Immunotherapy Is Shifting Role of Chemotherapy in Squamous NSCLC

Luis E. Raez, MD

The increasing significance of immunotherapy in oncology is changing the role of traditional chemotherapy, particularly in squamous cell non—small cell lung cancer (NSCLC), said Luis E. Raez, MD. However, chemotherapy remains an integral part of patient care.

"We still find value in the use of chemotherapy, [especially since] the combinations of chemotherapy with immunotherapy have consistently showed a greater response rate compared with immunotherapy alone," said Raez. "We need to wait for survival data but, at least in response rate, combinations were always superior."

For example, in October 2018, the FDA approved pembrolizumab (Keytruda) in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the frontline treatment of patients with metastatic squamous NSCLC. The approval is based on findings from the phase III KEYNOTE-407 trial, in which the regimen reduced the risk of death by 36% versus chemotherapy alone in this patient population. Moreover, the median overall survival (OS) was 15.9 months (95% CI, 13.2 — not evaluable) with the pembrolizumab approach versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017).

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Raez, medical director and chief scientific officer of Memorial Cancer Institute, Memorial Healthcare System, discussed major trials in squamous NSCLC and what lies ahead for immunotherapy.

OncLive: What is the state of immunotherapy in squamous NSCLC?

Raez: Immunotherapy in squamous cell carcinoma of the lung is a very exciting topic. For many years, this disease has been behind in drug development because agents, such as pemetrexed and bevacizumab (Avastin), did not have indications for squamous cell carcinoma.

However, thanks to the KEYNOTE-407 study, we use pembrolizumab with carboplatin and nab-paclitaxel or paclitaxel as a frontline therapy for patients with squamous cell carcinoma [of the lung]. This is an important study because it shows that the addition of pembrolizumab to chemotherapy improves disease-free survival and OS.

Will every patient receive that triplet regimen in the frontline setting?

It should be realistic to assume this because we want to treat our patients with the best approach. It is not enough to give these patients chemotherapy.

What other pivotal trials have read out in this space in recent years?

IMpower131 was a trial where the addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to carboplatin and nab-paclitaxel or paclitaxel showed an improvement in progression-free survival.

Also, a press release from Bristol-Myers Squibb in July 2019 said that the CheckMate-227 study showed superior outcomes, including OS, with a combination of nivolumab (Opdivo) and ipilimumab (Yervoy) compared with chemotherapy. We are excitedly awaiting those data because the results apply to squamous cell carcinoma [of the lung], too.

Pending those data, will immunotherapy solely take over the frontline setting? Will chemotherapy be eliminated?

Yes; KEYNOTE-024 was another study that examined precision immunotherapy in the frontline setting for squamous cell carcinoma. It showed that the use of pembrolizumab, as a single agent, with PD-L1 expression on at least 50% of tumor cells is superior to chemotherapy.

Therefore, either immunotherapy alone or the combination of chemotherapy and immunotherapy will stay as a frontline therapy for both squamous and nonsquamous cell carcinoma of the lung.

What are the major outstanding questions that could be addressed with ongoing trials?

An outstanding question for us is about biomarkers. We want to use immunotherapy, but we don't want to use the same agent in every patient like we do in chemotherapy.

We would like to use PD-L1 and tumor mutation burden in a more rational way to try to help predict which patients are going to respond. There are numerous studies evaluating these biomarkers. We are looking for a breakthrough because up to today, the results are controversial.

Is there anything else that you would like to mention?

Now, most of the immunotherapy agents are equivalent [to one another], but there is a lot of future ahead. We are only working with two checkpoint inhibitors, CTLA-4 and PD-1/PD-L1, but there are at least 30 others [in development]. It's exciting and there are a lot of investigations; for example, one is looking at LAG3.

In the future, we hope patients can have one checkpoint inhibitor after another—that way they do not have to go back on chemotherapy. Today, patients have to return to chemotherapy. We are looking for ways that we can rescue these patients by stimulating the immune system. That way, they can stay on an immunotherapy approach longer without chemotherapy.

Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.