Lung Cancer Today and Tomorrow: A Canadian Perspective by Dr. Parneet Cheema

At the 2018 Canadian Lung Cancer Conference (CLCCO), Dr. Parneet Cheema, a medical oncologist with the William Osler Health System in Brampton and Toronto, gave a Canadian perspective on recent therapeutic developments in lung cancer. Her presentation, summarized in this article, highlighted the significant developments in immunotherapies and next-generation targeted therapies, and the unique challenges that Canadian healthcare faces in adapting to them.

The treatment landscape for non-small cell lung cancer (NSCLC) has been rapidly evolving over the last couple of years. In this time, we have identified small populations of patients with lung cancer and we have been able to improve their outcomes by using targeted therapies. Several practice-changing studies were presented in 2017, notably ALEX, FLAURA, and PACIFIC. Additionally, recent press releases in 2018 highlighted findings from KEYNOTE-189 and CheckMate 227.

Recent advances in lung cancer

Significant advances have been made in the driver mutation-positive NSCLC world, where mutations in the anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) are the most common aberrations. Importantly, there has been significant Canadian representation in clinical trials with agents targeting these mutations. Recently, we have looked at moving ALK inhibitors into the first-line setting in the ALEX study with alectinib.1 Additionally, for the first time we have EGFR tyrosine kinase inhibitors (TKIs) being used in the first-line setting that address central nervous system (CNS) metastasis, as shown in the FLAURA trial with osimertinib.2

PACIFIC was another practice-changing study, demonstrating a significant improvement in progression-free survival (PFS) with durvalumab following chemoradiotherapy in patients with stage III, unresectable NSCLC.3 Many clinicians are encouraged that these findings will correlate to an overall survival (OS) advantage with durvalumab.

In 2018, we expect to see a lot of data being presented for patients with wild-type metastatic NSCLC. We have already seen chemotherapy and immunotherapy combinations used in the first line for patients with metastatic NSCLC, as was the case with pembrolizumab in the KEYNOTE-189 study.4 We have also heard about encouraging results with doublet immunotherapy combinations, such as in the CheckMate 227 study, which is investigating nivolumab and ipilimumab in first-line metastatic NSCLC, although the data has not yet been presented.5 Once again, there was a significant contribution to these trials from Canadian centres. This is important for our healthcare, because it provides Canadian clinicians with the expertise they need to use these products and combinations, ultimately making it easier to implement them at the ground level.

New advancements in lung cancer

There are other areas of research that have also been rapidly changing. We now have new biomarkers, such as tumour mutation burden (TMB), which was looked at in the CheckMate 227 trial.5 The encouraging results from this study raise the question of whether TMB will become a biomarker that we need to test patients for in the future. Our pathology colleagues will be crucial in helping us implement these new testing procedures.

In addition, new molecular targets for NSCLC have recently emerged, such as non-receptor tyrosine kinase (NRTK), and it seems that a new target is presented at almost every major conference. There are also new molecular techniques being implemented to varying degrees across Canada, such as circulating tumour DNA (ctDNA) and plasma testing for the exon 20 EGFR T790M resistance mutation (T790M). These are all new methods that we will have to efficiently implement into our practice moving forward. In fact, new data and techniques are pouring in so fast that by the time a set of guidelines are published, it may be time to update them again. This is illustrated by the need to add osimertinib in the first-line treatment of EGFR mutation-positive NSCLC to recently published guidelines.6 Some physicians even believe that we are reaching a point where findings may become less relevant in the time between online and print release of journal articles, once again highlighting the rapid progress that is being made in the study of lung cancer.

While molecular profiling has been a standard of care for patients with advanced NSCLC, we have traditionally thought of it only at the time of diagnosis. However, we are slowly changing our thinking towards re-evaluating a lung cancer patient’s molecular profile throughout their cancer journey. For example, patients with EGFR mutation-positive NSCLC, who have progressed after first- or second-generation EGFR TKIs, require a new biopsy and a re-evaluation of their molecular subtypes in order to identify a potential T790M mutation or small cell lung cancer, which would be treated differently. This concept is also starting to become relevant in patients with ALK rearrangements. We now question what we need to do after using second- and third-generation ALK inhibitors. In addition, we need to test for new mutations once they have been discovered, such as MET (mesenchymal-epithelial transition) exon 14 skipping, or an NRTK mutation, further highlighting the need to re-evaluate each patient’s molecular profile throughout their journey.

Clinical challenges of precision medicine in Canada

Our main clinical challenge in Canada is that the discovery of actionable targets in advanced NSCLC has significantly outpaced our ability to implement them in day-to-day clinical practice efficiently. The main reasons for this are difficulties with access to molecular testing and with access to the drugs that target these mutations. In Canada, it is important that as we develop new molecular techniques and as access becomes available, we need to re-evaluate our approach with patients.

I believe that it is never too late to test all patients for ROS1 (c-ros oncogene 1) fusion and BRAF (B-raf proto-oncogene) mutations, as long as they are stable, once we have access to the tests. However, there is limited testing for ROS1 mutations across Canada, with only three provinces having access to it: British Columbia, Quebec, and Ontario. Even within a province, such as Ontario, only some centres have access. We rely heavily on out-of-country testing and we use specific patient eligibility characteristics to decide who gets tested. As we know from the early days of ALK and EGFR testing, limiting testing based on patient characteristics can lead to patients missing the opportunity to get targeted therapy.

Another example that illustrates the disconnect in terms of access to drugs and molecular testing in Canada is the treatment of BRAF mutation-positive patients with dabrafenib and trametinib. BRAF mutations constitute about 1.5% to 2.8% of all patients with NSCLC.7 A clinical trial published in 2017 demonstrated an overall response rate of 66.7%, median PFS of 10.2 months, and median OS of 18.2 months when patients were treated with dabrafenib and trametinib.8 These numbers are on par with EGFR TKIs and ALK inhibitors. Based on the positive results, Health Canada approved the combination on June 2017 and the combination treatment has been offered to patients under a compassionate access program ever since.9 However, since its implementation, less than 20 patients have used it. Calculating the number of patients with NSCLC who harbour a BRAF mutation, one would expect about 50–100 patients eligible for the treatment. We now likely have a scenario where there is access to a beneficial therapy, but there is no universal access to molecular testing.

When looking at statistics across Canada, while access to testing for BRAF mutations is somewhat better than for ROS1, it is still limited to specific provinces or centres within provinces, and again, we rely heavily on out-of-country testing for BRAF.

Additionally, there is a disconnect between regulators and us as clinicians. When dabrafenib and trametinib were submitted for reimbursement to the pan-Canadian Oncology Drug Review (pCODR), the decision was thought to be a step backwards for precision medicine and lung cancer treatment in Canada. The claim from pCODR was that the combination did not meet an unmet need in the area as other treatment options, such as immunotherapy, were available. The Lung Cancer Canada Medical Advisory Committee had a rebuttal against the decision, arguing that lumping all patients together by saying “we have immunotherapy” discredits the approach of personalized medicine. This goes against one of the most recent advances in the treatment of lung cancer where we can tease out small groups of patients and treat them based on their individual disease or mutation. Decisions like these can lead to discrepancy in access, and potentially to a two-tier healthcare system in Canada, where certain therapies become available only to patients with private plans.

While lung cancer treatment has advanced significantly, the challenge now is how to make testing available to everyone and how to get all patients access to the agents that they need. Patient advocacy is more important than ever before and Lung Cancer Canada has been doing an excellent job with this.

A Canadian view on recent data

When considering some of the latest data that has been presented in NSCLC, we have to look at it through the lens of Canadian healthcare; in other words, how does this data fit into our practice? The FLAURA trial demonstrated a significant PFS advantage with third-generation EGFR TKI osimertinib over standard-of-care treatment in patients with EGFR mutation-positive NSCLC.2 If osimertinib is approved and funded, I suspect that the uptake will be a bit higher than expected. Osimertinib appears to address several clinical challenges that we face in Canada. First, we would not have to test for T790M given that osimertinib has demonstrated efficacy in that patient population and it targets common EGFR mutations in addition to T790M. As a result, the discrepancy in testing between the provinces may no longer be an issue. Second, it would negate the need for a second biopsy after progression, saving hospital and bed time. And finally, osimertinib also addresses patients with CNS metastases.

A multidisciplinary approach

A multidisciplinary approach is critical to the Canadian lung cancer landscape. Our pathologists have done an outstanding job in terms of validating biomarkers. We know as clinicians and medical oncologists that when we ask for a test, we can trust that the results from our colleagues in pathology are generated from a heavily validated process. This is due to the commitment of all the pathologists across the country, which allows us to work together as a lung cancer community. Furthermore, our thoracic surgeons and laboratory medicine colleagues also contribute heavily to this multidisciplinary approach.

One collaborative project, which I was part of for the year, was the National Working Group to implement T790M testing, where the goal was to develop evidence-based best practices in order to optimize testing with tissue and ctDNA. The implementation of these practices across Canada will likely prove to be the real challenge, but practice guidelines such as these are imperative to be able to implement advances in lung cancer.

In summary

The treatment algorithm for NSCLC in Canada is rapidly changing, with Canadian researchers contributing significantly to these advances. In recent years there has been a paradigm shift in molecular testing, where testing is now done throughout a lung cancer patient’s journey. However, given all the positive advances, there is still a disconnect between drug approval and access to molecular testing, as well as between regulatory bodies and clinicians regarding precision medicine. A strong Canadian multidisciplinary team working on implementation of new research will allow us to continue to improve outcomes for Canadian patients with NSCLC.

References: 1. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med 2017; 377(9):829–38. 2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med 2018; 378(2):113–25. 3. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 2017;377(20):1919–29. 4. Merck & Co., Inc. Keytruda® Press Release. http://investors.merck.com/news/press-release-details/2018/Mercks-KEYTRUDAR-pembrolizumab-Significantly-Improved-Overall-Survival-and-Progression-Free-Survival-as-First-Line-Treatment-in-Combination-with-Pemetrexed-and-Platinum-Chemotherapy-for-Patients-with-Metastatic-Nonsquamous-Non-Small-Cell-Lung-Cancer-/default.aspx. Accessed February 28, 2018. 5. Bristol-Myers Squibb Co. Opdivo® Press Release. https://news.bms.com/press-release/bms/pivotal-phase-3-checkmate-227-study-demonstrates-superior-progression-free-surviva. Accessed February 28, 2018. 6. Melosky B, Popat S, Gandara DR. An evolving algorithm to select and sequence therapies in EGFR mutation-positive NSCLC: a strategic approach. Clin Lung Cancer 2018;19(1):42–50. 7. Sanchez-Torres JM, Viteri S, Molina MA, et al. BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors. Transl Lung Cancer Res;2(3):244–50. 8. Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 2017;18(10):1307–316. 9. Novartis Pharmaceuticals Canada Inc. Tafinlar® and Mekinist® Press Release. https://www.novartis.ca/en/news/media-releases/combination-treatment-prtafinlarr-dabrafenib-plus-prmekinistr-trametinib. Accessed March 6, 2018.