Unanswered Questions Remain in Frontline NSCLC


Lecia V. Sequist, MD, MPH, highlights recent developments in NSCLC treatment and shared key questions that still need to be addressed.

Lecia V. Sequist, MD, MPH

The frontline treatment of patients with non—small cell lung cancer (NSCLC) has shifted in recent years, said Lecia V. Sequist, MD, MPH, and now the challenge lies in the decision of whether a patient should receive the combination of chemotherapy and immunotherapy or a checkpoint inhibitor alone.

“One of the big clinical questions when you have a patient who is a candidate for immunotherapy is whether or not to give it alone or with chemotherapy,” said Sequist. “For the first couple of years that this was a frontline paradigm, we had a strict [PD-L1 expression] cutoff of 50%. If PD-L1 [expression] was greater than 50%, you could do monotherapy with immunotherapy; if the expression was less than that, chemotherapy plus immunotherapy was a better choice.”

In April 2019, the FDA expanded the approval for frontline pembrolizumab (Keytruda) monotherapy for use in patients with stage III NSCLC who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression level of ≥1% and do not harbor EGFR or ALK aberrations.

The regulatory decision was based on data from the phase III KEYNOTE-042 trial, which demonstrated that frontline pembrolizumab monotherapy resulted in a median overall survival (OS) of 16.7 months versus 12.1 months with standard chemotherapy in patients with advanced or metastatic disease who had a tumor proportion score (TPS) ≥1%.1 Furthermore, in patients with a PD-L1 TPS of 1% to 49%, results from an exploratory analysis showed a median OS of 13.4 months and 12.1 months with pembrolizumab and chemotherapy, respectively.

Positive 5-year data with pembrolizumab monotherapy from the phase Ib KEYNOTE-001 trial showed that treatment with the agent led to an OS rate of 23.2% in newly diagnosed patients with advanced disease; the OS rate was 15.5% in those who had previously treatment.2 These data confirm the agent’s potential to improve long-term outcomes in this population, but questions remain.

“There are several questions that we don’t know the answers to,” said Sequist. “A big one [has to do with] patients [who have a PD-L1 expression that is] greater than 50%. Is it better to do monotherapy with immunotherapy, or is a chemotherapy/immunotherapy combination better? None of the studies, the big studies that have already presented data, really address that question.”

In an interview during the 2019 OncLive® State of the Science SummitTM on Non—Small Cell Lung Cancer, Sequist, the Landry Family Associate Professor of Medicine at Harvard Medical School, and director, Center for Innovation in Early Cancer Detection, Massachusetts General Hospital, highlighted recent developments in NSCLC treatment and shared key questions that still need to be addressed.

OncLive: How has the treatment of NSCLC evolved in recent years?

Sequist: The paradigm has completely shifted in terms of frontline therapy for advanced NSCLC over the past couple of years. It used to be that we would look for genetic markers for driver mutations, and if we didn’t find any, everyone would get chemotherapy. It would be a matter of deciding what type of chemotherapy regimen we should give. Now, it has totally flipped on its head. We still look for the markers for oncogenic drivers, but if there aren't any, then everyone gets immunotherapy. Now, the question is, “Do we give chemotherapy with the immunotherapy or just immunotherapy [by itself]?” [Our approach] has just completely changed.

What are some of the frontline regimens available to this patient population?

There are several frontline regimens of chemotherapy and immunotherapy that are now FDA approved in the United States for nonsquamous NSCLC. We have carboplatin/pemetrexed and pembrolizumab for squamous patients. We have carboplatin/paclitaxel, or you can use nab-paclitaxel (Abraxane), and pembrolizumab.

The most recent regimen to get approved is a 4-drug regimen composed of carboplatin, paclitaxel, bevacizumab (Avastin), and atezolizumab (Tecentriq). It’s a mouthful, but [approval of] that regimen was based on the data from the IMpower150 study, which looked at a couple of different questions. [It compared] chemotherapy versus chemotherapy with immunotherapy. It also looked at the question of whether or not you needed VEGF inhibition.

[The trial] suggested that there might be something additive about VEGF and immunotherapy, which is really interesting, and I believe this needs to be followed up in further studies as well. Finally, IMpower150 was the only study to include a subset of patients with driver mutations like ALK and EGFR. The trial suggested, although it was a very small group of patients, that there was a benefit to chemotherapy/immunotherapy in those patients. There are many interesting leads being generated from that study, but most patients in the community are currently getting one of the pembrolizumab regimens. This is just because 4 drugs together are a lot to handle. Nonetheless, many further studies will come out of these IMpower150 data.

How do you interpret the FDA’s decision to expand the approval for pembrolizumab to include patients with a PD-L1 expression TPS of ≥1%?

Recently, the FDA has approved pembrolizumab monotherapy if you have [a patient with a PD-L1 expression TPS ranging] anywhere from 1% or higher, based on data from the KEYNOTE-042 study.

This is an interesting conundrum because that study was positive. Investigators looked at pembrolizumab monotherapy versus a chemotherapy doublet and it was positive overall in those with greater than 1% PD-L1 expression for pembrolizumab; however, the positive signal was really driven by the patients [with PD-L1 expression] greater than 50%.

It is an option in my practice for patients who have a PD-L1 expression from 1% to 49%, if they are not great candidates for chemotherapy. However, if they are candidates for chemotherapy/immunotherapy combinations, I would prefer that at this time. This is because the survival from the KEYNOTE-042 trial was driven by the patients with the higher PD-L1 levels.

What role did PD-L1 expression play in the phase III KEYNOTE-189 trial?

That trial did show a bigger benefit the higher the PD-L1 level, but it was positive for the combination compared with chemotherapy alone in each arm. The overall positivity wasn’t driven by the highest expressing group. However, there still did seem to be even more benefit to the higher expressing group.

What unanswered questions with these combinations still need to be addressed?

There is a large study being conducted called the INSIGNIA study, which will help us answer what to do for patients with [PD-L1 expression] greater than 50%. Should we start with monotherapy or do we need to start with chemotherapy/immunotherapy?

Also, we need a lot more information about the driver mutation subgroups and many of the studies, especially KEYNOTE-189, specifically excluded, which were patients with EGFR and ALK [aberrations]. When those patients get through, have exhausted all their TKI options, they need chemotherapy and the question is, “Can they benefit from the addition of immunotherapy, too, just like patients with standard lung cancer?” There are some studies looking at that question, and it will be really important to see those results over the next couple of years.

Could you speak to the 5-year data with pembrolizumab monotherapy that were presented at the 2019 ASCO Annual Meeting?

In the last 1 to 2 years, we have seen some of the long-term outcomes from the very first trials of immunotherapy. A couple of years ago, the 5-year outcomes from the nivolumab (Opdivo) studies were published, and then, we saw the 5-year outcomes from the initial studies with pembrolizumab. Remember, these initial studies were not done in the frontline setting; these were heavily pretreated patients going on a phase I clinical trial. Still, even with that heavily pretreated patient population, we saw a 5-year OS rate of 23.2% among the pembrolizumab-treated patients, which was similar to what was seen with nivolumab a few years ago. Really, this confirms that this isn’t a fluke; immunotherapy is actually changing the curve, changing the inflection point for patients with lung cancer—at least for a subset of them.

In practice, how do you decide when it’s appropriate to give pembrolizumab alone versus pembrolizumab plus chemotherapy?

When a patient comes in with a PD-L1 expression higher than 50%, I take it on a case-by-case basis. If the patient is very symptomatic from their disease, and I want as fast of a response as I can get, then I tend to do chemotherapy and immunotherapy together because the response rate is higher than [what is seen] with pembrolizumab monotherapy.

On the other hand, if the patient is a bit borderline for receiving a triplet regimen, maybe they have some mild renal insufficiency or borderline performance status, then I feel very comfortable using immunotherapy alone because I know that their high PD-L1 level suggests that they will have a good benefit from single-agent pembrolizumab.

Could you discuss the work that is being done with canakinumab (Ilaris)?

Canakinumab is a really interesting drug because it wasn’t developed for cancer; it was initially developed for patients with heart disease to try and decrease mortality from cardiac-related events. Then, in a large randomized trial, unfortunately, it didn’t pan out to have cardiac benefit, but surprisingly, the patients who received the canakinumab had a much, much lower incidence of developing lung cancer. Therefore, it may be a drug that is useful in preventing lung cancer and in treating it. Both of these things are being investigated and I’m excited to see the results.

What is your advice for colleagues treating patients with advanced nonsquamous NSCLC?

The biggest take-home point for me, in today’s landscape of first-line treatment for non—small cell lung cancer, is to make sure you get genetic testing. That’s a common teaching point from 10 years ago, but it needs to still be emphasized today. In terms of immunotherapy and chemotherapy, what’s really great about some of the newer regimens that have come out is that they’re useful in patients with all different levels of PD-L1 expression and all different histologies. However, it’s really important to remember that these chemotherapy/immunotherapy combinations are not the standard of care if [the patient] has a driver mutation.

It’s important to check patients—especially if they have nonsquamous disease—and see if they might have EGFR, ALK, ROS1, and potentially RET or MET. In some of these mutant-driven cancers, for which we have really specific and active TKIs, those patients should not be receiving chemotherapy/immunotherapy in the frontline setting. If it’s an emergency and you cannot wait until the genetic testing comes back before you start something because they’re symptomatic, then chemotherapy alone is what should be started until you know the mutation status.


  1. Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(suppl 18, abstr LBA4). doi: 10.1200/JCO.2018.36.18_suppl.LBA4.
  2. Garon EB, Hellmann MD, Costa EC, et al. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: results from the KEYNOTE-001. J Clin Oncol. 2019;37(suppl 15, abstr LBA9015). doi: 10.1200/JCO.2019.37.15_suppl.LBA9015.
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