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Santiago Viteri
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.12 - Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets (ID 3399)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
- Presentation
Introduction
Exon 20 insertion mutations (Exon20ins) account for up to 10% of all mutations in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs). Exon20ins specific drugs are in development. Because Exon20ins are molecularly heterogenous, the ability to identify the range of variants is dependent on the test methods used. Real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS) are two molecular tests widely used to identify mutations in the EGFR. We analyzed real-world genomic data to determine the frequency of Exon20ins variants and to assess the ability of PCR and NGS to comprehensively identify them.
Methods
Two US-based genomic databases were utilized for this analysis. NGS data from US institutions were extracted from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database, version 8.5 (The AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831). The FoundationInsights™ database (Foundation Medicine, Cambridge, MA) was used to obtain EGFR Exon20ins variants in real-world NSCLC samples. Coverage of Exon20ins from commercially available PCR tests (therascreen® and cobas®) was obtained from their instructions for use.
Results
The GENIE database included 12,497 patients with NSCLC. A total of 2,316 patients with EGFR mutant lung adenocarcinoma were identified and of these patients, 175 (7.6%) harbored Exon20ins. A total of 40 unique Exon20ins variants were identified. Of the 9 most common Exon20ins variants (≥5 patients), only 4 would have been identified at the protein level using commercially available PCR tests. PCR tests would have identified only 89 (50.9%) of the 175 patients with Exon20ins identified by NGS (Figure). The FoundationInsights™ database included 627 patients with lung adenocarcinomas who harbored Exon20ins and identified 102 unique Exon20ins variants. Of the 17 most common variants (≥5 patients), only 4 would have been identified at the protein level with commercially available PCR tests. PCR tests would have identified just 305 (48.6%) of the 627 patients with Exon20ins identified by NGS (Figure).
Conclusion
PCR methods are projected to miss 50% or more of Exon20ins. Reliance on commercially available PCR kit methods may provide insufficient information to support appropriate decision-making for emergent Exon20ins-directed therapies. The large number of insertion variants suggests that NGS platforms, academic or commercially available, would also improve their detection rate by capturing the full breadth of variants that have been identified.
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FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP12.09 - Molecular Insight into NADIM Clinical Trial: Potential Immune Biomarkers of Pathological Response for NSCLC Patients. (ID 3552)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
- Presentation
Introduction
Many studies have demonstrated that chemo-immunotherapy is a promising approach for NSCLC patients but still exists a lack of prediction biomarkers of survival. We have recently showed that pathological response is a surrogate of progression free survival (PFS) including infiltrating immune cells as potential biomarker of pathological response in NADIM clinical trial (Provencio et al., 2020. Lancet Oncology, in press).
New biomarkers in peripheral blood are being described, focused on the immune system response. Preliminary data was presented at WCLC 2019 however additional results are included in this report. Here we describe the effect of chemo-immune neoadjuvant treatment on resectable NSCLC stage III patients’ immune system and describe blood biomarkers that could help to identify responders to this combination therapy.
Methods
Peripheral mononuclear cells (PBMCs) and plasma from NADIM clinical trial patients before and after chemo-immune neoadjuvant treatment were used. Phenotyping and activation levels of immune cell populations were analyzed by flow cytometry, focused on CD4 T cells, CD8 T cells, T cells NK like and NK cells. Moreover, characterization of the immune response was evaluated by a cytokine array.
Clinical evaluation of pathological response, classified patients in 3 groups, complete (CPR, 0% tumor cells), major (MPR, <10% viable tumor) and incomplete (IPR, >10% viable tumor). Wilcoxon and Kruskall-Wallis statistic tests were used.
Results
Even though we have previously described a decrease of T lymphocytes on tissue after treatment, we do not see these changes on blood. Thus, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neoadjuvant treatment. However, lower levels of activated CD4 T cells and NK cells were observed. Interestingly, this decrease was exclusively statistically significant for patients who achieved a CPR, but no differences were observed for MPR or IPR. As expected, detection of PD1+ cells after neoadjuvant Nivolumab (anti-PD1) treatment was almost completely abrogated, however, a trend for higher PD1+ cell proportions was observed in patients achieving CPR at diagnosis.
Furthermore, many cytokines involved in immune response and described as putative biomarkers for immunotherapy in NSCLC as IL-2, IL-15, IL-6, IL-13 or IFN-gamma, among others, were decreased after neoadjuvant treatment. Notably, stratifying by pathological responses, this decrease was statistically significant only for non-complete responses.
Conclusion
The analysis of immune cell markers on blood samples could be a source for potential surrogate markers of pathological response to neoadjuvant treatment on NSCLC patients.
Similarly, to what occurs in tissue, CPRs showed differences compared to MPR or IPR in some blood markers, both at the cellular and cytokine level. Thus, after treatment, patients achieving CPRs do not seem to reduce their levels of cytokines such as IL-2, IL-15, IL-6, IL-13 or IFN-g associated with anti-tumor response, but they do reduce their levels of activated CD4 and NK cells
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.15 - Neratinib-Based Combination Therapy in HER2-Mutant Lung Adenocarcinomas: Findings from two International Phase 2 Studies. (ID 1894)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
- Presentation
Introduction
Somatic HER2 mutations are present in 3–5% of lung cancers, which induce constitutive HER2 signaling and oncogenesis. Neratinib, an irreversible pan‑HER tyrosine kinase inhibitor, has demonstrated antitumor activity across a spectrum of HER2-mutated solid cancers and a manageable safety profile [Hyman et al. Nature 2018]. Findings from a HER2-mutant lung cancer model suggest that neratinib activity is enhanced when given in combination with an mTOR inhibitor (temsirolimus) or anti-HER2 antibody (trastuzumab) [Ivanova et al. Clin Cancer Res 2020]. We present data from two international phase 2 studies of neratinib-based therapy in patients with HER2-mutant lung cancer: PUMA-NER-4201 – a randomized study of neratinib ± temsirolimus (NCT01827267); PUMA-NER-5201 (SUMMIT) – a multi‑tumor ‘basket’ trial including patients treated with neratinib ± trastuzumab (NCT01953926).
Methods
Patients with histologically confirmed advanced HER2-mutant non-small cell lung cancers (NSCLC) were treated with oral neratinib 240 mg once daily alone (both studies) or in combination with temsirolimus 8 mg once weekly intravenously with optional dose escalation to 15 mg/week if tolerated (PUMA-NER-4201) or trastuzumab 8 mg/kg initially then 6 mg/kg every 3 weeks intravenously (SUMMIT). Protocol-defined endpoints common to both studies were confirmed objective response rate (RECIST v1.1), best overall response, clinical benefit rate, duration of response, progression‑free survival, overall survival, and safety (NCI CTCAE, v4.0).
Results
In PUMA-NER-4201, 62 patients with HER2-mutant NSCLC were enrolled (60 evaluable for efficacy). In SUMMIT, as of 17 July 2020, 78 HER2-mutant lung cancer patients were enrolled and received at least one dose of study drug (all evaluable for efficacy). Baseline characteristics across both studies: median age range 62–66 years, female 66%, adenocarcinoma 92–100%. Exon 20 insertion mutations accounted for 95% of tumors in PUMA-NER-4201 and 66% of tumors in SUMMIT. The most common mutant allele across both studies was Y772_A775dup (53% PUMA-NER-4201; 28% SUMMIT). The safety profile of neratinib was consistent with previous reports, with diarrhea being the most common adverse event (81–86% any grade, 12–40% grade ≥3) in both monotherapy and combination arms. Efficacy results are summarized in the table.
Conclusion
Neratinib, as monotherapy, has limited activity in HER2-mutated NSCLC. Neratinib combined with either an mTOR inhibitor (temsirolimus) or anti-HER2 antibody (trastuzumab) produced numerically greater efficacy including durable responses in a subset of pre-treated patients. Genomic analysis from a subset of responders is forthcoming. Additional novel combinations of neratinib with other HER2-directed therapies in HER2-mutant NSCLC are being considered.
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MA04 - Health Policy and the Real World (ID 217)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA04.07 - Comparative Clinical Outcomes for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutations and Common EGFR Mutations (ID 3390)
16:45 - 17:45 | Author(s): Santiago Viteri
- Abstract
- Presentation
Introduction
Approximately 85–90% of the mutations seen in EGFR-mutant non-small cell lung cancers (NSCLCs) are common mutations (cEGFR), Exon 19 deletions and Exon 21 L858R. Up to 10% of EGFR-mutant NSCLC harbors Exon 20 insertion mutations (Exon20ins). We conducted a retrospective cohort study using real-world data to compare clinical outcomes between patients harboring Exon20ins and cEGFR.
Methods
This retrospective cohort study included patients from the Flatiron Health database (1 January 2011 through 31 May 2020) who had advanced NSCLC. The objectives of the study were to assess the prognostic value of Exon20ins compared with cEGFR (start date of first-line therapy as the index date) and the effect of tyrosine kinase inhibitor (TKI) treatment between the groups (start date of first TKI line as the index date). Analysis was stratified by line of TKI use. Endpoints included real-world overall survival (rwOS), progression-free survival (rwPFS), and time to next therapy (rwTTNT) and were analyzed using multivariable Cox proportional hazards model and summarized by Kaplan-Meier method.
Results
Among 62,464 patients with advanced NSCLC, 181 with Exon20ins and 2833 with cEGFR met eligibility criteria. Population demographics between the groups were comparable with minor exceptions. With median 34-month follow-up, Exon20ins was associated with a 75% increased risk of death (adjusted hazard ratio [adjHR] of 1.75 [95%CI, 1.45–2.13]; p˂0.0001); median rwOS was 16.23 (95%CI, 11.04–19.38) for Exon20ins and 25.49 months (95%CI, 24.48–27.04) for cEGFR (Table). The estimated 5-year survival rate for Exon20ins is 8% compared with 19% for cEGFR.
The predictive value of TKI treatment, stratified by line, was assessed in 76 Exon20ins and 2749 cEGFR patients who were treated with TKIs. With median 20.6-month follow-up, there was a 170% increase in risk of progression or death associated with Exon20ins (adjHR of 2.7 [95% CI, 2.06–3.55]; p˂0.0001); median rwPFS was 2.86 months (95%CI, 2.14–3.91) compared with 10.45 months (95%CI: 10.05–10.94) for cEGFR. Furthermore, there was a 170% increased risk of death (adjHR of 2.70 [95% CI, 2.04–3.57]; p˂0.0001) associated with Exon20ins; median rwOS was 7.46 months (95%CI, 5.45–13.34) for Exon20ins and 25.49 months (95%CI, 24.28–26.81) for cEGFR (Table).
Conclusion
Patients with Exon20ins have a worse prognosis compared with patients with cEGFR. Furthermore, EGFR TKI treatment was substantially less effective for patients with Exon20ins, as the risk of disease progression and mortality was higher compared with patients with cEGFR. These findings highlight the need for new treatment options for Exon20ins.
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MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 14:15 - 15:15, Scientific Program Auditorium
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MA11.05 - Tepotinib in Patients with MET exon 14 (METex14) Skipping Advanced NSCLC: Updated Efficacy Results from VISION Cohort A (ID 1361)
14:15 - 15:15 | Author(s): Santiago Viteri
- Abstract
Introduction
In the Phase II VISION study (NCT02864992), tepotinib demonstrated durable efficacy and a tolerable safety in patients with NSCLC harboring METex14 skipping. Here, we report updated efficacy outcomes from a preplanned data cut-off (July 1, 2020) in patients with at least 9 months of follow-up, including detailed subgroup analyses of treatment-naïve and previously treated patients.
Methods
Patients with advanced, EGFR/ALK wild-type, METex14 skipping NSCLC received oral tepotinib 500 mg once daily. Patients enrolled in Cohort A with ≥9 months of follow-up were assessed for efficacy. All patients with METex14 skipping NSCLC who received tepotinib in Cohort A, or confirmatory Cohort C, were assessed for safety. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) using RECIST 1.1. Secondary endpoints included ORR by investigator assessment, duration of response (DOR), and safety.
Results
As of July 1, 2020, 146 patients had ≥9 months of follow-up and were assessed for efficacy; 255 patients were evaluated for safety. In the efficacy population, patients had a median age of 73.4 years (range 41 to 94), 76 were male (52.1%), 76 had a smoking history (52.1%), and 81 had received prior treatment for advanced/metastatic disease (55.5%). 72 patients had received prior platinum-based chemotherapy for metastatic disease, either alone (n=63) or in combination with immunotherapy (n=9).
The overall ORR by IRC was 45.2% (95% confidence interval [CI]: 37.0, 53.6), with a median DOR of 11.1 months (95% CI: 8.4, 18.5). ORR by investigator assessment was 54.1% (95% CI: 45.7, 62.4), with a median DOR of 12.7 months (95% CI: 9.7, 18.3).
ORR by IRC was similar in patients who were treatment-naïve (44.6%; 95% CI: 32.3, 57.5) or previously treated for advanced/metastatic disease (45.7%; 95% CI: 34.6, 57.1), and in those who received prior-platinum based chemotherapy for metastatic disease (50.0%; 95% CI: 38.0, 62.0). ORR was also comparable in patients who received immunotherapy, regardless of the treatment regimen used (figure).
Grade ≥3 treatment-related adverse events (TRAEs) were reported in 25.1% of patients; 27 (10.6%) discontinued due to TRAEs. Peripheral edema was mostly low grade and rarely led to discontinuation (3.5%). The safety profile was similar across subgroups.
Conclusion
In VISION, the largest study in patients with NSCLC harboring METex14 skipping, treatment with tepotinib showed durable clinical activity that was consistent across clinically relevant subgroups. Tepotinib demonstrated a safety profile consisting of mostly mild-to-moderate AEs with few treatment discontinuations.
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)
11:45 - 12:45 | Author(s): Santiago Viteri
- Abstract
- Presentation
Introduction
Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).
Methods
The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.
Results
In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).
Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.
Conclusion
Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.
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P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 3
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P60.07 - TMB and Selected Mutations in Resectable Stage IIIA NSCLC Patients Receiving Neo-Adjuvant Chemo-Immunotherapy from NADIM Trial (ID 2142)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
Introduction
Tumor Mutational Burden (TMB) assessment and identification of specific mutations associated to anti-PD1 blockade therapy resistance have become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, the clinical relevance of these parameters in terms of pathological response and PFS in neo-adjuvant chemo-immunotherapy has not been established. To answer this question we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab.
Methods
Pretreatment TMB, defined as the number of nonsynonymous variants (missense and nonsense single nucleotide variants (SNVs)), plus insertion and deletion variants (INDELs) detected per megabase (Mb) of exonic sequence, was estimated from 27 patients that had enough diagnostic material for next generation sequencing using the Oncomine Tumor mutation Load assay (ThermoFisher) following manufacturer’s instructions. The panel covers 1.7 Mb of 409 genes with known cancer associations. Regarding pathological responses, patients were classified into 3 groups: pathologic complete response (pCR) (0% viable tumour at any localization tested), major pathologic response (MPR, <10% viable tumour) and pathologic incomplete response (pIR) (>10% of viable tumour). At data analysis, median follow-up time was 22.7 months.
Results
Median TMB was 5.89 (range 1.68 – 73.95). No differences in TMB value between histologies (adenocarcinoma vs squamous cell), smoking status (former vs current), age or sex were observed. Somatic mutations were identified in lung cancer driver genes such as TP53, KRAS, EGFR, CDKN2A, NOTCH1, BRAF and in specific genes associated with resistance to immunotherapy such as STK11, KEAP1, and RB1. No genomic alterations in ALK, ROS1, PTEN or ERBB2 were found.
Based on literature, a poor prognosis mutation signature (presence of EGFR, STK11, KEAP1 or RB1 mutations) was generated. A third of the sequenced patients (9/27) harboured at least one mutation in one of these genes.
Pathological response data was available from 23 out of 27 patients sequenced. Both the TMB value and the presence of these resistance mutations were not associated with the degree of pathological response.
Regarding PFS, TMB alone was not predictive of disease progression using different thresholds. However, the presence of these resistance mutations was associated with shorter PFS (log-rank p-value=0.032). The median PFS for mutated patients was 21.4 months (95% CI 16-26 months) while median PFS was not reached in non-mutated patients.
Additionally, the combination of this mutational signature with TMB (absence of resistance mutations and TMB-Higher than median) was able to distinguish patients that strongly benefit from this therapy. Although the median PFS was not reached in both groups yet, statistically significant differences were observed (log-rank p-value=0.046). PFS at 18 and 24 months was 100% (95% CI not estimable) for Non-mutated patients with TMB-High vs 70% (95% CI 50-89%) and 58% (95% CI 35-81%) for the rest of patients (mutated patients plus Non-mutated patients with TMB-Low).
Conclusion
TMB did not predict benefit from chemo-immunotherapy induction in our cohort. However, the presence of EGFR/STK11/KEAP1/RB1 mutations alone, or in combination with TMB, may help identify patients that unlikely benefit from neo-adjuvant chemo-immunotherapy
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P60.11 - TCR Repertoire Predicts Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemoimmunotherapy from NADIM Trial (ID 3417)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
Introduction
Characterization of the T-cell receptor (TCR) repertoire has become a novel approach to monitor immunotherapy responses, however there is lack of knowledge about its clinical relevance as predictive biomarker of pathological response in neoadjuvant chemoimmunotherapy. For this purpose, we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant Paclitaxel + Carboplatin + Nivolumab for 3 cycles, achieving a 63% of complete pathologic responses (CPR). PD-L1 TPS and TMB as CPR biomarkers showed AUC ROC of 0.77 and 0.55, respectively, reinforcing the need for new biomarkers (Provencio, M. et al. 2020).
Methods
TCR repertoires from primary tumours or lymph nodes of 19 NSCLC patients were obtained, at both time points: diagnosis and after neoadjuvant treatment. TCR repertoire was analysed in terms of convergence, diversity, evenness and clonal space, defined as the summed frequency of clones belonging to a frecuency group (top 1%, top 1% to 2%, 2% to 5%, and >5%) relative to the total T-cell repertoire. The results were correlated with pathological response groups and ROC curve analysis was performed to test if TCR repertoire-derived parameters could identify patients with CPR.
Results
There were no statistically significant differences observed in TCR repertoire in biopsy samples in terms of diversity (p = 0,797) or convergence (p = 0,202) between the three pathological response groups or between biopsy and surgery samples. However, we observed differences in terms of evenness in biopsy samples between the pathologic response groups (p=0.037), which were lower in those patients who achieved CPR. The AUC for evenness was 0.844 (IC: 0.667-1.000), p=0,011. An evenness value of <0.8639 showed a sensitivity of 50% and specificity of 100% identifying patients with CPR.
Moreover, the clonal space of the TOP 1% clones in diagnostic samples was higher in patients that achieved CPR (p=0.002). The AUC of this novel biomarker was 0.9667 (IC: 0.897-1.036) (p=0.0006). A TOP 1% clonal space higher than 0.1607 showed a sensitivity of 90% and specificity of 88.9% identifying patients with CPR.
Conclusion
Our results support the association between the uneven distribution of T-lymphocytes clones proportions present in the tissue at diagnosis and response to chemoimmunotherapy. Specifically, higher clonal space occupied by the TOP 1% clones seems to outperform PD-L1 and TMB as predictive biomarker of CPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy.
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P60.12 - Baseline Tumor Immune Cell Infiltration and Activation can Predict Checkpoint Inhibitor Pneumonitis in Lung Cancer Patients (ID 3620)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
Introduction
Treatment with anti PD-1/PD-L1 antibodies has demonstrated clinical efficacy in non-small cell lung cancer (NSCLC), increasing its use significantly. Besides anti-tumoral activity in some patients (pts), T-cell activation after immune checkpoint inhibitors (ICIs) can lead to an imbalance in the immune system and induce self-reactive T-cells in the lung tissue. This process can eventually lead to life-threatening immune-related adverse events (irAEs), like checkpoint inhibitor pneumonitis (CIP). We hypothesized that a pre-treatment state of chronic inflammation or immune system imbalance within the lung tissue could predict which pts are at higher risk of developing CIP.
Methods
Pre-ICI-treatment FFPE tissue samples from 18 pts that developed CIP and from 27 pts that did not, were retrospectively collected. Gene expression analysis was performed using the NanoString nCounter platform with the Human PanCancer IO360 panel, harboring 770 genes related to tumor biology, immune response and microenvironment. In addition, the IO360 panel contains gene signatures to measure immune system activity. Differential expression (DE) analysis was carried out based on the development of CIP. Finally, a classifier algorithm was created using a recursive feature selection with a leave one out cross validation method to predict which combination of genes is most effective to predict CIP development. In addition, we analyzed healthy adjacent lung tissue from 4 CIP, and 5 non-CIP pts.
Results
DE analysis revealed 72 differentially expressed genes (DEGs) in pre-treatment tissue of pts with- and without CIP development. Most DEGs were upregulated in pts that developed CIP. The algorithm yielded a 16-gene signature that was able to separate pts that developed CIP from patients that did not with receiver operating characteristic (ROC) areas under the curve (AUCs) of 0.80 to 0.92. Genes with an increased expression in the CIP developing cohort were found to be involved in apoptosis, MAPK pathway, antigen presentation and costimulatory signaling. Panel-incorporated immune signatures were also evaluated. Neutrophil-, NK-cell and TH1 cell populations were found to be lower in pts that developed CIP. This indicates a general lower pre-treatment immune cell population abundance and activation in CIP developing pts. Since the overall response rate (ORR) in these pts was high (52.1%), it can be hypothesized that there is a common antigen recognition for T-cells between tumor and healthy lung cells after ICI treatment. In addition, stronger activation of self-reactive T cells in the surrounding healthy lung tissue, instead of within the tumor and tumor microenvironment, could explain the occurrence of CIP in a subgroup of pts. Analysis of the healthy adjacent lung tissue revealed that CIP pts have higher macrophage, T-cell and neutrophil infiltration and activation in their healthy tissue, compared to nonCIP pts.
Conclusion
We have developed a 16-gene signature that can predict which pts are more likely to develop CIP. This could be exploited by extensively monitoring those pts to allow for early intervention. In addition, we found that CIP developing pts have a higher immune cell infiltration in their healthy tissue which could explain CIP development. These findings need further validation in a larger patient cohort.
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P61 - Tumor Biology and Systems Biology - Basic and Translational Science - KRAS (ID 199)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P61.01 - Imipramine Blue (IP) plus MET Tyrosine Kinase Inhibitors (TKI) Suppress Lung Adenocarcinoma (LUAD) KRAS Mutation Tumor Growth (ID 1348)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
Introduction
KRAS mutations in LUAD co-occur with TP53 mutations and LKB1 non-synonymous mutations (nsm), portending a poor prognosis. MET amplification has not been considered. Previously, we identified OTSSP167 as a PAK1 kinase inhibitor with significant activity in A549 (KRASG12-C and LKB1nsm). OTSSP167 plus auranofin (PKCι) shows high synergism and inhibits tumor growth in mice in the H23 cell line (KRASG12-C, p53mut and LKB1nsm) (Ito et al, Cell Comm and Signaling 2019). In addition, OTSSP167 has a potent MELK inhibition effect. We hypothesize that MET expression could be upregulated in KRAS-mutant cell lines, based on the fact that the putative signaling pathway, MELK-forkhead box M1 (FOXM1)-MET, could be present in KRAS mutant cells. In the current study, we examined the combination of MET TKIs with imipramine blue (FOXM1 inhibitor).
Methods
Quantitative real time PCR of MET and FOXM1 was performed in 4 KRAS-mutant cell lines (A549, H23, H460 and Calu6). LKB1 mRNA was assessed in 32 advanced KRAS-mutant LUAD patients. Cell proliferation assays were performed in A549 and H23, and in the EBC1 (MET amplified lung cancer cell line). Synergy was defined by a combination index (CI) of < 0.75 by Chou-Talalay. Cell lines were treated with IP and MET TKIs (crizotinib, savolitinib and tepotinib).
Results
MET mRNA was elevated in A549 and H23 (which both carry LKB1nsm) but not in H460 and Calu6. FOXM1 mRNA was overexpressed in H23. Synergy (CI<0.75) was seen with IP plus tepotinib in the A549 and H23 cell lines, but not in H460 and Calu6. Synergy was also noted with IP plus crizotinib, but not with savolitinib. The CI of IP plus MET TKIs in the EBC1 cell line (which is only MET amplified) was >1. The median overall survival for KRAS-mutant LUAD patients with low LKB1 was 1.1 months versus 19.4 for those with high LKB1 (p=<0.005).
Conclusion
The bona fide of MET TKIs (tepotinib) plus IP in KRAS cell lines with LKB1 nsm, encourages the determination of clinical benefit of tepotinib plus IP in KRAS mutant LUAD patients. The liaison of MET and LKB1 nsm should be further investigated. LKB1 mRNA expression, together with MET and FOXM1 mRNA expression, warrants assessment in KRAS LUAD patients.
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P84.01 - The ARIA Study: Activity of Next-Generation ALK TKIs Based on ALK Resistance Mutations Detected by Liquid Biopsy in ALK Positive NSCLC Patients. (ID 3092)
00:00 - 00:00 | Author(s): Santiago Viteri
- Abstract
Introduction
Detection of resistance mechanisms to tyrosine kinase inhibitors (TKI), in particular ALK mutations (ALKm), could help to select the subsequent treatment in ALK-positive NSCLC patients. Liquid biopsy can identify these ALKm from ctDNA in up to 29% of patients after 2nd-generation TKI-failure. We assessed the activity of next-gen TKIs based on the presence of ctDNA ALKm.
Methods
Patients with ALK-positive advanced NSCLC pretreated with 1st and/or 2nd-generation ALK-TKI were selected in 9 European centers. Liquid biopsy was collected immediately before starting brigatinib or lorlatinib. ALKm were defined by commercial or homemade next-generation sequencing run on ctDNA and covering ALK exon 22/23/25. We correlated the activity of brigatinib or lorlatinib based on three ctDNA molecular groups: presence ALKm (if one: single; if ≥2: complex); other mutations and no detectable mutations. We assessed progression-free survival (PFS), objective response rate (ORR), intracranial ORR according to the clinical routine of each center and overall survival (OS).
Results
62 patients were identified, 58 evaluable at cutoff data (Jul-20): 16 before brigatinib and 42 before lorlatinib. Median age was 53 [27-80], 64% were female, 67% nonsmoker; 97% with adenocarcinoma; 7% and 10% with isolated thoracic and brain disease, respectively. The median (m) number of TKIs was 3 [2-7]; 90% received 2nd-generation TKIs. The mFU since liquid biopsy was 24.8 months. ALKm were detected in 28% (3 brigatinib; 13 lorlatinib), 9 single and 7 complex; others were detected in 17% (n=10) and none in 55% (n=32). The most common mutation was G1202R (7 before lorlatinib), followed by G1269A and F1174L in 3 cases each, all pretreated with 2nd-generation TKIs. The TKI outcomes according to the ctDNA molecular groups is summarized in table 1. In the ALKm group, lorlatinib showed an ORR of 46% and 56% of intracranial ORR with mPFS of 6.5 months (7=single/6=complex) while no responses were observed in the 3 cases treated with brigatinib, with mPFS of 3.5 months (2=single/1=complex).Those 7 cases harboring the G1202Rmut (4=complex) had an ORR of only 14% but an intracranial ORR of 50%; mPFS was 3.6 mo. No differences were observed among ctDNA molecular groups.
ConclusionOverall
ALK mutations
Others
None
BRIGATINIB
N=16
n= 3
n=3
n= 10
PFS, median (95% CI)
5.6 months
(4.27-16.79)
3.5 months
(2.63-NR)
6.2 months
(4.27-NR)
8.1 months
(4.40-NR)
12 months-PFS rate
27.3 %
(11.9-62.6)
33.3%
(6.7-100)
0%
40%
(18.7-85.5)
ORR
27%
(4/15)
0%
(0/3)
67%
(2/3)
22%
(2/9)
ORR CNS
50%
(6/12)
0%
(0/2)
100%
(2/2)
50%
(4/8)OS*, median (95% CI)
62.6 months
(31.7-not reached)
38.4 months
(31.7-NR)
62.6 months
(21 .4-NR)
NR
(24.5-NR)
LORLATINIB
N= 42
n= 13
n= 7
n= 22
PFS, median (95% CI)
7.6 months
(5.26- 11.14)
6.5 months
(3.61-NR)
7.6 months
(5.22-NR)
7.3 months
(4.63-NR)
12 months-PFS rate
29.5%
(17.7-49.1)
30%
(12.0-74.7)
28.6%
(8.9-92.2)
30%
(14.6-61.6)
ORR
38%
(16/58)
46%
(6/13)
71%
(5/7)
23%
(5/22)
ORR CNS
62%
(18/29)
56%
(5/9)
60%
(3/5)
67%
(10/15)
OS*, median (95% CI)
55.5 months
(45.0-NR)
62.6 months
(54.8-NR)
45.0 months
(24.5-NR)
NR
(41.9-NR)
PFS: progression-free survival; ORR: objective response rate; CNS: central nervous system; OS: overall survival; *since systemic therapy start
In our study, lorlatinib showed activity in heavily-pretreated patients with ALK-positive NSCLC, regardless the ctDNA molecular groups. Poor outcomes were observed for brigatinib in 3 heavily-pretreated patients with ctDNA ALKm. The recent use of 2nd-gen TKI upfront calls for similar studies to confirm if ctDNA may be a biomarker for guiding the sequential therapy.
