Despite Treatment Advances, Chemotherapy Retains Role in Metastatic NSCLC

Ryan D. Gentzler, MD

Although immunotherapy and targeted agents are revolutionizing the treatment paradigm in metastatic non—small cell lung cancer (NSCLC), chemotherapy retains a vital role for the majority of patients, according to Ryan D. Gentzler, MD.

“The data that we have now suggest that chemotherapy plus immunotherapy is the only combination strategy we have that has shown an overall survival (OS) improvement. The chemotherapy backbone is still an important one for patients,” said Gentzler.

As reported in the New England Journal of Medicine and presented at the 2018 AACR Annual Meeting, the first-line combination of pembrolizumab (Keytruda) with standard chemotherapy reduced the risk of death by more than 50% in patients with nonsquamous NSCLC without EGFR or ALK mutations in the phase III KEYNOTE-189 trial.

In the study, patients were randomized to frontline pembrolizumab or placebo in combination with pemetrexed and either cisplatin or carboplatin. The estimated 12-month OS rate at a median follow-up of 10.5 months was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm versus 49.4% (95% CI, 42.1%-56.2%) in the control arm (HR, 0.49; 95% CI, 0.38-0.64; P <.001). Notably, an OS benefit was seen regardless of PD-L1 status. The median PFS was 8.8 months (95% CI, 7.6-9.2) versus 4.9 months (95% CI, 4.7-5.5) in the pembrolizumab and placebo arms, respectively (HR, 0.52; 95% CI, 0.43-0.64; P <.001).^1,2

In August 2018, the FDA granted a full approval to the combination based on these phase III data. However, Gentzler explained that there are patients with NSCLC who may benefit from combination immunotherapy, such as nivolumab (Opdivo) and ipilimumab (Yervoy) as seen in the CheckMate-227 trial. Until physicians see greater standardization of biomarkers such as tumor mutational burden (TMB), the decision of which combination to use should be individualized to each patient, he added.

OncLive: Does chemotherapy have a role in the frontline treatment of metastatic NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit^™ on Advanced Non—Small Cell Lung Cancer, Gentzler, assistant professor, Division of Hematology/Oncology, University of Virginia Health System, highlighted how chemotherapy remains a critical component of the metastatic NSCLC treatment paradigm.Gentzler: This has been an evolving field, particularly in the last several years—maybe even just the last 6 to 12 months. The theme of my talk was what role chemotherapy has in our treatment of this disease. There has been a lot of progress in the last decade or so of moving away from chemotherapy. We've now identified multiple oncogenic driver mutations that exist in lung adenocarcinoma [that we’re] able to successfully pair a targeted therapy to. We have been able to delay the need for chemotherapy in a large portion of patients.

More recently, we have identified that immunotherapy can be quite effective in the rest of the population. This includes those who were smokers and those who don't have these oncogenic driver mutations. Our hope has always been that we can get away from cytotoxic chemotherapy and the side effects that come along with those treatments and replace it with a single-agent tyrosine kinase inhibitor or an immunotherapy drug.

What chemoimmunotherapy combinations are we looking at?

What we found in the data that have been released over the last year or so is that chemotherapy still seems to have an important role. When we add chemotherapy to an immunotherapy regimen it seems as though there may be a better chance of response or a longer duration of response. Several studies have looked at chemotherapy as a backbone with immunotherapy. Now, trials are showing OS improvement by adding PD-1/PD-L1 drugs to standard chemotherapy.There are several immunotherapy/chemotherapy combinations that have been looked at. The KEYNOTE-189 trial looked at pembrolizumab plus chemotherapy. There was a similar trial that was for patients with squamous cell lung cancer that looked at platinum-doublet chemotherapy plus pembrolizumab; that was the KEYNOTE-407 trial. That study also showed a survival improvement in that group. There has been a combination of chemotherapy plus atezolizumab (Tecentriq) plus bevacizumab (Avastin) that has also resulted in an OS improvement compared with chemotherapy alone.

How will you decide which combination to give?

We have data from immunotherapy combinations, such as ipilimumab and nivolumab, that have been compared with chemotherapy alone, particularly in a subset of patients who have a high TMB. That was the CheckMate-227 trial, which showed an improvement in PFS with the combination. The CheckMate-227 trial had multiple arms, and one of the subsets that was looked at was the low PD-L1 expression group in which chemotherapy plus nivolumab was compared with chemotherapy alone. There was also an improvement in PFS within that comparison group.The data that we have now suggest that chemotherapy plus immunotherapy is the only combination strategy we have that has shown an OS improvement. The chemotherapy backbone is still an important one for patients. Certainly, in subsets of patients who may have PD-L1—negative or TMB-high tumors, there may be a role for combination immunotherapy. However, that regimen has not been compared head-to-head with chemotherapy plus immunotherapy with an OS endpoint.

How do the toxicity profiles differ?

There are also patients with high PD-L1 status at ≥50%. Data from the KEYNOTE-024 trial showed a consistent OS benefit with pembrolizumab alone versus chemotherapy [in this population].The side effects that are associated with chemotherapy plus immunotherapy are largely additive side effects rather than synergistic. You get all of the traditional side effects from platinum-doublet chemotherapy, and you have side effects from single-agent PD-1/PD-L1 inhibitors. Most of the time, those are not overlapping toxicities. A lot of this is what we are accustomed to with chemotherapy. You add on some additional side effects with immune-related adverse events (irAEs).

Is TMB ready for clinical use?

What is the biggest challenge you have encountered?

The combination of nivolumab and ipilimumab is similar to the side effects that we see with single-agent PD-1/PD-L1 inhibitors, except they occur at a much higher frequency. Therefore, with that combination, we are looking at irAEs. Things such as colitis and pneumonitis occur at a little bit of a higher frequency than with single-agent immunotherapy. When you give that regimen, you don’t have any of the hematologic toxicity that we see with chemotherapy.One of the challenges is that TMB is not a well-standardized and readily available test that can be turned around in a fast enough time for most patients. If it takes 3 to 4 weeks to get those results, sometimes patients need to get started on treatment before that. That is one limitation with using first-line ipilimumab/nivolumab.One of the challenges that we have with all of these new chemotherapy and immunotherapy regimens is knowing which to choose for an individual patient. If a patient has an intermediate PD-L1 status and an unknown or low TMB status, should they get chemotherapy plus pembrolizumab or should they get ipilimumab/nivolumab if they have a high TMB and high PD-L1 [expression]?

What clinical trials or combinations are you looking forward to hearing about?

Will chemotherapy have a role in the treatment paradigm 10 years from now?

Even in the high PD-L1 expression group, there are some patients who may derive some benefit from getting chemotherapy plus pembrolizumab. We saw that with the KEYNOTE-189 trial, in which there appears to be a response rate of 60% compared with the KEYNOTE-024 response rate of 45%. Individualizing all of these options for a specific patient is a challenge. Is the patient highly symptomatic and needs the best chance of response upfront? Or, do they have more time to wait and try a monotherapy regimen that has a lesser chance of responding upfront but has the same durability?I'm anxious to see the OS results from the CheckMate-227 trial. If we can show that TMB [determines that using an immunotherapy combination] improves OS, that would make that regimen much more appealing.I'm hopeful that other combinations [will come forward], whether it's immunotherapy combinations or targeted therapy plus immunotherapy combinations so we can continue to save the side effects of chemotherapy for a larger proportion of patients. There will be subsets of patients where even chemotherapy alone will still be an important tool in our armamentarium.

References

1. 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.
2. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801005.