Navigating Treatment Decisions With Immunotherapy in Squamous NSCLC

Shiven B. Patel, MD, MBA, FACP

Immunotherapy has emerged as the preferred frontline treatment for several patients with stage IV squamous non—small cell lung cancer (NSCLC), according to Shiven B. Patel, MD, MBA, FACP, but it remains unclear which subsets benefit most from using it in combination with chemotherapy.

“Immunotherapy has a very prominent role in this space,” said Patel. “With the recent data that [have emerged, I feel that] this approach should be used in the frontline setting in just about every patient with this disease, unless there's a contraindication to them receiving it.”

In the phase III KEYNOTE-024¹ and KEYNOTE-042² trials, pembrolizumab (Keytruda) monotherapy demonstrated a significant overall survival (OS) benefit over standard chemotherapy in the frontline treatment of patients with NSCLC whose tumors expressed high levels of PD-L1 as well as those with a low PD-L1 tumor proportion score (TPS), respectively. The PD-1 inhibitor is indicated for both patient populations.

In an effort to improve on the benefit seen with pembrolizumab, the agent was examined in combination with chemotherapy in the phase III KEYNOTE-407 trial.³ After a median follow-up of 7.8 months, median OS was 15.9 months (95% CI, 13.2-not evaluable) in the chemoimmunotherapy arm versus 11.3 months (95% CI, 9.5-14.8) in the placebo arm (HR, 0.64; 95% CI, 0.49-0.85; P = .0017). Notably, the OS benefit was found to be consistent, regardless of the level of PD-L1 expression. Based on these data, in October 2018, the FDA approved the PD-1 inhibitor in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous NSCLC.

“Lingering questions remain with regard to the high—PD-L1 [TPS] subset. Should we be using immunotherapy by itself as described in KEYNOTE-024, or should we be giving everyone chemotherapy plus immunotherapy?” questioned Patel. “The available data show that all of the patients with lower PD-L1 expression should receive both chemotherapy and immunotherapy if they can tolerate it; that should be the standard of care.”

Pembrolizumab is not the only immunotherapy agent to have been investigated in combination with chemotherapy. The addition of atezolizumab (Tecentriq) to carboplatin and nab-paclitaxel led to a clinical OS benefit among a subgroup of patients with advanced squamous NSCLC and a high level of PD-L1 expression, according to the final data from the phase III IMpower131 trial.⁴

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Patel, an assistant professor of medical oncology, Huntsman Cancer Institute, provided further insight into these key trials in squamous NSCLC and how to apply the data to practice.

OncLive: How has the role of immunotherapy evolved in stage IV squamous disease?

Patel: We were first using immunotherapy in the second-line setting. As trials have come out [over the years]—especially KEYNOTE-024 and KEYNOTE-042—it transitioned to the first-line setting as monotherapy. Now, we're seeing it used in combination with chemotherapy in this setting as well.

What were the key takeaways from the KEYNOTE-407 research?

This trial was done in patients with stage IV squamous NSCLC. Participants were randomized to receive either a chemotherapy regimen, which was comprised of a platinum plus a taxane, or the same chemotherapy regimen plus immunotherapy. Investigators looked at outcomes, response rate, how long before the cancer progressed, and then how long patients lived. The subgroup analysis was stratified by PD-L1 expression TPS. The data showed that regardless of subgroup, there was a benefit with chemoimmunotherapy over chemotherapy alone.

The IMpower131 trial also examined the use of chemoimmunotherapy in patients with squamous NSCLC. What do the data presented to date indicate?

[Data from the IMpower131 trial] have only been presented at global meetings in abstract form. As such, [I can’t speak to this in] great detail, but in the whole population, that data didn't show a dramatic difference in survival, either OS or PFS.

Notably, however, at the 2019 World Conference on Lung Cancer, investigators highlighted that in their high—PD-L1 [TPS] subset, there was a pretty impressive difference in OS in patients who received chemoimmunotherapy compared with immunotherapy alone. But again, that was only shown in the patients [with high PD-L1 TPS].

How are you taking these data and applying the knowledge to clinical practice?

Unfortunately, we're going to have to do some cross-trial comparisons; this is never ideal, and the trials aren't perfectly matched, but that's the best that we're going to be able to do. [In my presentation], I discussed data from KEYNOTE-024, KEYNOTE-042, and KEYNOTE-047. The populations weren't the same [across the trials]. KEYNOTE-024 and KEYNOTE-042 included patients with squamous as well as nonsquamous disease. I did my best to compare them side-by-side. I told the audience how I interpret [these trials] and how I approach [treatment] in the clinic for each PD-L1 [TPS] subgroup: 0%, 1% to 49%, and ≥50%; this is how I stratify them.

[PD-L1 expression] is just one level of looking at patients. You also have to factor in their wishes, how healthy they are in terms of their performance status, and how sick they are with their burden of disease. You have to consider these factors before making a decision in clinic.

Could you provide some examples of that decision-making process?

In general, if a patient [has a PD-L1 TPS] between 1% and 49%, I believe chemotherapy plus immunotherapy is the standard of care. However, I have had several patients in their 80s who just don't want chemotherapy. [There have been many times where], personally, I didn’t think they were fit enough to receive chemotherapy. For those patients, I would just treat them with immunotherapy alone, which is FDA approved, and they have actually done quite well. There is a role for [immunotherapy monotherapy] even though my preference is to give [most patients] chemoimmunotherapy if they can tolerate it, and if they want it. We have some flexibility there. Our job is to tailor [treatment] to each particular patient.

Another example would be a patient who has very high PD-L1 [expression, with a TPS of ≥50%], is very sick, and has a high burden of disease. For this patient, I know I need to get a quick response. Even though it seems like the survival [benefits] are pretty similar between immunotherapy alone and chemoimmunotherapy in that population, we know that response rates are higher [when we use] chemoimmunotherapy. Therefore, in that case, even though they have a PD-L1 [TPS] of ≥50%, I would still probably give them chemoimmunotherapy to try to shrink down their tumor so they can feel better.

What is your advice to your colleagues working in this space? Many great strides have been made in lung cancer, especially with the advent of immunotherapy, and we've all learned how great it can be for our patients—as well as the associated toxicities. We are all very thankful, but we also know that response rates to immunotherapies in lung cancer are still less than 50%. As such, we are still doing a lot of research and trying hard to figure out how to get that number higher. I'm hoping that over the course of my career, [we will be able] to figure out how to [improve those rates]. My hope for the future is that we keep on conducting combination immunotherapy trials and see how we can keep on improving outcomes.

References

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37(7):537-546. doi: 10.1200/JCO.18.00149.
2. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, control, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7.
3. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Eng J Med. 2018;379(21):2040-2051. doi: 10.1056/NEJMoa1810865.
4. R. Jotte, F. Cappuzzo, I. Vynnychenko, et al. IMPOWER131: final OS results of carboplatin + nab-paclitaxel ± atezolizumab in advanced squamous NSCLC. Presented at: International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA14.02.