This transcript has been edited for clarity.
Hello. It's Mark Kris from Memorial Sloan Kettering, here to give my top 10 developments in thoracic oncology in the year 2020. Lord, it's been a crazy year. We have all been mightily distracted by the COVID pandemic, but I don't want to lose sight of the important developments that happened last year in the field of thoracic oncology.
#10: Agents for RET-Altered Lung Cancers
Number 10 is the emergence and US Food and Drug Administration (FDA) approval of two agents, selpercatinib and pralsetinib, specifically targeting patients with RET-altered lung cancers. These two agents yield response rates of approximately 50% and are available to any patient that we find with RET-altered lung cancers. [Editor's note: The ORRs for selpercatinib and pralsetinib were 64% and 57%, respectively.]
#9: Agents for MET-Altered Lung Cancers
In a similar vein is the emergence of agents for MET-altered lung cancers. Capmatinib was approved by the FDA and included in the National Comprehensive Cancer Network (NCCN) guidelines for those lung cancers that have high amplification of the MET gene. Unlike crizotinib, with response rates in the 30% range, tepotinib and capmatinib response rates are in the 50% range.
#8: Agents for HER2-Altered Lung Cancers
Number eight is the emergence of therapies for HER2-altered lung cancers. With the addition of trastuzumab deruxtecan to ado-trastuzumab emtansine in the NCCN guidelines, you now have two antibody drug conjugate [options] for patients with lung cancers that are HER2 mutant or HER2 amplified. The drugs are very effective and there is much experience using these agents in breast cancer.
#7: Targeted Agents for KRAS
Number seven is the emergence of specific targeted agents for KRAS. It's been a dream of most of the thoracic oncologists that we would have drugs for KRAS. We finally have at least two drugs, sotorasib and adagrasib, marching toward FDA approval. Not quite there yet but getting close. Accelerated approval is in the offing for these and breakthrough designation. The agents lead to durable, meaningful responses for patients. How to integrate them into the care of patients is going to be our challenge going forward this year and in the years to come.
#6: Next-Generation Sequencing Testing
All of these developments lead to number six, and that is the emergence of next-generation sequencing (NGS) testing. It's absolutely clear now that NGS testing is a standard of care. It needs to be done for all patients. I'd urge that it be done as soon as the diagnosis of lung cancer is suspected, to help in diagnosis, to help plan therapy, and to help choose the best treatment sequence for patients. We have very good tests. We have both blood and tissue testing that can do this. And in addition to the diagnostic capabilities, we are seeing now that comprehensive NGS testing can be used to guide therapy — not just to choose drugs, but to see whether drugs are working, both in the advanced setting and also in the locally advanced setting. Many clinical trials are underway now looking at intensifying therapy when cell-free DNA is present after treatment with a given therapy. I think the work of Max Dean from Stanford clearly has paved the way here, using cell-free DNA to guide therapeutics. After you have given a definitive therapy and cell-free DNA is still present or if cell-free DNA is present at diagnosis, it indicates a higher degree of risk, and we would want to give our most intensive therapies to those patients. The last great thing is that these standard NGS tests — the Foundation Medicine ones, for example — are now the FDA-approved companion diagnostics for choosing our targeted therapies. Targeted therapies are now available for probably half of patients with lung adenocarcinomas. While any individual target may be a small percentage, when you put them all together, it's a huge percentage and it justifies doing NGS testing on everybody.
#5: 'Reemergence' of Chemotherapy
Our number-five development is the "reemergence" or the "rediscovery" of chemotherapy. We have seen that chemotherapy is a very important complementary therapy to immunotherapeutics. We have had data for many years giving it with anti-PD-1 and PDL-1 agents. This year we saw data adding chemotherapy to ipilimumab and nivolumab, a chemotherapy regimen that has fallen out of favor in many respects but is very helpful when given with immunotherapeutics and in the right situation. The other development were two papers in the Journal of Clinical Oncology (JCO) on adding chemotherapy to the targeted therapies gefitinib or erlotinib in patients with EGFR-mutant disease. In both cases, there were improvements in progression-free and overall survival, which led the editorialists from those two manuscripts to say that adding chemotherapy to gefitinib or erlotinib as initial therapy is now a new standard of care. Who would have thought?
#4: Neoadjuvant Approaches
I think number four is the emergence of neoadjuvant approaches, particularly with neoadjuvant immunotherapeutics. This year, the International Association for the Study of Lung Cancer has published a comprehensive work detailing how pathologic specimens can be assessed for pathologic response. Also, many pieces of data were published and reported on how immunotherapeutics alone (data from the Lung Cancer Mutation Consortium, for example) or immunotherapeutics and chemotherapy (data from Mariano Provencio and from Catherine Shu at Columbia) show very high rates of pathologic complete response and major pathologic response, which translates into survival benefit for those patients. And there was an early report from a phase 3 trial comparing nivolumab and chemotherapy to chemotherapy alone, showing an increase in pathologic complete response rate, which in all the past literature translates into an improvement in overall control. I think we are going to see more neoadjuvant immunotherapeutics, and given with chemotherapy as well.
#3: Concurrent Checkpoint Inhibitor and Radiotherapy
Number three is additional information that combining a checkpoint inhibitor with concurrent radiotherapy in a treatment program leads to long-term results. This year at the European Society of Medical Oncology (ESMO) meeting, 4-year survival data and progression-free survival (PFS) data, more importantly, were reported. We now have data on the original trial adding durvalumab to concurrent chemo/radiation that adding that drug to our best regimens of concurrent chemotherapy and radiation improves PFS by 15% at 4 years. That is getting closer and closer to what we are really looking for: a long PFS and perhaps cure. We got more data at the ESMO meeting this year that that is going to happen. This is now a standard of care and we got a reassurance that it's an important one.
#2: Osimertinib in Resected EGFR-Mutant Disease
Number two is the emergence of targeted therapy of osimertinib for patients with EGFR-mutant lung cancers who have had complete resections of their cancer. That data — very, very potent — shows that improvements in PFS, the goal of this trial, were very dramatic for all stages. That has now been added to the NCCN guidelines and has now been approved by the FDA. For the first time, we have an approved therapy for stage IB lung cancers. We also have an approved targeted therapy. I think that is going to open the door for more and more testing of targeted therapies in the neoadjuvant and adjuvant settings.
#1: Hope for Stage IV Lung Cancer
Number one is bending the PFS curve for patients with stage IV lung cancers. In the paper reported by Roy Herbst in the JCO, what you see when comparing pembrolizumab to docetaxel is persistent improvements in PFS out to 4 years plus. That can translate into a cure. And who would have thought that patients with metastatic disease, in this case in a second-line setting, would have not just long remissions, but remissions that don't seem to end, and maybe the possibility of cure. I think that is the most dramatic piece of data that I've seen this year, and it gives us the greatest encouragement.
In summary, I think we have had an amazing year. We have had hints that we can clearly improve PFS and perhaps [achieve] cure in patients with both locally advanced and metastatic disease. A paper in The New England Journal of Medicine, published a few months ago, showed for the very first time that mortality has decreased in all patients with lung cancer. And the reason is the therapies we give. It's great news that our therapy impacts patients in a very meaningful way. We have a lot more work to do, but we should be encouraged by the deluge of data that we have had this past year. We are going to do even better, not just to lengthen life, but to cure our patients with lung cancers, both locally advanced and metastatic.
Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.
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Cite this: Mark G. Kris. Top 10 Advances in Thoracic Oncology in 2020 - Medscape - Jan 19, 2021.