Pioneers and Progress in Personalized Lung Cancer Treatment

The treatment of lung cancer with personalized medicine has come a long way in recent decades, but still more achievements remain to be seen, said Bruce Johnson, MD, FASCO, immediate past president of the American Society of Clinical Oncology, during his keynote speech opening the Business of Oncology Summit hosted by the Florida Society of Clinical Oncology in Kissimmee, Florida.

Moderator Thomas Marsland, MD, of St. Joseph Health, explained that Johnson would set the tone for the summit’s theme of ensuring access to the “wonderful lifesaving therapies” resulting from new developments in oncology. He introduced Johnson, who is the chief clinical research officer at Dana-Farber Cancer Institute, as the “premier lung oncologist and the godfather of targeted therapy.”

Johnson said that his strategy for attacking cancer dates back to ancient history, when Philip of Macedonia and Julius Caesar used the tactic “divide and conquer” to split the enemy. Millenia later, Johnson and other researchers fight a different battle by using biomarkers to identify subsets of patients who are most likely to respond to targeted therapies.

From the start of his research in the 1980s, Johnson followed 3 principles of establishing permanent cell lines from all patients’ tumor specimens, comparing the tumor models’ behavior with patient outcomes, and leveraging the early capabilities of molecular biology techniques to study the cell lines.

In the early 2000s, investigators first showed an association between tumor response to gefitinib and erlotinib and mutations of the EGFR gene. Soon, published results showed that 25 of 31 patients who showed response had the mutation, and none of the nonresponders had the mutation.

“We were pretty sure, based on the laboratory results plus the clinical observations, that this was likely the reason why these patients had dramatic responses,” Johnson said.

This new understanding soon led to a new paradigm in which clinicians would treat lung cancer with a targeted agent, biopsy a patient to find out why it’s working, and then design a drug that works in that situation. As these new drugs began to show efficacy in previously treated patients, they began to move into the first line of treatment—for instance, in 2018 the FDA approved osimertinib as first-line therapy for patients with EGFR+ non—small cell lung cancer (NSCLC). These approvals meant that oncologists could have “a very different conversation with these patients” in which they could realistically discuss time frames of survival longer than a few months.

While Johnson does not see EGFR tyrosine kinase inhibitors curing these patients, Johnson said, they are especially valuable in combination with other treatments. For instance, after achieving tumor response with the drug, isolated areas of resistance can be treated locally with surgery or radiation.

To illustrate the power of this treatment strategy, Johnson showed results from a trial of crizotinib that began in 2013 and did not publish the final survival analysis until 2018.

“I thought I would never live to see the day where you have to wait for 5 years to get the survival for a lung cancer study,” said Johnson. He added that more than half of the patients are still alive, which “shows what can happen when you have a targetable lesion and you develop effective drugs.”

Another exciting area transforming the field is immunotherapy, which earned researchers Tasuko Honjo, MD, PhD, and James Allison, PhD, the Nobel Prize in Medicine in 2018. As recently as 2012, the finding that a few patients had dramatic tumor responses to anti—programmed death ligand 1 antibody was like seeing a “singing pig,” said Johnson; it might not sing well, but the amazing part is that it can sing at all.

By 2016, published results of a randomized trial of pembrolizumab against chemotherapy in NSCLC had demonstrated a hazard ratio of 0.60 for survival. These findings led Johnson to write in an accompanying editorial that “Immunotherapy with checkpoint inhibitors will displace chemotherapy in yet another subset of patients with lung cancer.”

In terms of the future, Johnson discussed several conditions necessary to ensure further progress in personalized medicine for lung cancer. He called for improved decision support at the point of care to help clinicians interpret genotypic findings and select the appropriate therapy, as well as the need for guidance around choosing appropriate next-generation sequencing panels. He also encouraged the ongoing development of potent and specific inhibitors (eg, osimertinib, alectinib) and the design of drugs with better central nervous system penetration.

Finally, he called for increased public and private support for drug development, which poses an economic challenge for manufacturers looking to recoup costs on the small subsets of patients treated with these highly specific therapies. The high prices of the drugs mean that the total costs of treatment combinations get expensive, especially with longer survival and treatment times.

“I don’t think you can ignore the economic piece of this,” said Johnson. “From a societal standpoint, trying to make this available to the public without the country going broke is a real challenge.”