1. Nalley, Catlin

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Great strides have been made in the treatment of lung cancer, especially with the onset of precision medicine. During the 2020 ASCO Virtual Education Program, the Science of Oncology Award was presented to Pasi A. Janne, MD, PhD, MMSc, Professor of Medicine at Harvard Medical School, Scientific Co-Director of the Belfer Center for Applied Cancer Science, and Director of the Lowe Center for Thoracic Oncology.

Pasi A. Jnne, MD, Ph... - Click to enlarge in new windowPasi A. Janne, MD, PhD, MMSc. Pasi A. Janne, MD, PhD, MMSc

Janne, who is one of the co-discoverers of EGFR mutations, was honored for his extensive contributions to the development of therapeutic strategies for patients with lung cancer, specifically EGFR-mutant disease. His interest in lung cancer began during his oncology training. With a bleak outlook, he believed there was an opportunity to make a difference in the lives of lung cancer patients.


"The discovery of EGFR mutations really arose from multiple efforts that were happening simultaneously in the early 2000s," he said, noting this advancement helped change the standard of care for a subset of lung cancer patients with this mutation. Today, as opposed to using these therapies after patients have exhausted systemic therapies, which include chemotherapy, we use EGFR inhibitors as frontline therapy," Janne explained. "This has led to improvements in patients' outcomes and in overall survivals (OS) compared to what those were in the early 2000s before the EGFR mutation discovery.


"Over the subsequent 15 years, multiple other genetic alterations have been discovered," he continued. "The discovery of EGFR mutations helped catalyze precision medicine."


During his lecture, Janne recalled the first patient he treated with osimertinib, a mutant-selective EGFR inhibitor. "Seeing those scans improve and seeing that patient feel better was really amazing," he said. "As a scientist, one always hopes that the scientific discoveries you make have an impact. When those discoveries not only get tested in the clinic, but they help somebody [...], it's really an amazing feeling to be a part of that and to have contributed to that outcome I'm very honored and humbled to receive [this award] from ASCO."


Throughout his lecture, entitled "Precision Therapy for Lung Cancer-2020 and Beyond," Janne outlined the evolution of precision therapy while highlighting advancements. Precision therapy for lung cancer, specifically lung adenocarcinoma, is a relatively new field. A number of specific oncogenic subsets have been identified in lung adenocarcinoma, leading to approved targeted therapies for many of these patients.


"However, in some of these cases, we still don't have any approved therapies, including for KRAS-mutant cancers or for ERBB2-mutant/amplified cancers, as well as some of the others," Janne explained, noting there is encouraging clinical data emerging on KRAS G12C inhibitors, as well as therapeutic strategies to target mutant ERBB2."


Janne highlighted lessons learned over the last 15 years, including the key principles of precision medicine: use the best drug first, don't forget about CNS, drug repurposing only gets you so far, and incorporate effective genotype-directed therapies in earlier disease settings.


Effective treatments are available that target EGFR-mutant and ALK-rearranged lung cancer. Data has shown that osimertinib, when compared to prior generation EGFR TKIs, is associated with an improvement in median OS. Similarly, Janne noted alectinib is associated with an improvement in median OS compared to crizotinib.


"Not only are these agents more effective at delaying progression, but they also improve OS and, hence, have become our agents of choice in first-line treatment," he explained. "Both of these agents also have effects on the central nervous system (CNS).


"As we develop more effective systemic therapies for our patients, relapses in the CNS, specifically in the brain as well as in the leptomeninges, become an increasing problem," Janne said. "Having pharmacological agents that can penetrate the CNS is certainly a welcome [addition] to our therapeutic armamentarium."


When discussing the categories of EGRF mutations, Janne noted therapeutic approaches have improved with the approval of several drugs. There is, however, a subset of EGFR-mutant patients-those with exon 20 insertion mutations-who have no approved options.


Despite this, there are promising approaches on the horizon. "We have seen encouraging early data from TAK-788, as well as JNJ-372," Janne said. "Both agents have FDA Breakthrough Designation and, hopefully, will receive regulatory approval sometime in the near future."


While approved therapies for more common EGFR mutations are effective, Janne noted that "we're not curing anyone with advanced EGFR-mutant lung cancer." To address this, researchers are focusing on two approaches to improve therapies.


"First is to understand the mechanisms of drug resistance, and if we can identify those, is it better to target the emergent resistance mechanism or prevent it in the first place?" he asked. "A second, but not mutually exclusive, approach is to enhance our initial therapy and ask: why do not all EGFR-mutant cancer cells die with EGFR inhibition? And if we could develop strategies to enhance the initial effect of EGFR inhibition, would that ultimately lead to prolonged outcomes and improved survivals for patients?"


With a plethora of ongoing research, Janne suggested there are several areas that could potentially improve the efficacy of these therapies. "In the treatment-naive state, we can study targeted therapy combinations," he explained. "We can also study chemotherapy combinations, which are now being tested in EGFR-mutant lung cancer.


"In patients with drug resistance, we can target specific resistance mechanisms or develop broader strategies to target multiple resistance mechanisms simultaneously," he continued. "In patients that have developed MRD, can we use local therapy? Or can we use pharmacological studies to specifically eliminate these cells and, again, enhance the initial effect of EGFR inhibition and hopefully achieve prolonged outcomes?"


At this year's ASCO annual meeting, a phase III clinical trial looked at stereotactic radiation in combination with EGFR TKIs as first-line therapy in patients with EGFR-mutant lung cancer.


"[It] demonstrated improvement in progression-free survival and OS for the combination approach compared to a TKI alone," he said. "I look forward to seeing additional studies like this, specifically targeting this MRD state as a novel approach to improving outcomes for patients with EGFR-mutant and other oncogenic forms of lung cancer."


What comes next? "We have multiple effective therapies and multiple effective targeted therapies, but we still have many unanswered questions," noted Janne, who identified a number of areas for growth, including identification of "low-risk" and "high-risk" cancers; improving strategies to combat CNS disease; and development of effective immune therapies for lung cancers with oncogenic alterations.


"And finally, we've discussed somatic genomic alterations, but what about germline genomics?" he concluded. "We're just at the infancy in understanding the impact of germline genomics on cancer development and treatment outcomes. And, no doubt, these features can also impact the efficacy of targeted therapies in patients with lung cancer."


Catlin Nalley is a contributing writer.


ASCO Science of Oncology Award & Lecture