As a follow-up to our recent conversation with Enriqueta Felip, MD, PhD, Aptitude Health also spoke with Dr William N. William to gain a Latin American perspective on the management of non-small cell lung cancer (NSCLC). Dr William is national leader of Thoracic Oncology at Oncoclínicas&Co., São Paulo, Brazil, and adjunct associate professor at the University of Texas MD Anderson Cancer Center (MDACC) in Houston. He graduated from and did his internal medicine residency at the University of São Paulo, then completed his oncology fellowship at Hospital Sírio-Libanês and his thoracic-head and neck fellowship at MDACC. He served as faculty in the Department of Thoracic-Head and Neck Medical Oncology at MDACC for over 10 years. Dr William is a medical oncologist caring for patients with lung and head and neck cancers. His clinical and translational research career is focused on developing novel strategies for the prevention and treatment of aerodigestive tract malignancies. He is author or co-author of over 100 articles in peer-reviewed journals such as Nature Medicine, Proceedings of the National Academy of Sciences of the United States of America, JAMA Oncology, and Lancet Oncology.
Here is a recap of our conversation:
What recent advancements in the management of NSCLC do you consider the most groundbreaking?
Over the past few decades, the 2 most important advances we’ve seen in terms of NSCLC treatment have been the development of immunotherapies and the development of targeted therapies. Looking back to the early 2000s, patients with metastatic disease would receive any platinum-based chemotherapy. There wasn’t a big difference between which drugs you would choose as the partner of the platinum agent, and the median overall survival was around 8 to 10 months. This has completely changed now that we’ve identified subgroups of NSCLC as defined by molecular abnormalities and specific mutations, and we’ve been able to develop targeted therapies for those mutations as well as immunotherapies, primarily for those patients that do not harbor actionable genomic alterations. Now for the first time, we’ve been seeing long-term survivors with disease control after 5 years of treatment, even among heavily pretreated patients whom we wouldn’t expect to live more than 3 to 6 months.
Given the progress in comprehending gene mutations and biomarkers, what is your perspective on how these findings will shape the future of NSCLC diagnostics and treatment in Latin America, particularly with the decreasing size of target populations and the rising cost of diagnostic panels?
The more we can subclassify patients with NSCLC, the more we can offer them better treatment options with better outcomes and fewer toxicities. We’re even moving those treatments up to potentially curable disease. Until recently, for example, the 2 most widely tested biomarkers were EGFR mutations and ALK translocations, for the sole purpose of identifying the best treatment options for patients with metastatic disease. Now, we can use EGFR mutations to tailor adjuvant therapy for patients in a potentially curable situation, and more recently, an ALK inhibitor was approved in the adjuvant setting in many parts of the world that will hopefully soon also receive approval in Latin America.
On the one hand, it makes management of the disease more complex, because now a patient cannot simply be identified as having NSCLC—we have to subclassify it, in addition to understanding the extent of the disease and identifying the potential therapeutic implications for that.
But on the other hand, what we’re able to offer these patients is much broader and much more precise than what we could before. This requires subspecialization of medical oncologists because we must know all the data and stay on top of new data as they are shared. It is very hard for someone who is not a lung cancer specialist to follow the vast literature that is being generated. Also, some of these therapies will have higher costs because they target a very small patient population, impacting access to the drugs, expenses to payors, as well as profits for manufacturers.
Are there barriers to patients receiving access to testing panels in Latin America?
The biggest barrier is cost. The good news is that the cost has been decreasing, particularly for broad-panel next-generation sequencing (NGS) profiles, which gives more patients access to these very important diagnostic tools. We’re also seeing new technology being developed in the region. Latin America is becoming less and less dependent on technologies that are developed in the US or Europe, with many local labs adopting these technologies. However, one key limitation is the interpretation of the raw data generated by next generation sequencing, requiring analysis by bioinformatics teams. There’s still a lot of training that needs to happen in the region, so this part of molecular assessment is often outsourced to other regions of the world, where there is a larger pool of people trained in this particular skill.
I do think that Latin America has been creative in trying to improve access to molecular tests. For instance, Brazil has been a very good example of how partnerships with the pharmaceutical industry can help increase access to care. Specific to NSCLC, there is a consortium of pharmaceutical companies that funds molecular testing for every patient diagnosed with metastatic, nonsquamous NSCLC in the country. It doesn’t matter whether the patient is treated in the public or in the private system. It doesn’t matter whether the patient is going to eventually receive a drug from any of these pharmaceutical companies or not. They provide funding for a broad NGS panel for every single patient who is diagnosed, and there are many advantages to this. First, the patients don’t need to bear the cost of molecular testing. The pharmaceutical companies increase the pool of patients who are identified with molecular alterations for whom their drug may be appropriate. For the physician, it’s a win as well, because they can now apply their knowledge to actual patients they see in the clinic. This also decreases the burden to the payor system, whether it’s public payment or payment through health insurance, because the cost is absorbed by the pharmaceutical company.
In a recent commentary published in Nature, medical researchers associated with Gustave Roussy and Paris-Saclay University present a forward-thinking perspective on cancer classification. They propose a shift away from the conventional practice of categorizing cancers according to the organ of initial manifestation to a biological classification based on their molecular characteristics. In your opinion, what benefits do you foresee from adopting a molecular-based classification approach for patients with conventionally categorized lung cancer and for cancer treatment overall?
Yeah, that’s a provocative commentary. I appreciate that the authors are trying to simplify our understanding of this disease, but I’m not sure I agree with every point that was made. As an example, in trying to categorize all cancers that have a BRAF mutation under one umbrella, they are trying to simplify something that is not so simple. The biology of the disease is much more complex than that. I think the context where these mutations happen makes a difference. For example, BRAF mutations in colorectal cancer differ from BRAF mutations in melanoma. When you inhibit a BRAF mutation pharmacologically in melanoma, you typically have a tremendous response. That’s not the case when you do that for a patient with colorectal cancer because for colorectal cancer, there are a number of other bypass mechanisms that are activated, and you need to inhibit BRAF plus additional pathways such as the EGFR pathway for the treatment to be effective. So it’s not going to work exactly the same in every tumor type, and I think the organ of origin makes a difference.
The other thing that I see as a complexity of reclassifying the disease that way is that we might be ignoring co-mutations, and we know that co-mutations or other molecular alterations also play a very important role in determining the natural history of the disease and response to therapies. It is not enough just to say that a tumor has an EGFR mutation. We’re now coming to appreciate that in the context of EGFR mutations, co-mutations happen. These co-mutations change the way that cancers behave, and that may be organ-specific as well.
Lastly, I think that this type of classification is geared toward metastatic disease, but we must consider that a lot of these cancers are being diagnosed in earlier stages where local therapies play a big role, also affecting decisions regarding surgery or radiation therapy. Trying to lump them all together—for example, a melanoma with a colorectal cancer just because they share a BRAF mutation—doesn’t necessarily determine how we address earlier-stage disease.
What challenges might healthcare systems face in implementing such a shift in classification, and how quickly do you think such an approach may be implemented in daily clinical practice in Latin America?
There are few aspects of this that can be adopted easily, and I think we’ve already started doing that with the prospective approvals of some immunotherapies for patients with high tumor mutation burden independent of where their tumor initiated. That research has increased access to drugs for many patients, and we’re now seeing some other drugs being approved in an agnostic way in Brazil and other regions in Latin America. One example is RET inhibitors for patients with RET alterations. We may also see another approval soon for trastuzumab deruxtecan for those whose cancers have HER2 overexpression. So in some respects, yes, this may be applicable to metastatic disease, but again, I think reclassifying the whole field on the basis of that is a little bit premature.
Where do you think we should focus the research in the future?
There are several gaps in NSCLC, but perhaps one of the most important is our understanding of mechanisms of resistance, whether to immunotherapies or to targeted therapies. We’ve made some progress in the realm of targeted therapies, and there are even some newer-generation drugs that might be able to address some mechanisms of resistance in NSCLC. In terms of the mechanisms of resistance to immunotherapy, whether de novo or acquired resistance, our understanding has been lagging. We also need to start moving these therapies toward earlier-stage disease. We’ve been able to do that with immunotherapies and some targeted therapies, but we need to understand exactly what the potential benefits are and how these drugs affect overall survival in patients with earlier-stage disease. We also need to determine what are some of the other potential biomarkers of benefit from these drugs so that we can tailor and apply these treatments to the population that needs them most.
Considering our conversation today, how do you envision the evolution of NSCLC treatment in Latin America over the next 3 to 5 years?
I think we will see more and more therapeutic options available for lung cancer. When I first started specializing in lung cancer, nobody wanted to treat these patients because there weren’t many options. Now, lung cancer is the poster child for personalized medicine, and this is very exciting. We’re going to see novel immunotherapies and will be able to better tailor these treatments to the patients in greatest need on the basis of their molecular markers of benefit. I think we will also make great strides in terms of identifying those at highest risk for toxicities on the basis of biomarkers, and hopefully we’ll be able to adjust therapies or follow patients more carefully depending on their risk for toxicities. I also think some novel combination therapies are going to emerge. Lastly, we are thinking more and more about germline alterations that up until now didn’t seem to play a big role in lung cancer because the disease is primarily driven by environmental factors such as smoking. A sizable proportion of these lung cancers, even in people who have been exposed to cigarette smoking, carry some germline alterations that can serve as therapeutic targets and can also help us understand a better way to manage the disease and screen for earlier stage disease in high risk families.
