Immunotherapy Slows Limited Metastatic Non-Small Cell Lung Cancer After Surgery or Radiation

Patients with non-small cell lung cancer that has spread to a few parts of the body can delay disease progression after surgery or radiation by taking immunotherapy.

Researchers who generated those results in a phase 2 study at the University of Pennsylvania’s Abramson Cancer Center found that adding immunotherapy after locally ablative therapy (LAT) — which uses surgery, radiation or other methods to try to eliminate all sites of the disease — tripled the time without disease progression, also known as progression-free survival. In the study, immunotherapy brought progression-free survival to about 19 months, while expected progression-free survival without it would have been 6.6 months.

The use of the immunotherapy Keytruda (pembrolizumab) after LAT was tested in 45 patients between February 2015 and September 2017. The patients had oligometastatic disease, meaning that their cancer had spread to four or fewer locations in their bodies. While previous research has shown that cancers that express a lot of the protein PD-L1 tend to respond especially well to immunotherapy, Keytruda was given to patients in this study regardless of whether their cancers expressed the protein.

All the patients took Keytruda; there was no control group that skipped the immunotherapy for the sake of comparison. However, researchers compared patients’ PFS results with those of similar patients in a 2013 study who were treated with LAT only.

Lead study author Dr. Joshua Bauml, assistant professor of medicine at the Hospital of the University of Pennsylvania, discussed the findings with CURE.

What was the design of the study?

Patients had locally ablative therapy using surgery, radiation or another form of definitive therapy. Then, four to 12 weeks later, they got six months of pembrolizumab monotherapy. If it was tolerated well and there was no evidence of progression, they were eligible to get an additional six months of immunotherapy.

We compared our progression-free survival finding of 19.1 months to a historical reference population whose progression-free survival was 6.6 months. With that reference population, researchers started the clock at the time that LAT began, so to do a fair comparison we calculated PFS from the start of the most recent LAT. The problem is, that treatment happened before the patients entered our trial. So, to provide a more conservative estimate, we also counted from the time they started pembrolizumab, and there we saw a median PFS of18.7 months — still quite an impressive result.

In the study, you and your co-authors state that there’s a strong biological rationale for the use of immunotherapy after cancer has been largely eliminated. What is that rationale?

From other forms of cancer, we know that if someone has minimal residual disease — or no measurable cancer — it’s easier for the immune system to attack remaining cells. If you look at patients who have leukemia and are about to undergo allogeneic stem cell transplant, it’s done only after the patient has no evidence of disease – you wouldn’t put them through it otherwise. That’s the idea we’re talking about: These patients who have minimal residual disease are maybe more likely to respond. Every patient on our study was in that category – they had no measurable cancer at the time of enrollment.

Keytruda is already approved by the FDA for the treatment of specific groups of patients with non-small cell lung cancer. How would this use be different?

Pembrolizumab is currently approved in metastatic non-small cell lung cancer for patients with (disease that expresses) PD-L1 and in combination with chemotherapy regardless of PD-L1 status.

These indications do not include the use of ablative therapy to visible sites of metastatic disease. In fact, patients with metastatic disease did not historically undergo such ablative therapies, as their cancers were deemed incurable. With recent data indicating that the role of ablative therapies may be increasing, we wanted to see if adding immunotherapy could improve outcomes further.

What should the next steps in this research be?

It’s reassuring that these results are intriguing and promising. But this was a single-arm study, and the results need to be validated in a randomized, controlled trial.

There are multiple ongoing randomized trials to evaluate the role of LAT in oligometastatic disease, incuding the LU002 study through the NRG cooperative group and led by Dr. (Puneeth) Iyengar.

(At Abramson Cancer Center,) we’re still developing a study of patients assigned to LAT with or without pembrolizumab.