Uncertainty Surrounds Nondriver NSCLC Treatment After Progression

Hossein Borghaei, DO, MS

Immunotherapy alone or in combination with chemotherapy has become the standard of care for those without oncogene-driven lung cancer; however, the decision upon progression is not as clear, explained Hossein Borghaei, DO, MS.

In August 2018, the FDA granted a full approval to the combination of pembrolizumab (Keytruda) and standard chemotherapy for patients with nonsquamous, non-oncogene driven non—small cell lung cancer (NSCLC) based on data from the phase III KEYNOTE-189 trial. Data showed a more than 50% reduction in the risk of death and an overall survival (OS) benefit irrespective of PD-L1 status.

However, patients who have ≥50% PD-L1 expression may also be candidates for single-agent pembrolizumab, which improved OS versus chemotherapy in the phase III KEYNOTE-024 trial.

Though patients who receive frontline immunotherapy can switch to a platinum doublet in the second-line setting, Borghaei explained that the options for patients who received an upfront combination of chemotherapy and immunotherapy are limited.

“We need to do more trials. Unless we're happy to go with old-fashioned docetaxel or other drugs, we're going to have to participate in studies,” Borghaei said in advance of his presentation at the 2018 New York Lung Cancers Symposium. “We're going to have to encourage everyone to seek out trials to figure out what the next best treatment option is for our patients.”

OncLive: You are presenting on subsequent therapies for non-oncogene driven lung cancer. What would you like to emphasize in that space?

In an interview with OncLive, Borghaei, chief of thoracic medical oncology at Fox Chase Cancer Center, discussed current and potential therapeutic approaches for patients with non-oncogene driven lung cancer who progress on frontline treatment.Borghaei: The overwhelming data that we have for patients who do not have an oncogene-driven tumor suggest that a combination of chemotherapy plus immunotherapy or potentially single-agent immunotherapy is the standard of care. [Single-agent immunotherapy should only be considered in] certain patients, namely those with PD-L1 expression greater than 50%.

That raises the question of what to do in the second-line setting. In the case of a patient who has at least a 50% PD-L1 expression and has gotten single-agent immunotherapy, which is typically pembrolizumab, the choice is a little clearer. If they're clearly progressing on immunotherapy, the standard is to switch to chemotherapy because those patients have not seen a platinum doublet. The idea of continuing immunotherapy and adding chemotherapy has been raised. I can tell you that there will be a combined ECOG/SWOG national study with multiple arms that will address that specific issue. I'm the national principal investigator of the study, along with Dr Anne Chiang from Yale Cancer Center.

If the platinum doublets don’t work, and in the absence of clinical trials, you are back to docetaxel or any of the other drugs that are out there. That is not something that we want to go back to because we have experienced this “shiny new tool” of immunotherapy. We like the way it behaves, and we like the better quality of life patients have on it. We're hoping to develop other combination therapies that can overcome this immune resistance.

For patients who get chemotherapy plus immunotherapy and then have progression, the question is even more difficult. Again, you’re back to the old-fashioned docetaxel or docetaxel plus ramucirumab (Cyramza). The combination of docetaxel and ramucirumab, regardless of how small the improvement was, did show an improvement over docetaxel monotherapy. There is logic to want to use a combination that maximizes benefit. In the absence of clinical trials, it's hard to identify specific regimens that are going to be any different than what we've seen before. We're going back to docetaxel or gemcitabine.

I don't have any great insight to say, “If somebody is progressing through chemoimmunotherapy, you should absolutely use drug ‘X.’” I don't think anybody has a crystal ball to predict what is going to happen. It's an area that we need additional drug development in. We need to concentrate on the patients who are going to come off of chemoimmunotherapy. In my experience, these patients have a really good performance status. They're very interested in continuing treatments beyond that stage.

Could you highlight any of those trials?

We have an obligation to figure out why they're progressing through immunotherapy by doing additional studies to define the tumor milieu. We know there are a group of patients who progress through immunotherapy because they develop a beta-2 microglobulin mutation [and have] no antigen presentation. Perhaps that patient population needs to be treated with a different combination. Additionally, trying to design studies that address the specific issues that these tumors have will be important. At this point, clinical trials are the best option for a patient who is progressing on chemoimmunotherapy.A lot of them are in early-stage development in the phase II setting. They're usually nonrandomized, single-arm studies that are attempting to define the clinical efficacy of the combinations. There are too many to mention in one setting—in one interview. If you talk to different doctors, you're going to get different opinions because that's how we are. We like certain combinations. Personally, the combination of an immunotherapy drug plus a VEGF inhibitor is a very attractive option. The preclinical data and limited clinical data we have from early-stage protocols suggest that that combination can be active in a portion of patients. Who exactly benefits is still an unknown. That's where the biology, preclinical work, and correlative studies have to take place.

There are a number of cytokines, including interleukin-2 (IL-2), that have received a lot of attention because of early hints of clinical activity. We're not using the old-fashioned IL-2 with all of the toxicities, [but rather] a pegylated form that has made the drug more tolerable. As far as I'm concerned, that [agent] with a PD-1/PD-L1 inhibitor can be effective. There are a number of other combinations that have been presented at various meetings. I don't want to omit anybody, but I would say that there’s just too many of them. I don't really have any other insight as to which one is going to go any further.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.