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Keith Kerr
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.03 - The International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer (Now Available) (ID 1198)
14:30 - 16:00 | Author(s): Keith Kerr
- Abstract
- Presentation
Background
Evidence-based standards for molecular testing of lung cancer have been established, but the global frequency and practice of testing are not well understood. The IASLC conducted an international survey to evaluate current practice and barriers to molecular testing.
Method
Distributed to IASLC members and other healthcare professionals, content included: 7-question introduction, 32 questions for those requesting tests/treating patients, 45 questions on performing/interpreting assays, and 24 questions on tissue acquisition. All respondents were asked to provide 3-5 barriers to implementing/offering molecular testing.
Respondents’ countries were grouped by geography or developing/developed using IASLC and World Bank criteria. Surveys were available in 7 languages. Regional comparisons used the Chi-squared test or ANOVA; free-text was analyzed with Nvivo.
Result
We obtained 2,537 responses from 102 countries. Respondents were 45% Medical Oncologists, 12% Pulmonologists, 12% Thoracic Surgeons, 9% Pathologists, and 22% scientists or other. 56% of responses were from developing countries, 44% developed. Regions included: 52% Asia, 19% Europe, 11% Latin America, 11% US/Canada, 7% Other.
1683 (66%) chose the requesting/treating track (50% government, 42% academic, 8% other). 61% reported most patients in their country do not receive molecular testing, with the lowest rates in Latin America/Other (p<0.0001). 39% were not satisfied with the conditions of molecular testing in their country. Indications for requesting testing included: adenocarcinoma (89%), never-smoker (61%), female (57%), and young (54%) (variable by region, p<0.0001). 99% ordered EGFR, 95% ALK, 84% PDL1, 79% ROS1, all other tests <50%. 56% typically received results within 10 days. Only 67% were aware of CAP/IASLC/AMP guidelines, least frequently in Asia/Other (p=0.041). 37% have trouble understanding molecular testing result reports, most of whom cited a need for more technical and scientific knowledge. 75% had multidisciplinary tumor boards, but 23% met <1/month.
The 316 (12%) testing track respondents were from laboratories that were 49% academic, 35% government, and 16% private/other. 94% of laboratories offered EGFR, 83% ALK, 69% KRAS, 68% BRAF, 64% ROS1, 56% HER2, and others <50%; 68% tested for PDL1. 57% offered Multiplex assays, less frequently in Latin America/Asia (p=0.0294). 69% tested blood-derived DNA, less frequently in US/Canada/Other (0.0013). 23% of respondents reported >10% of cases are rejected due to inadequate samples; however, 47% stated there is no policy or strategy to improve the quality of the tissue samples in their country. 52% reported patients/physicians are not satisfied with the state of molecular testing in their country. Respondents performing/interpreting assays (334, 14%) were typically informed of biopsy results (91%), and notified when the sample was inadequate (84%).
The most frequent barrier to molecular testing in every region was cost, followed by quality/standards, turnaround-time, access, and awareness. After cost, time was the most common barrier in developed countries, while it was quality in developing countries. The second largest barrier was quality in Asia, access in Europe/Latin America/Other, and turn-around time in US/Canada.
Conclusion
These preliminary analyses show molecular testing usage varies across the globe. Barriers vary by region, and one-third of respondents were unaware of evidence-based guidelines. Global and regional strategies should be developed to address barriers.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)
10:15 - 18:15 | Author(s): Keith Kerr
- Abstract
Background
PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.
Method
The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).
Result
344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.
Conclusion
There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.
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PL01 - New Questions with Imaginative Answers (ID 88)
- Event: WCLC 2019
- Type: Plenary Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Enriqueta Felip, Giorgio Vittorio Scagliotti
- Coordinates: 9/08/2019, 08:15 - 09:45, Barcelona (2005)
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PL01.02 - The Evolution of Tissue Testing for Immunotherapy - Where Next? (Now Available) (ID 3581)
08:15 - 09:45 | Presenting Author(s): Keith Kerr
- Abstract
- Presentation
Abstract
Biomarkers have, to date, had an uneasy relationship with immunotherapy in lung cancer, a conflict between the degree of biomarker expression (largely PD-L1) being related to treatment efficacy, and a desire to give these drugs to everyone, either as monotherapy or, increasingly, in combination with other drugs. PD-L1 immunohistochemistry (IHC) is well established as a companion or complementary diagnostic, depending on indication, and tumour mutational burden (TMB) is an item of interest, with a surrogate, MSI-high, approved by the FDA in a tumour-type agnostic setting for second/greater line therapy.
Where is PD-L1 testing going?
PD-L1 IHC will remain a useful test. PD-L1 IHC scoring in cytology-type samples has been validated outside clinical trials and will become accepted in daily practice. New IHC clones will challenge the place of existing ones, hopefully validated by comparative study and EQA. Data are emerging on the clinical validity of PD-L1 scoring on small amounts of tumour (the heterogeneity issue), how few cells can be used, and the clinical impact of scoring PD-L1 on insufficient material.
Tumour Mutational Burden
Difficulties with the PD-L1 IHC biomarker drove the search for alternatives and TMB, as a several times removed surrogate of tumour immunogenicity, emerged. The place for TMB in the diagnostic algorithm remains uncertain but clinical trials looking at tumour tissue or blood TMB continue to provide promising, if confusing, results. Many of the issues with PD-L1 IHC are also in play with TMB. There is no consensus about what is ‘high TMB’? TMB is another biological continuum, like PD-L1 expression, so the creation of a binary high vs low categorization potentially ignores relative biological significance of different levels. There is huge variability in the methodology used to derive or predict TMB, the amount of the genome screened, different definitions of a ‘mutation’, different next generation sequencing platforms, different contexts (tumour tissue vs blood) and a lack of published data on how these different TMB assessment approaches vary. Anecdotal reports so far indicate substantial variation.
As a predictive biomarker in this setting, TMB works; it enriches a treatment group for benefit. But we have seen relatively little comparative data to suggest superiority over any other singular biomarker in this treatment area. TMB is a crude predictor of tumour neo-antigenicity and perhaps we should look to more specific measures of this aspect of sensitivity to immunotherapy. It is possible to predict probable neo-antigenicity from deep analysis of sequencing data. Neo-antigens should be clonal, rather than subclonal, to maximize their immune impact. Are their particular genes whose alteration would predict greater (or lesser) tumour ‘visbility’ to the immune system, be they involved in DNA repair, maintaining genome stability or integrity, antigen processing and presentation, or more likely to generate immunogenic proteins? Other factors such as loss of heterozygosity at MHC coding genes may also provide useful information.
So, it may well be possible to refine our assessment of TMB into a more specific and meaningful metric. This then raises the question of whether it is practical to do so, and whether this provides clinically useful information.
Tumour inflammation
For immune checkpoint inhibitors (ICI) to work, a tumour specific immune response must be ‘available’ and somehow inhibited by the checkpoints being therapeutically targeted. Assessments of tumour inflammation, as a presumptive sign of such an available but inhibited immune response, have been successfully used to enrich a treatment group for benefit from ICI therapy. In lung cancer, these assessments of inflammation have been relatively complex assays of immune gene signature expression using mRNA extracted for fresh/frozen tumour tissue. Initially large panels of immune response-related genes have been reduced to single digit-sized panels. Interferon gamma seems to be important as is, unsurprisingly, PD-L1.
The same questions arise with respect to immune gene signatures. Is this any better than a more simplistic approach such as PD-L1 IHC? Evidence is at best marginal, that it would be superior. Is this practical and affordable in a daily practice setting? Probably not. Are there alternative ways to derive the same information? Probably yes. In other tumour sites, a morphological assessment of tumour inflammation has been more keenly pursued than in lung cancer. This approach has tended to focus on the presence and location of the immune cell infiltrate and to some extent, on the nature of the infiltrating cells. When tumour sample area allows, immune cell activity at the tumour-stromal interface, and the presence of CD8-expressing T cells have been associated with better responses to ICI. There is much more that could be investigated, especially in relation to other immune-active or immune-suppressive cell types and their location within the tumour and its microenvironment (TME). Immunohistochemistry is readily available, but in order to understand the complexity of this process and find new biomarkers, in limited tissue samples, multiplex IHC and digital pathology analysis tools will almost certainly be required. These tools already exist but the challenge will be generating the data in relation to clinical response and then deployment in daily practice.
Other regulation in the TME
Other factors in the TME, such as tissue hypoxia and lactate dehydrogenase, are relevant biomarkers, indicating an immune-suppressive environment, and potential resistance to ICI therapy. Other factors like IDO, and other immune checkpoints like LAG3 and TIM3 may also confer resistance to current ICI therapy and provide new therapeutic targets.
Conclusion
There is much more to be learned about factors that regulate responsiveness to ICI therapy. The multifactorial complexity of the immune response suggests that combinations of biomarkers are more likely to provide better prediction of therapeutic benefit. Many of these factors are more likely to be continuous variables rather than binary metrics, and oncology will have to learn to deal with this situation, perhaps more akin to a complementary rather than a companion diagnostic, leading to more nuanced therapeutic decisions. It remains to be seen whether oncology, regulatory authorities or industry has an appetite for such an approach.
References
Blank CU et al. Science 2016;352,658
Camidge DR et al. Nat Rev Clin Oncol 2019;16,341
Only 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.
