Immunotherapy Could Restore the Value of Neoadjuvant Therapy in Lung Cancer

David Spigel, MD

The radiographic and pathologic responses that have been seen with checkpoint inhibitors in lung cancer bodes well for the use of neoadjuvant therapy. However, the relationship between response and long-term outcomes, specifically with regard to overall survival, will have to be teased out before they become standard practice, explained David Spigel, MD.

“Patients and partners have asked me whether we can use [neoadjuvant immunotherapy] now, and the answer is no. It’s not a standard way to treat lung cancer at this point,” said Spigel. “[However,] at the pace and way end points read out [by way of] pathologic response rates and disease-free survival, we [won’t be] waiting 5 or 10 years for these long-term outcomes. I’m guessing we’ll see some readouts in the next 1 to 3 years.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Spigel, chief scientific officer and director of the Lung Cancer Research Program, and principal investigator at Sarah Cannon Research Institute, discussed ongoing research with immunotherapy in early-stage lung cancer.

OncLive^®: Does immunotherapy have potential to be brought into neoadjuvant and adjuvant settings in lung cancer? 

Spigel: A lot is happening in early-stage lung cancer, [which was a setting in which] we didn’t have any options. Even adjuvant platinum-based chemotherapy became something that was accepted only about 12 to 15 years ago.

There’s a lot of excitement, certainly about neoadjuvant approaches, but more pointedly [regarding the use of] immunotherapy in that space. Adjuvant immunotherapy is [also] going to find its way forward.

Even in limited-stage small cell lung cancer, a potentially curable setting, there are opportunities for developing other treatments like immunotherapy. 

How has immunotherapy helped to illustrate the value of neoadjuvant therapy? 

We’ve always had neoadjuvant therapy. [Even] when platinum-based adjuvant therapy became more standard, we were doing neoadjuvant therapy. Typically, it was: Could we find a role to downstage disease to make surgery possible or more successful? But neoadjuvant therapy kind of went away, because the pivotal, randomized, registrational trials were in the adjuvant setting. There were some pivotal neoadjuvant studies, but adjuvant therapy just became kind of the accepted way to go, and neoadjuvant therapy was something we kind of thought about on a case-by-case basis, usually for more locally advanced settings, like stage III and obviously in settings like pancoast tumors, which still is the case. 

With immunotherapy, I give a lot of credit to Patrick Forde, MBBCh, and his team at Johns Hopkins Medicine, but certainly [investigators] in New York as well, who started to show the value of neoadjuvant immunotherapy. For a couple of years now, we have seen impressive radiographic and pathologic responses with very brief exposures to checkpoint inhibitors. I’ve seen patients have amazing, even complete responses at the time of surgery. Now, we’re waiting on randomized trials to see if this [should be a] standard [approach].

Is there sufficient evidence to suggest that a patient who achieves a pathologic complete response to neoadjuvant therapy will have a favorable outcome? What research is being done to determine the relationship between response to neoadjuvant and adjuvant therapy and prognosis? 

Plasma-based assays [may be able to] help us understand what’s going on with a patient who was treated for cure in the adjuvant setting. Can we monitor patients’ disease in the blood and see if they’ve cleared a clone or [whether] clones reemerge? A good friend and colleague, Charlie Swanton, [FRCP, BSc, PhD, of Crick Institute], has helped open our eyes to this possibility. Studies are in progress to look at this question.

Particularly for neoadjuvant studies, unlike in breast cancer, the lung cancer field is not as advanced in terms of understanding the impact of a pathologic complete response rate. It’s probably the same––that the less tumor that’s present at the time of resection bodes well for a good prognosis down the road. We don’t know that as well in lung cancer, although it’s probably true. We need a little bit more work to understand whether the early findings at the time of surgery are a good surrogate for how patients do long term. 

If you’re going to use drugs, like osimertinib [Tagrisso] or atezolizumab [Tecentriq] in early-stage disease, should you ever use those strategies again, if and when a patient has disease recurrence down the road? How, what, and when should you use it? Those are questions we don’t know, and we’ll have to figure out [the answers to].

Where is research headed in the early-stage setting?

We’re all waiting for the early-stage trials with immunotherapy to read out. We’re waiting for some additional work with osimertinib in the stage III unresectable setting. We are waiting for new drugs to prove that new targets are important, like KRAS G12C in the stage IV setting. As new therapies make it into stage IV disease, the obvious question is going to be the value of those therapies in earlier stages of disease.

We have to get effective drugs in stage IV disease into earlier stages of cancer. However, we can’t assume it’s a one-size-fits-all approach, or that it’s going to work. Drugs that improve response rates don’t necessarily improve survival, so we have to solve that.