; 36% immuneCI as third-line or beyond (median time from first-line to immuneCI of 7.5 m). 20 tumors had KRASm in codon 12, 3 codon 13 and 2 in codon 61. Overall, CBR was 36% (CI95% 19%-57%) and median TTP was 3.7 m (CI95% 2.2-NA). Coexisting KRASm/ TP53m (n = 11) did not associate with higher CB (27% vs 50%, p = 0.56). A trend for lower TTP in the KRASm/ TP53m vs TP53 wild-type was observed (2.1 vs 5.6 m, HR 0.3; p = 0.11). Conclusions: NSCLC patients whose tumors are KRASm can have substantial benefit with immuneCI. In our series, the population with KRASm/ TP53m tumors did not derive higher clinical benefit from this therapeutic intervention

Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xuanzong Li ◽  
Linlin Wang
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Rank Test ◽  
Wild Type ◽  
Exact Test ◽  
Entire Cohort ◽  
Kaplan Meier ◽  
Tumor Mutational Burden ◽  
The Difference ◽  
Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

Clinical characteristics of NSCLC harboring ALK 2p23 translocation at Cleveland Clinic.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18085-e18085
Author(s):  
Yan Feng ◽  
Nathan A. Pennell ◽  
Julia Samsa ◽  
Christopher Lanigan ◽  
A. Valeria Arrossi ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Cleveland Clinic ◽  
Cost Effective ◽  
Molecular Therapy ◽  
Screening Tests ◽  
Rank Test ◽  
Available N ◽  
Exact Test ◽  
Metastatic Sites ◽  
Nsclc Patients

e18085 Background: The ALK 2p23 translocation, ALK(+), is an important druggable target in 5-7% of non-small cell lung cancer (NSCLC). However, the break-part FISH assay is labor-intensive. Better understanding of the target population’s clinical features and alternative screening tests are desirable to enable cost-effective patient selection for molecular therapy. Methods: NSCLC patients (N=120) seen at the Cleveland Clinic (CC) who had clinical screening ALK 2p23 FISH (Abbott Molecular) were included in this retrospective analysis. Biopsy specimens were also tested using immunohistochemistry (IHC) for ALK overexpression via clone D5F3 (Cell Signaling Tech.) with OptiView ultrasensitive detection (Ventana Medical Sys.). Clinical data were extracted from electronic medical records. Comparison was performed using Fisher’s exact test, Wilcoxon rank sum test or log-rank test. Results: Of the 120 tumors tested, 34 (28.3%) were ALK(+) by FISH, predominantly adenocarcinomas (33/34). 97% of the samples were also tested by ALK-IHC, with a concordance rate of 99%. Comparing to ALK (-) group, ALK(+) patients were younger (median 53 vs 65, p<0.01) and mostly never/light smokers (91% vs 43%, p<0.01). ALK(+) tumors tended to have higher number of metastatic sites at diagnosis, especially for liver metastasis (26.5% vs 10.5%, p=0.04). Interestingly, venous thrombosis (DVT/PE) was also significantly more common in ALK(+) patients (35.3% vs 16.3%, p=0.03). 17 (50%) patients were treated with crizotinib in the ALK(+) group. Two cases with positive screening ALK-IHC helped to identify FISH(+) tumor areas. Of those tumors with EGFR status available (n=103), 6 were EGFR mutation-positive, all being ALK(-). No significant OS difference was seen in ALK(+)/EGFR(-) patients (n=28) compared to ALK(-)/EGFR(-) patients (n=69). Conclusions: ALK 2p23 (+) NSCLC at CC was more commonly seen in younger patients and never/light smokers. They tended to have greater number of metastases, especially in the liver, and significantly higher risk of venous thrombosis. ALK-ultrasensitive IHC using the D5F4 clone helped to identify FISH(+) tumor areas and may be considered a cost-effective screening test demonstrating high concordance with ALK FISH.

Lymphocytes and neutrophils count after two cycles and TTF1 expression as early outcome predictors during immunotherapy (IT) in stage IV non-small cell lung cancer (NSCLC) patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20553-e20553 ◽  
Author(s):  
Iosune Baraibar ◽  
Ricardo Oroz ◽  
Marta Roman ◽  
Patricia Martin ◽  
Mariano Ponz-Sarvisé ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Benefit ◽  
Stage Iv ◽  
Response To Treatment ◽  
Rank Test ◽  
Exact Test ◽  
Early Predictors ◽  
Small Series ◽  
Student’S T ◽  
Nsclc Patients

e20553 Background: NSCLC therapeutic paradigm has changed with immune checkpoint blockers. Biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT. Methods: We retrospectively analyzed 26 consecutive patients with stage IV NSCLC treated with IT at Clínica Universidad de Navarra (Spain) during 2016. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC ( < 1,000 vs > 1,000) and ANC ( < 4,000 vs > 4,000) after 2 cycles and response to IT. TTF-1 expression was correlated with treatment response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC. Results: An ALC increase after 2 cycles was significantly associated with DCR compared to progression (192 vs -155; p = 0.043). ALC > 1,000 after 2 cycles was more frequent among patients experiencing DCR compared to progression (87% vs 50%; p = 0.07). ALC > 1,000 after 2 cycles was more frequently observed among patients with TTF1+ tumors (93% vs 55%; p = 0.03). Patients with ANC < 4,000 showed a longer median OS (NR vs 19.25 months; p = 0.03). TTF1 expression in adenocarcinoma (n = 18) was associated with response to IT (83% vs 16%, p = 0.01). Conclusions: Despite this retrospective small series’ limitations, our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger prospective series.

Association of immune-related adverse events (irAEs) with clinical benefit in patients with metastatic urothelial carcinoma (mUC) treated with immune-checkpoint inhibitors (ICIs).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16038-e16038 ◽  
Author(s):  
Nuzzo Pier Vitale ◽  
Gregory Russell Pond ◽  
Sarah Abou Alaiwi ◽  
Amin Nassar ◽  
Ronan Flippot ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Tumor Burden ◽  
Rank Test ◽  
P Value ◽  
Exact Test ◽  
Objective Reduction ◽  
Clinical Benefits ◽  
Grade 3

e16038 Background: In other cancers such as metastatic lung and melanoma, pts who experience irAEs may have a greater degree of clinical benefit. We sought to evaluate whether the development of irAEs correlates with clinical benefits in mUC pts. Methods: We identified mUC pts who received PD-1/L1 inhibitors at the Dana-Farber Cancer Institute (DFCI). The severity of irAEs was graded using CTCAE v.5.0. Clinical benefit was defined as any objective reduction (complete- or partial- response) in tumor burden. Fisher’s exact test was used to evaluate for differences in the proportion of pts experiencing clinical benefit between pts experiencing an irAEs within 90 days after starting therapy and those who did not experience an irAEs. The log-rank test assessed differences in progression-free survival (PFS) and overall survival (OS) between cohorts. Results: A total of 199 mUC pts were enrolled between July 2013 and October 2018 [median (range) age, 69.6 (26.6-89.0) years; 141 men (70.9%), 58 women (29.1%)]. 114 (57.3%) pts were treated with anti-PD-1 and 85 (42.7%) with anti-PD-L1. irAEs were observed in 67 pts (33.7%), of which 34 (17.1%) < 90 days from start of therapy. Common irAEs included 20 (29.9%) hypothyroidism, 17 (25.4%) colitis, 12 (17.9%) rash/pruritus, and 10 (14.9%) transaminitis. Grade ≥3 irAEs were observed in 14 pts (20.9%).13 (40.6%) pts with irAE < 90 days experienced clinical benefit compared with 21 (17.8%) of pts with no irAE (p-value = 0.008). No difference (p = 0.26 and 0.18) was observed for either PFS (6-month PFS = 19.2% vs 35.3% for no irAE and irAE < 90 days) or OS (1-year OS = 41.8% vs 57.7% for no irAE vs irAE < 90 days). Conclusions: The development of irAEs within 90 days from starting therapy in mUC pts may herald clinical benefit in pts with mUC. Further evaluation of this potential relationship in a large prospective study is warranted.

Cisplatin(P)-including triplets versus P-free doublets in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC): SICOG 0101 randomized trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7103-7103 ◽  
Author(s):  
P. Comella ◽  
S. Palmeri ◽  
G. De Cataldis ◽  
G. Filippelli ◽  
R. Cioffi ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Locally Advanced ◽  
Stage Iv ◽  
Standard Of Care ◽  
Rank Test ◽  
Stage Iiia ◽  
Log Rank Test ◽  
Grade 3 ◽  
Metastatic Sites ◽  
Nsclc Patients

7103 Background: We previously reported that triplets with P-gemcitabine (G) plus vinorelbine (V) (PGV) or paclitaxel (T) (PGT) prolonged the survival (S) of advanced NSCLC patients (pts) in comparison with P-based doublets (PG or PV). Aims of the present study were: (1) to compare (log-rank test) the S of P-based triplets vs P-free doublets, and (2) to compare (Fisher test) safety and response rate (RR) of T- and V-regimens. Methods: A 2x2 factorial design was adopted. Pts aged ≤ 70 years, with PS (ECOG) < 2, inoperable stage IIIA, IIIB, or IV NSCLC were randomly treated with: GV = G 1,000 mg/m2 + V 25 mg/m2 on day (D) 1 and 8; GT = G 1,000 mg/m2 + T 125 mg/m2 on D 1 and 8; PGV = P 50 mg/m2 on D 1 and 8 + GV; PGT = P 50 mg/m2 on D 1 and 8 + GT. In all arms, cycles were repeated Q 3 weeks. Only responder pts after 3 cycles received further chemotherapy (CT). Thoracic RT was delivered after CT to pts with intra-thoracic disease. 330 events were required to have a 90% power to demonstrate (two-sided P < 0.05) a 30% reduction of hazard of death. Results: From April 2001 to December 2005, 431 pts were recruited in the 4 arms. Characteristics in % were well balanced in P-based triplets and P-free doublets: males, 84/91; PS 0, 25/23; squamous cell carcinoma, 38/42; weight loss, 22/29; stage IV, 66/65; CNS metastases, 5/8; ≥ 2 metastatic sites, 29/30. So far, 411 pts were assessed for response: RR of triplets vs doublets was 88/204 (43%) vs 68/207 (33%) (P = 0.020), and of T-based vs V-based regimens was 40% vs 36% (P = 0.218). To date, 313 deaths were registered: median and 1-year S were 10.6 mo. and 41% for pts treated with triplets, and 10.4 mo. and 39% for pts treated with doublets (P = 0.786). Over initial 3 courses, occurrence of grade ≥ 3 toxicity (T vs V, % pts) was: neutropenia, 18% vs 30% (P < 0.004); febrile neutropenia, 4% vs 7%; platelets, 7% vs 12% (P = 0.056); anemia, 5% vs 7%; vomiting, 1% vs 2%; diarrhea, 6% vs 3%; stomatitis, 3% vs 0.5%. Grade ≥ 2 neurotoxicity occurred in 1% of both groups. Conclusions: Activity was significantly higher with P-based triplets, but they did not affect the OS. T-based regimens were equally active and less toxic than V-based regimens. Therefore, the GT regimen may represent a new standard of care for advanced NSCLC pts. No significant financial relationships to disclose.

Activated c-Met[pY1003]: A potential marker of intrinsic resistance and therapy target to restore sensitivity to gefitinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7624-7624
Author(s):  
P. A. Zucali ◽  
M. Gallegos Ruiz ◽  
E. Giovannetti ◽  
A. Destro ◽  
K. Floor ◽  
...  
Keyword(s):  
Growth Factor ◽  
Rank Test ◽  
Intrinsic Resistance ◽  
Exact Test ◽  
Fisher's Exact Test ◽  
Log Rank Test ◽  
Fisher’S Exact Test ◽  
Nsclc Patients ◽  
Egfr Tkis ◽  
E Cadherin

7624 Background: Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) show anti-tumor activity in only 10% of Caucasian non-small cell lung cancer (NSCLC) patients. Aim of this study was to evaluate several biological parameters potentially related to EGFR, including c-Met activation, as potential markers of intrinsic resistance to EGFR-TKIs in NSCLC. Methods: P-Akt, p-Erk, c-Src, E-Cadherin, c-Met[pY1003] and c-Met[pY1230/1234/1235] status was immunohistochemically determined on a tissue micro-array of tumor samples from 51 NSCLC patients treated with gefitinib. EGFR, k-ras, and c-Met mutation analysis was also carried out. A panel of NSCLC cell lines expressing c-Met[pY1003] were treated with gefitinib (0.01–100μ M) alone or in combination with hepatocyte growth factor (40 ng/ml) and the c-Met-agonistic antibody DN-30 (80 μg/ml) for 72 hours in 0.5% FCS medium. Drug interaction between gefitinib and DN-30 was assessed, at a non-constant concentration ratio, using the combination index (CI) method. Results: There was no association between p-Erk, c-Src, E-Cadherin, c-Met[pY1230/1234/1235], and k-ras status and response or survival. EGFR exon 19 deletion and p-Akt nuclear staining were significantly associated with response (P<0.0001; Fisher's exact test) and longer time to progression (TTP) (P=0.007; log-rank test), respectively. High c-Met[pY1003] membrane staining was significantly associated with progressive disease (P=0.019; Fisher's exact test) and shorter TTP (P=0.0416; log-rank test), but not with survival. Multivariate analysis confirmed a significant relationship between c-Met[pY1003] and increased risk of disease progression (HR=2.464, 95% CI 1.293–4.696, P=0.006). No c-Met mutations were found. In vitro, the combination with DN- 30 synergistically (CI<1) enhanced gefitinib-induced growth inhibition in all c-Met[pY1003]-expressing NSCLC cells studied (H460, SW1573, A549 and H292). Conclusions: Activation of c-MET may be a biological marker of intrinsic resistance to gefitinib in NSCLC patients, and combined inhibition of c-Met and EGFR may be a suitable therapeutic approach in patients with activated c-Met[pY1003] tumors. No significant financial relationships to disclose.

KRAS mutations and outcomes for patients with stage IV NSCLC treated with frontline platinum/pemetrexed based chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18139-e18139 ◽  
Author(s):  
Benjamin Levy ◽  
Nagashree Seetharamu ◽  
Stacie Richardson ◽  
Daniel Jacob Becker ◽  
Walter Choi ◽  
...  
Keyword(s):  
Stage Iv ◽  
Retrospective Chart Review ◽  
Rank Test ◽  
Fisher Exact Test ◽  
Kras Mutations ◽  
Exact Test ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Former Smokers ◽  
Few Data

e18139 Background: KRAS mutations are the most common driver mutation indentified in NSCLC, occurring in 20 - 30% of adenocarcinomas. While several studies suggest KRAS predicts for lack of response to TKI therapy, few data exist regarding its association with outcomes for patients treated with cytotoxic chemotherapy. This study explores the association between KRAS mutations and outcomes (RR, PFS) in a cohort of patients treated with frontline platinum/pemetrexed (PPm) based therapy. Methods: In this retrospective chart review, we evaluated RR and PFS for 16 KRAS + EGFR – pts treated with carboplatin (AUC 5-6) or Cisplatin 75mg/m2 and (Pm)pemetrexed (500 mg/m2) +/- (B)bevacizumab 15mg/kg. For comparators, we identified 19 KRAS - EGFR - patients treated with the same regimen. Maintenance therapy with Pm or Pm+B was given at the discretion of the treating physician. KRAS and EGFR mutational status were assessed by RT-PCR on tumor tissue collected at first diagnosis. RR was assessed using RECIST criteria. Kaplan-Meier estimates for PFS were evaluating using log rank test. Fisher exact test was used to assess the association between KRAS mutation status and response rate. Results: The groups were similar in age (KRAS + mean 61 vs. 60; p=0.87), gender (62% vs. 57% F; p= 0.9), ECOG 2 (0 vs. 10%,p=0.47), smoking hx (93% vs. 94% current/former smokers, p=0.7), brain mets (0% vs. 18% p=0.22), mean number induction cycles (4 in each, p=0.6), cisplatin and bevacizumab use (12% vs 10%, p > 0.1;10% vs. 40%, p=0.10). Pm maintenance was used in 31% KRAS+ (5/16) and 26% KRAS-(5/19) (p=0.79). P+B maintenance was used in 12% (2/16) and 5% (1/19) (p=0.70). RR was 56% in the KRAS + (9/16) vs. 36% KRAS- (7/19) respectively (p=0.3). There was a statistically significant improvement in PFS in the KRAS + group (10.3 mos vs. 5.7 mos, p =0.03). Conclusions: In this small retrospective review, KRAS mutations appeared to be associated with a non-significant improvement in RR and significant improvement in PFS for patients treated with frontline PPm based therapy. Future prospective studies should investigate and validate the predictive value of KRAS for this cytotoxic regimen. [Table: see text]

Impact of immune checkpoint protein expression in tumor cells and tumor infiltrating CD8+ T cells on clinical benefit from PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 477-477 ◽  
Author(s):  
Jean-Christophe Pignon ◽  
Opeyemi Jegede ◽  
Kathleen M. Mahoney ◽  
Raphael Brandao Moreira ◽  
Jesse Novak ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Clinical Benefit ◽  
Predictive Biomarkers ◽  
Patient Characteristics ◽  
Fisher Exact Test ◽  
Cell Renal Cell Carcinoma ◽  
Exact Test ◽  
Prior Therapy ◽  
Inhibitory Molecules

477 Background: PD-1 blockade with nivolumab has demonstrated efficacy in mccRCC patients who have failed prior therapy; however, durable benefit is observed only in a subset of patients. Correlative studies have demonstrated that tumor PD-L1 expression alone fails to reliably identify patients likely to benefit. Therefore, the development of more robust predictive markers is warranted. Methods: We studied 20 mccRCC patients treated with nivolumab (n=17) or atezolizumab (n=3) with distinct clinical outcomes: 8 pts who experienced durable clinical benefit (DCB) for ≥ 12 months and 12 pts with limited clinical benefit (LCB) for ≤ 6 months from start of therapy. Expression of PD-L1 and PD-L2 on tumor cells and density of tumor infiltrating CD8+ T cells and Foxp3+ cells were evaluated by immunohistochemistry. Percentages of tumor infiltrating CD8+T cells expressing the immune-inhibitory molecules PD-1, TIM-3, or LAG-3 either alone or in combination were determined by multiplex immunofluorescence, using the Inform algorithm (Perkin Elmer). The association between clinical benefit (CB) and biomarker expression was assessed using Fisher exact test. Results: Baseline patient characteristics were similar in the DCB and LCB groups. When analyzed separately, tumor cell expression of PD-L1 or PD-L2 showed no association with CB. However, when positivity was defined as expression of either or both PD-L1(≥ 1% cutoff) and PD-L2 (≥ 5% cutoff), a significant association with CB was found (7/8 DCB vs 4/11 LCB, p = 0.04). A low percentage of tumor infiltrating CD8+PD-1+ T cells co-expressing either or both TIM-3 and LAG-3 (75thpercentile cutoff) was also significantly associated with CB (8/8 DCB vs 7/12 LCB, p = 0.05). Conclusions: Our results suggest that expression of a PD-1 ligand on tumor cells (PD-L1 and/or PD-L2), and a low percentage of severely exhausted T cells, i.e. CD8+PD-1+ T-cells co-expressing the immune-inhibitory receptors TIM-3 and/or LAG-3, might represent valuable predictive biomarkers for response to PD-1 blockade in mccRCC. Independent validation in a larger patient cohort is ongoing.

Correlation of BMAL1 expression in colorectal cancer with resistance to anti-VEGFA therapy with bevacizumab.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 705-705
Author(s):  
Elke Burgermeister ◽  
Fagr Eladly ◽  
Wen Wu ◽  
Nadine Schulte ◽  
Johannes Betge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Tumor Cells ◽  
Cell Lines ◽  
T Test ◽  
Rank Test ◽  
Trend Test ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Armitage Trend Test

705 Background: Mechanisms underlying failure of colorectal cancer (CRC) patients to respond to anti-vascular endothelial growth factor A (VEGFA) therapy with bevacizumab in combination with chemotherapy are largely unknown, and novel predictive markers required. Methods: Tumours from patients/mice and CRC cell lines were analysed by IHC, PCR, EMSA, ChIP, ELISA and Western blot. Statistics of (pre)clinical data was calculated with SAS and Graphpad Prism. Response outcomes including progression-free survival (PFS) and restaging according to RECIST (PR/SD/PD) were analyzed. Results: Circadian rhythm transcription factor and heme receptor REVERBA and its target gene BMAL1 promoted binding to and activation of the -700kB RORE DNA-element in the VEGFA promoter resulting in increased VEGFA mRNA expression and VEGFA protein secretion from human CRC cell lines. Conversely, REVERBA siRNA and its antagonist (Fe3+) hemin inhibited VEGFA synthesis. In C57BL/6J Apcmin/+ mice treated with murinized VEGFA Ab (n=11 mu_chimeric_B20-4.1 vs. n=42 mock; 10 mg/kg*week; i.p.; 4 weeks), Vegfa mRNA was reduced, as was incidence (*p=0.0411 Fisher Exact Test) and multiplicity (*p=0.0157 Cochran Armitage Trend Test) of vascularized CRCs. However, Bmal1 mRNA was up-regulated, and high BMAL1 protein expression in tumor cells positively correlated with Ki67+ proliferation (n=3 B20 vs. n=3 mock; *p<0.05 t-test) in treated Apcmin/+ CRCs. BMAL1 protein was also induced in xenografts from BALB/c nude mice s.c. implanted with the human CRC cell line HCT116 and treated with humanized VEGFA Ab (n=4 bevacizumab vs. n=4 vehicle; 10 mg/kg*week; i.p.; 3 weeks; *p<0.05 t-test). In CRC patients, high BMAL1 protein expression in tumor cells was associated with clinical non-response to bevacizumab (n=15 SD vs. n=29 PD: BMAL1- vs. BMAL1+, *p=0.0061 Cochran Armitage Trend Test,*p=0.0130 Fisher Exact Test) and reduced PFS (BMAL1- [671 days] vs. BMAL1+ [368 days], *p=0.0030 log rank test, HR=0.4792 [95%CI 0.3103-0.7871], n=74). Conclusions: BMAL1 may represent a predictive marker for bevacizumab non-response. Due to its drugability, the REVERBA-BMAL1-VEGFA axis may be a potential target to prevent resistance to anti-angiogenic therapy in CRC.

Efficacy and toxicity of immunotherapy with immune checkpoint inhibitors in gynecologic cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18092-e18092
Author(s):  
Michelle Kuznicki ◽  
Amy Joehlin-Price ◽  
Peter Graham Rose ◽  
Haider Mahdi
Keyword(s):  
Stable Disease ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gynecologic Cancer ◽  
Objective Response ◽  
Complete Response ◽  
Rank Test ◽  
First Line

e18092 Background: There is limited data on outcomes for gynecologic cancer patients treated with immune checkpoint inhibitors (ICI) outside the scope of clinical trials. Here we present our Institutional experience with a cohort of endometrial (EC) and ovarian cancer (OC) treated with ICI. Methods: 59 patients who received ICI were included (23 OC and 36 EC). Progression-free (PFS) and Overall survivals (OS) were determined by Kaplan-Meier (KM) curve and log rank test. Comparison of duration of response (DOR) and stable disease (DOSD) was done with unpaired t-test or one-way ANOVA. Rates of objective response (ORR) including partial response (PR) and complete response (CR), and stable disease (SD) were compared by Fischer’s exact test. Results: Median age was 66 years. 23 patients were microsatellite stable (MSS), 23 microsatellite instability high (MSI-H). Median number of prior lines was 2 (0-11). PFS and OS for EC and OC were overlapping; therefore outcomes for both were combined [(PFS 6.4m OC vs 7.3 m EC, p = 0.61), (OS 15.9 m OC vs 14.2 m EC, p = 0.78)]. Response rates consisted of 20.3% PR, 8.5% CR, 37.3% SD. Differences in responses were noted for clear cell carcinoma (CC) (33.3% PR, 11.1% CR, 33.3% SD) and MSI-H (36.4% PR, 18.2% CR, 22.7% SD) compared to MSS (11.8% PR, 0% CR, 47% SD). MSI-H had higher ORR vs. MSS (54.1% vs 11.8%, p = 0.0078). CC trended toward improved ORR vs. MSS (44.4% vs 11.8%, p = 0.14). PFS was improved for MSI-H vs. MSS (10m v 5.0m, p = 0.03). OS for CC compared to any other histology was improved (NR vs 12.8m respectively, p = 0.009). 5 recurrent MSI-H EC patients received ICI as first line monotherapy. Responses included 4 PR and 1 SD (80% ORR, 100% clinical benefit). PFS was 9.2m (3.3-13.3). 80% remained progression-free at last follow up. Overall, 38.9% experienced toxicity: hypothyroidism (15%), dermatitis (5%), pneumonitis (10%), LFT elevation (2%), amylase/lipase elevation (3%), colitis or diarrhea (5%), uveitis (2%) or nephritis (5%). 10% of patients required discontinuation of ICI secondary to toxicity. Trends for PFS and OS favored improved outcomes in patients with toxicity vs. no toxicity [(PFS 12.9m vs 5.6m, p = 0.07), (OS 22.9m vs 13.1m, p = NS)] respectively. Conclusions: In this study, immunotherapy with ICI outcomes favor MSI-H and CC compared to MSS disease. CC had promising OS compared to other histology types. ICI showed promising efficacy in MSI-H EC with 100% clinical benefit rate in chemonaive patients. First line ICI should be investigated in these patients. Positive correlation between toxicity and outcome is noted and will be further investigated.

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