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Keith M Kerr
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.07 - ROS1 (SP384) Immunohistochemistry Inter-Reader Precision Between 12 Pathologists (ID 12387)
14:10 - 14:15 | Presenting Author(s): Keith M Kerr
- Abstract
- Presentation
Background
ROS1 positive non-small cell lung cancer (NSCLC) patients can be treated with specific tyrosine kinase inhibitors including crizotinib. ROS1 positivity is often clinically detected by fluorescence in situ hybridization (FISH), however ROS1 IHC can be used to screen samples prior to FISH confirmation of ROS1 status. The ROS1 (SP384) antibody detects ROS1 with high sensitivity, specificity, and consistency. Consistent interpretation of a ROS1 IHC assay between pathologists is important patient evaluation. Here we present inter-reader precision of 12 pathologists across 60 FFPE cases stained with ROS1 (SP384).
a9ded1e5ce5d75814730bb4caaf49419 Method
A retrospective cohort of 60 FFPE NSCLC cases stained with H&E, Rabbit Monoclonal Negative Control Ig, and ROS1 (SP384) were selected to represent positive, negative, and borderline ROS1 IHC status. Twelve practicing lung pathologists independently scored the cases as positive or negative around a cutoff of cytoplasm staining in > 30% tumor cells at a ≥2+ intensity level using Pathotrainer software (Pathomation bvba). Scoring was blinded to other readers and ROS1 status of the cases. Overall percent agreement (OPA), negative percent agreement (NPA), and positive percent agreement (PPA) were calculated in comparison to the group mode. Average overall percent agreement (AOPA), average positive agreement (APA), and average negative agreement (ANA) were calculated pairwise for each reader pair. Following independent assessment, participating pathologists conducted a discordant case review establishing consensus reads for all 60 cases and compared 44 cases to available FISH results.
4c3880bb027f159e801041b1021e88e8 Result
OPA of each of the 12 readers to the mode was 96.4% (95% CI 93.9-98.6) with PPA of 96.3% (95% CI 92.7-99.4) and NPA of 96.5% (95% CI 92.8-99.5). Pairwise AOPA between each of the 12 readers was 94.5% (95%CI 91.2-97.7) with APA 94.0% (95% CI 89.5-97.6) and ANA 95.0% (95%CI 91.2-97.9).
Consensus IHC scores were concordant with FISH 90.0% (40/44 cases).
8eea62084ca7e541d918e823422bd82e Conclusion
Inter-reader precision around a cutoff of >30% tumor cells with cytoplasmic staining at a ≥2+ intensity level was high in interpreting ROS1 (SP384) in NSCLC samples. Case review highlighted confirmation with FISH in questionable cases and staining patterns to be considered when interpreting ROS1 (SP384) IHC.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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OA03 - Advances in Lung Cancer Pathology (ID 897)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (ID 14530)
10:50 - 11:00 | Presenting Author(s): Keith M Kerr
- Abstract
- Presentation
Background
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-25 - Analysis of EGFR Mutations Using Circulating Tumour DNA (ctDNA) in Non-Small Cell Lung Cancer Patients in North East Scotland (ID 13346)
16:45 - 18:00 | Author(s): Keith M Kerr
- Abstract
Background
Treatment with 1st or 2nd generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) can benefit patients with EGFR-TKI sensitising mutations but eventually patients develop resistance. The main cause of resistance - EGFR c.2369C>T (T790M) mutation - can now be targeted using 3rd generation EGFR-TKIs. EGFR testing using ctDNA provides a minimally invasive method of mutation detection. This study aimed to:
1) Validate the Roche CE-IVD cfDNA workflow for EGFR mutation detection.
2) Assess the usefulness of monitoring patients using ctDNA EGFR testing throughout EGFR-TKI treatment, particularly to determine whether EGFR c.2369C>T resistance mutation could be detected prior to clinical progression
a9ded1e5ce5d75814730bb4caaf49419 Method
Control samples with known allele frequencies and 86 blood samples, collected from 17 patients throughout EGFR-TKI treatment, were analysed. The ctDNA was extracted using the cobas® cfDNA sample preparation kit and mutation analysis conducted by the cobas® EGFR mutation test v2. The semi-quantitative index (SQI) was used to indicate intra-patient fluctuations in mutation level between sequential samples. Mutation results were correlated with clinical status.
4c3880bb027f159e801041b1021e88e8 Result
Control samples proved the method was highly sensitive, with the ability to detect a range of EGFR mutations present at 1% allele frequency, with 100% specificity. A valid result was obtained for all patient samples tested. Radiological/clinical assessment of 11/17 patients indicated progression; 6/11 (55%) displayed T790M in ctDNA which was detectable prior to clinical progression in 4 patients. Other well documented resistance mechanisms were not sought in this study. The original EGFR mutation was not detected in sequential ctDNA samples during treatment in 7 patients. Within this group, 3/7 patients continued to respond well to treatment. However, 4/7 displayed signs of clinical progression including brain metastasis only progression. The lack of mutation detection in these patients may be due to false negative results relating to inadequate ctDNA level, in particular due to the blood-brain barrier.
8eea62084ca7e541d918e823422bd82e Conclusion
Analysis of controls and sequential samples obtained from patients undergoing EGFR-TKI treatment showed the technique to be sensitive and specific with the ability to detect original sensitising mutations and emergence of T790M. There is evidence that this technique can be useful in identifying the T790M mutation prior to signs of clinical progression, and that results from ctDNA generally correlate well with clinical status.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 965)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.16-03 - CheckMate 816: A Phase 3 Trial of Neoadjuvant Nivolumab Plus Ipilimumab or Chemotherapy vs Chemotherapy in Early-Stage NSCLC (ID 12599)
16:45 - 18:00 | Author(s): Keith M Kerr
- Abstract
Background
Approximately 20–25% of patients with NSCLC are diagnosed with early or localized disease, which has a relapse rate of 30–80% with surgery. Although neoadjuvant chemotherapy can reduce the risk of relapse, it only provides a pathological complete response (pCR; no viable tumor cells) rate of 4%. The neoadjuvant setting presents abundant tumor-associated neoantigens derived from the primary tumor that may allow immunotherapy to prime a long-lasting immune response. Clinical trial results support the use of immuno-oncology agents as neoadjuvant treatment for early-stage NSCLC. In a pilot study in patients with untreated, surgically resectable early-stage (stage I–IIIA) NSCLC, nivolumab (a fully human PD-1 immune checkpoint inhibitor antibody) administered as neoadjuvant treatment (3 mg/kg for 2 cycles during the 4 weeks prior to surgery) induced a pCR in 10% of patients and a major pathological response (MPR; ≤10% residual viable tumor cells in resected primary tumor) in 45% of patients, did not delay surgery, and was associated with an acceptable safety profile. Combining immuno-oncology agents with distinct mechanisms of action, such as PD-1 and CTLA-4 inhibitors, offers the possibility of a synergistic response and may improve antitumor activity compared with either agent alone. The combination of an immuno-oncology agent and chemotherapy may also offer synergistic activity, given that chemotherapy results in tumor cell death and subsequent antigen release that can activate an immune response. Promising results have been noted with nivolumab plus ipilimumab (a CTLA-4 immune checkpoint inhibitor antibody) and nivolumab plus chemotherapy in patients with treatment-naïve stage IIIB/IV NSCLC in the multicohort phase 1 CheckMate 012 study. CheckMate 816 (NCT02998528) is a phase 3 study evaluating nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, and platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Approximately 642 patients aged ≥18 years with early-stage (stages IB–IIIA) resectable NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, Asia, and Africa. Patients are ineligible if they have active autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Patients will be randomized (1:1:1) to receive neoadjuvant nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, or platinum-doublet chemotherapy. Primary endpoints are event-free survival and pCR. Key secondary endpoints are overall survival and MPR (<10% residual tumor in lung and lymph nodes). The start date was January 2017. The estimated primary completion date is May 2023.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
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PL03 - Call to Action - Challenges Ahead (ID 851)
- Event: WCLC 2018
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 08:15 - 09:45, Plenary Hall
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PL03.05 - It's All In The Tissue (ID 11653)
09:15 - 09:30 | Presenting Author(s): Keith M Kerr
- Abstract
- Presentation
Abstract not provided
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