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J.E. Chaft
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.06 - Evaluation of PD-L1 Expression in Metachronous Tumor Samples and FDG-PET as a Predictive Biomarker in Ph2 Study (FIR) of Atezolizumab (MPDL3280A) (ID 2207)
10:45 - 12:15 | Author(s): J.E. Chaft
- Abstract
- Presentation
Background:
PD-L1 expression on tumor-infiltrating immune cells (IC) and/or tumor cells (TC) can inhibit antitumor immunity. Atezolizumab (MPDL3280A) is an anti-PDL1 antibody that has shown efficacy across multiple tumor types. The efficacy and safety of atezolizumab in the Phase 2 FIR study has been reported previously (Spigel et al, ASCO 2015). Efficacy appeared to correlate with PD-L1 expression on IC and/or TC, with higher ORRs observed in patients with the highest expression of PD-L1, indicating that PD-L1 may be a predictive biomarker for response to atezolizumab. FIR was also designed to address questions of potential heterogeneity and changes in tumor PD-L1 expression in metachronous tissue samples, as well as the utility of using FDG-PET as a biomarker for response to atezolizumab in PD-L1–selected patients with NSCLC.
Methods:
FIR is a 3-cohort, single-arm, Phase 2 study of atezolizumab in PD-L1–selected patients with stage IIIB/IV NSCLC. Cohort 1 included chemo-naive patients, Cohort 2 included ≥ 2L patients without a history of brain metastases, and Cohort 3 included ≥ 2L patients with asymptomatic treated brain metastases. PD-L1 expression was centrally assessed by immunohistochemistry (IHC) using the SP142 antibody assay in archival and/or fresh tumor biopsies or resections and scored as IC0, 1, 2 or 3 and TC0, 1, 2 or 3. Patients with PD-L1 IC2/3 or TC2/3 tumors were enrolled and received 1200 mg atezolizumab IV every 3 weeks (last patient entered Jun 27, 2014). Responses were measured by RECIST v1.1, modified RECIST and FDG-PET using EORTC criteria. Exploratory objectives included the evaluation of potential predictive biomarkers, including the comparison of PD-L1 expression in matched archival and fresh tumor specimens, as well as the utility of FDG-PET in assessing response to immune checkpoint blockade.
Results:
From 1009 screened patients, 95 paired archival and fresh tumor samples were obtained. In these samples, the agreement of PD-L1 expression between fresh and archival tissue at the TC3 or IC3 cutoff was 88% when the same type of tissue procurement method was used (resection or biopsy), compared with 65% when different methods of procurement were used. To date, FDG-PET response has been centrally assessed in 71 of the 138 patients enrolled in FIR. Patients with metabolic response by EORTC criteria on 6-week scans had a higher ORR per RECIST v1.1 (72% [13/18]) than metabolic non-responders (ORR 4% [2/53]).
Conclusion:
There was a high agreement in TC3 or IC3 PD-L1 expression between archival and fresh tumor specimens. This work demonstrates that intra-patient heterogeneity in PD-L1 expression is low in metachronous tissues, indicating various types of tumor samples, including fresh or archival, can be reliably used to assess PD-L1 expression. In addition, FDG-PET has potential as an early on-treatment measure of response to atezolizumab. Further analyses will be presented. (NCT01846416)
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.03 - Spatiotemporal Effects on Programmed Death Ligand 1 (PD-L1) Expression and Immunophenotype of Non-Small Cell Lung Cancer (NSCLC) (ID 1609)
16:45 - 18:15 | Author(s): J.E. Chaft
- Abstract
Background:
PD-L1 is one of the immune-checkpoint molecules that regulates Th1 immune responses and mediates cancer immune evasion. PD-L1 can be expressed on tumor cells (TC) or tumor-infiltrating immune cells (IC) and expression in both cell types can negatively regulate T-cell function in the tumor microenvironment. The goal of this study was to evaluate the intra-patient heterogeneity and temporal changes in PD-L1 expression and overall immune phenotype in NSCLC using paired synchronous and metachronous tumor specimens.
Methods:
Thirty-nine patients (pts) with NSCLC treated at Memorial Sloan Kettering Cancer Center were evaluated as part of an IRB approved project. Most were former/current smokers (n=30, 77%) and had adenocarcinoma histology (n=36, 92%). 17 pts were KRAS mutant (45%), and 5 were EGFR mutant (13%). Paired synchronous samples were collected from 17 pts with stage IIIA-N2 resected primary lung and metastatic lymph node (met LN) tissue. Paired metachronous samples were collected from 23 pts (including one patient also with synchronous tissue) with at least two metachronous primary/metastatic (n=14) or metastatic/metastatic tissues (n=9). In pts with metachronous samples, 14 (61%) had systemic intercurrent anti-cancer therapy and 9 (39%) had none. PD-L1 expression was assessed by IHC (clone SP142) on TC and IC. CD8 expression was evaluated by IHC using the C8/144 clone. In addition, expression of ~600 immune genes was analyzed by iChip.
Results:
Twenty-five out of 39 tissue pairs were evaluable by PD-L1 IHC (14/17 synchronous, 11/23 metachronous). Among pts with synchronous samples, in the primary tumor, PD-L1 was expressed in <1% of TC or IC in 6 pts, in 1-4% of cells in 5 pts, and in ≥5% of cells in 3 pts. Among those with metachronous samples, in the first collected sample, the PD-L1 expression in <1% of TC or IC was detected in 6 pts, in 1-4% of cells in 2 pts, and in ≥5% of cells in 3 pts. PD-L1 expression was similar across all paired tissues. PD-L1 status at the TC or IC 5% cut-off remained unchanged in all evaluable paired specimens and at the TC or IC 1% cut-off remained unchanged in 80% (11/14 synchronous and 9/11 metachronous) pairs. In both synchronous and metachronous samples, CD8 expression was also similar across paired specimens. The median inter-sample difference in CD8+ T-cell infiltration was 0.5% (95% CI: -0.6% - 3.4%) in synchronous pairs; three pts had a difference >5%. In metachronous pairs, the median difference was -0.4% (95% CI: -1.4% - 0.1%); one pt had a >5% change in CD8+ T-cell infiltration.
Conclusion:
In this study, there was a high agreement in PD-L1 expression and CD8+ T-cell infiltration in both paired synchronous and metachronous NSCLC specimens. The low intra-patient heterogeneity of PD-L1 and CD8 expression in this study suggests any available tissue (e.g. primary or met) may be reliable to assess these markers in NSCLC. Overall immune characterization by gene expression analysis in paired tumor specimens will be presented.
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P1.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 212)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.03-004 - Occult Primary Non-Small Cell Lung Cancer with Mediastinal Lymph Node Involvement (ID 1573)
09:30 - 17:00 | Author(s): J.E. Chaft
- Abstract
Background:
Non-small cell lung cancer (NSCLC) involving mediastinal lymph nodes without an identifiable primary tumor is a rare presentation. While definitive surgery or radiotherapy with or without concurrent chemotherapy is typically recommended, little is known about the treatment outcomes. As such, we reviewed our institutional experience to determine if subsequent development of lung tumors is common and whether prognosis is comparable to stage III NSCLC in general.
Methods:
This study was an IRB-approved retrospective review of an institutional NSCLC database. Twenty-six patients with biopsy-proven NSCLC involving mediastinal lymph nodes with no identifiable lung primary lesion and no evidence of distant metastases treated with curative intent between 1995-2013 were identified. PET-CT staging was performed in 25 of 26 patients. All followup was calculated from date of diagnosis.
Results:
The median followup was 44 months. The median age at diagnosis was 60 years (range 51-81) among the 18 males (69%) and 8 females (31%). N2 and N3 disease were each present in 13 (50%) patients, respectively. Histologies included adenocarcinoma in 12 (46%), squamous cell carcinoma in 10 (38%), NSCLC not otherwise specified in 3 (12%), and large cell lung carcinoma in 1 (4%). Eleven patients underwent EGFR mutation analysis, with no sensitizing mutations identified. All patients had a smoking history (median 35 pack-years). Four (15%) patients underwent complete surgical resection, of whom 3 underwent induction chemotherapy and 1 was treated with surgery alone. One of the four patients underwent post-operative radiation therapy to 54 Gy. Twenty-two (85%) patients were treated with definitive radiation therapy including sequential chemotherapy and radiation in 8 (mean RT dose = 70 Gy), concurrent chemoradiation in 10 (mean RT dose = 60 Gy), neoadjuvant chemotherapy followed by concurrent chemoradiation in 3 (mean RT dose = 66 Gy), and radiation alone in 1 (treated to 60 Gy). The median overall survival was 78.1 months with actuarial 2- and 5-year survival rates of 78% and 67%, respectively. Five patients developed intrathoracic failure at a median of 19.8 months. One patient had an isolated lung failure at 13.6 years, but this likely represents a secondary primary and not tumor recurrence. Two patients had isolated mediastinal lymph node failures at 18.1 and 19.8 months and 2 patients initially had a mediastinal lymph node recurrence at 0.2 and 3.4 years, but subsequently failed in the lung at 8.5 and 3.6 years respectively. The actuarial 2- and 5-year intrathoracic control rates were 85.7% and 78.6%. Nine patients developed metastatic disease at a median of 16.5 months. The 2- and 5-year actuarial freedom from distant metastases was 70.9% and 59.1%. Among patients receiving definitive radiation, there was no difference between those receiving concurrent chemotherapy and those who did not.
Conclusion:
To our knowledge, this is the largest reported series of occult primary NSCLC involving mediastinal nodes. Definitive local therapy, including radiotherapy and surgery, was associated with very favorable locoregional control and survival, particularly compared with expected outcomes for stage III NSCLC.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-032 - Prognostic Impact of EGFR and KRAS Mutations in Patients with Lung Adenocarcinoma Treated with Definitive Radiation Therapy (ID 2422)
09:30 - 17:00 | Author(s): J.E. Chaft
- Abstract
Background:
An association of EGFR and KRAS mutations with radiation sensitivity has been postulated in preclinical studies. Recent clinical studies reported longer local control and survival in patients (pts) harboring EGFR mutations treated with definitive radiotherapy (RT). Here, we sought to evaluate the prognostic impact of EGFR and KRAS mutations in 223 adenocarcinoma pts treated with definitive RT at our institution.
Methods:
Between 2004 and 2013, 466 inoperable pts with non-squamous lung cancer were treated with definitive RT ± chemotherapy. Mutational testing was performed in 223 pts. 44% were male, 56% female. 65% were former, 13% never, and 22% current smokers. Clinical stage was II in 5%, IIIA in 37% and IIIB in 58%. Median size of tumor was 3.8 cm (range 0.5-12.2 cm). 60% received concurrent, 31% sequential chemo-RT and 9% RT alone. The median RT dose was 63Gy (range 50-80Gy). OS was estimated by the Kaplan-Meier method. Cumulative incidence functions were used to estimate local failure (LF) and distal failure (DF), using death without failure as a competing risk. Association of factors with OS was analyzed by Cox regression and association with LF and DF by competing risk regression.
Results:
EGFR status was wild-type in 205 pts (92%) and mutated in 18 (8%). The most common EGFR mutations were exon 19 deletion (8 pts), followed by exon 21 L858R (7 pts), and exon 20 insertion (3 pts). KRAS status was wild- type in 142 pts (64%), mutated in 63 (28%), and not performed in 18 (8%). The most common mutations were G12C (13%), followed by G12V (5%) and G12A and G12D (3% each). With a median follow-up among survivors of 32.7 months (range 0.6-114), the median OS was 38 months for pts with EGFR mutation versus 26 months for pts without (p=0.96); 21 months for patients with KRAS mutation versus 31 months for pts without (p=0.24). 2-year LF was 37% and 46% for pts with and without EGFR mutation, and 48% and 46% for pts with and without KRAS mutation, respectively. 2-year DF was 80% and 64% for pts with and without EGFR mutation, and 62% and 64% for pts with and without KRAS mutation, respectively. On univariate analysis, factors significantly associated with improved OS included KPS ≥ 80 (p=0.01), increasing RT dose (p=0.04) and use of concurrent chemotherapy compared to RT alone (p=0.001). Factors associated with higher risk of LF included stage IIIB (p=0.04) and sequential rather than concurrent chemotherapy (p=0.05). Factors associated with a higher risk of DM included stage IIIB (p=0.03) and lower RT dose (p=0.003). Association of EGFR and KRAS mutations did not reach statistical significance on univariate analysis, thus we did not further investigate their effects by multivariable analysis.
Conclusion:
Despite analyzing the largest patient population to date, we did not identify a significant prognostic impact by EGFR or KRAS mutational status. The lack of an observed association could be related to the low rate of EGFR mutations identified. RT dose and use of concurrent chemotherapy were significantly associated with overall survival.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-075 - Phase 2 Trial of Bortezomib in KRAS G12D Mutant Lung Cancers (ID 2943)
09:30 - 17:00 | Author(s): J.E. Chaft
- Abstract
Background:
KRAS mutations are the most common oncogenic drivers in lung cancers without any approved targeted therapy. Preclinical evidence suggests that KRAS mutations are highly dependent on the NF-kB pathway. Bortezomib, a small molecule proteasome inhibitor, has been shown to downregulate the NF-kB pathway and lead to objective responses in patients with KRAS G12D in early phase clinical trials. In this single-institution, open label, phase II study we assessed the efficacy and safety of subcutaneous bortezomib in KRAS mutant lung cancers.
Methods:
Patients with advanced KRAS G12D mutant lung cancers were eligible. Bortezomib was administered at 1.3mg/m2/dose subcutaneously on days 1, 4, 8, and 11 of a 21 day cycle until disease progression or unacceptable toxicity. The primary objective was radiographic response rate (RECIST version 1.1). The secondary endpoints were progression free survival (PFS) and overall survival (OS) determined from the time of first bortezomib treatment. Simon two-stage minimax design was used (H0=10%, H1=30%, power=90%).
Results:
Sixteen patients with KRAS G12D mutant lung adenocarcinomas were treated on study: 44% women, 38% never smokers, 31% former smokers ≤15 pack years, and 69% with invasive mucinous adenocarcinomas. Patients received treatment for a median of 2 months (range 1-12months). One patient had a partial response with a 66% reduction in disease burden (6% observed rate, 95% CI 0.2 to 30.2%). Of the 6 patients (40%) with stable disease, 2 remained on study for over 5 months. The median PFS was 1 month (95% CI 1-6). The median OS was 13 months (95% CI 6-NA). The median OS from date of diagnosis of metastatic disease was 39 months (95% CI 35-NA). The most common treatment-related toxicities of any grade were fatigue (50%), diarrhea (38%), nausea (31%), and papulopustular rash (31%). Treatment-related peripheral neuropathy occurred in 25% of patients (3 patients with grade 1, 1 patient with grade 2).
Conclusion:
In patients with G12D KRAS mutant lung cancers, bortezomib was well tolerated and associated with modest anti-tumor activity and durable disease control in a small subset of patients. Further investigation into predictive biomarkers for the efficacy of bortezomib should be pursued. Without a clear biomarker, no further study of bortezomib in KRAS- mutant lung cancers is warranted.
