乌鸦传媒

The combined effects of immunotherapy and targeted therapy have revolutionized treatment for non-small cell lung cancer (NSCLC). Clinical guidelines recommend some form of immunotherapy as frontline treatment for most cases of advanced disease, and targeted therapies prevail for niche categories of NSCLC with actionable mutations.

As lung cancer continues its cat-and-mouse mutational evolution, resistance to targeted therapy inevitably occurs, but when it does, immunotherapy has disappointed in mutation-driven NSCLC.

"Maybe I would use [immunotherapy] as a last resort," said Vamsidhar Velcheti, MD, of NYU Langone Perlmutter Cancer Center in New York City. "In my own experience, patients with EGFR mutations or who have ALK fusions, they do very poorly with immunotherapy. The response rate is very, very low."

"Recent clinical trials with pembrolizumab (Keytruda) and nivolumab (Opdivo) in patients who had already failed targeted therapy, even then, when you add immunotherapy to chemotherapy, these drugs really don't add that much," he added.

Most recently, the KEYNOTE-789 trial of pembrolizumab and chemotherapy did not show a benefit in tyrosine kinase inhibitor (TKI)-resistant NSCLC. The results showed a numerical improvement in progression-free survival (PFS) and overall survival (OS), but the difference from chemotherapy plus placebo did not meet prespecified levels of statistical significance.

Nonetheless, some lung cancer specialists remain hopeful that continued investigation will identify patients who might benefit. Following the presentation of the KEYNOTE-789 results at the American Society of Clinical Oncology meeting, invited discussant Jonathan Riess, MD, of the University of California Davis, said, "There is likely a population of EGFR-mutated lung cancer that benefits from immunotherapy in some way. We just need to do a better job of identifying and targeting that population."

Some lung cancer experts found reason for optimism in the IMpower150 trial with atezolizumab (Tecentriq). Adding the PD-L1 inhibitor to bevacizumab (Avastin) and carboplatin-paclitaxel chemotherapy in the first-line setting of advanced NSCLC significantly improved OS, irrespective of PD-L1 expression or .

Unlike most studies of immunotherapy for NSCLC, the trial allowed enrollment of patients with driver mutations, and about 100 patients, mostly with EGFR mutations, participated, said Hossein Borghaei, DO, of Fox Chase Cancer Center in Philadelphia.

"In that very limited number of patients, there were responses and clinical efficacy in patients with EGFR mutation-positive tumors," he told 乌鸦传媒. "There were some issues about whether all the patients in that small cohort actually had EGFR activating mutations, so the FDA did not approve the quadruple combination for that patient population. However, it became a hypothesis-generating idea that has led to a number of different studies."

The studies include a large ongoing randomized phase II trial led by Fox Chase investigators. They hope to get a definitive answer to the question of whether the combination of a PD-1/L1 inhibitor, a VEGF inhibitor, and chemotherapy can overcome anti-PD-1 resistance in patients with EGFR mutations.

"We think that VEGF inhibition, with a drug like bevacizumab or ramucirumab [Cyramza], can be immune stimulatory to a couple of different mechanisms that were worked out a while ago," said Borghaei. "Now that we have immune checkpoint inhibitors, we've gone back to some of that data, trying to figure out how best to use it."

"Outside of a clinical trial, I would be hesitant about offering checkpoint inhibitors to patients with these molecularly driven tumors in the metastatic setting," he added. "However, in the context of a clinical trial, I think this is a really important question for us to address, and I would be willing to discuss a study like this with my patients and see whether they would be willing to participate."

The rationale for combining chemotherapy with immunotherapy is sufficient to suggest the strategy to selected patients who have already been treated with a targeted drug, said Jonathan Goldman, MD, of the University of California Los Angeles (UCLA).

"I think that's a very reasonable and appealing choice for patients when they've had appropriate TKIs and you're looking at chemotherapy and thinking about the possibility of immunotherapy benefit," he said. "That's often when I will recommend immunotherapy and a chemotherapy combination for mutation-driven cancers. I like the one [from IMpower150] since it has the most data."

An showed the survival hazard ratio had declined to about 0.90 but still represented about a 6-month improvement with the addition of immunotherapy.

"It's appealing but certainly not definitive information," said Goldman.

UCLA is participating in a trial that he hopes could provide the definitive answer to the question about using immunotherapy in NSCLC with driver mutations. Investigators are evaluating the investigational agent ivonescimab, a combination PD-1/VEGF inhibitor, plus chemotherapy versus chemotherapy alone in the post-osimertinib (Tagrisso) setting of NSCLC.

"The trial has a very specific prospective analysis on this question, and I really do think this will be definitive," said Goldman. "There is some thought that adding the VEGF-inhibitor quality to immunotherapy may be helpful, particularly in EGFR mutants, so I'm hoping this will really shed the most important light on this question."

Not all driver mutations respond the same way to immunotherapy, he added. KRAS, MET, and possibly HER2 do not seem to be negative predictors of benefit. EGFR and ALK are "the real unknown questions, and I hesitate to use immunotherapy by itself."

"I still often like to give immunotherapy with chemotherapy, figuring that there will be at least the protection against rapid progression by also having the chemotherapy as part of the regimen," he noted.

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