Pembrolizumab Approval in Squamous NSCLC Expands Treatment Arsenal

Viola W. Zhu, MD, PhD, explains how the use of immunotherapy has improved survival for patients with advanced squamous cell non–small cell lung cancer.

Viola W. Zhu, MD, PhD

Platinum-doublet chemotherapy is no longer standard of care for patients with advanced squamous non—small cell lung cancer (NSCLC) following the results of the KEYNOTE-407 trial, which demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) irrespective of PD-L1 expression, explained Viola W. Zhu, MD, PhD.

In the phase III trial, previously untreated patients with advanced squamous NSCLC who received the combination of pembrolizumab (Keytruda), carboplatin, and either paclitaxel or nab-paclitaxel (Abraxane) had a median overall survival (OS) of 15.9 months versus 11.3 months in those who received chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017).1 Based on the data, the FDA approved the frontline regimen in this setting in October 2018.

Further, data from the phase III IMpower131 trial showed that the addition of atezolizumab (Tecentriq) to frontline carboplatin and nab-paclitaxel delayed the risk of progression or death by 29% (HR, 0.71; 95% CI, 0.60-0.85; P = .0001) compared with chemotherapy alone for patients with advanced squamous NSCLC.2 At the time of the analysis, data did not show a statistically significant benefit in OS with the addition of atezolizumab to standard chemotherapy. Further OS data from the study are eagerly anticipated. “The data speak for themselves. Since receiving the positive data from the KEYNOTE-407 trial, the regimen has been rapidly adopted in clinical practice,” said Zhu. “Certainly, we will see follow-up data from the IMpower131 trial. If the OS data turn out to be positive, I imagine the FDA may approve this regimen as well. Then, we’ll have 2 choices for first-line treatment of metastatic squamous NSCLC.”

Unlike the frontline treatment of advanced squamous cell NSCLC, data regarding the optimal treatment for emerging driver mutations such as NTRK, RET, MET, HER2, and tumor mutational burden (TMB) are not as robust, making comprehensive molecular profiling and subsequent clinical trial enrollment imperative for patients with stage IV adenocarcinoma.

In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Zhu, medical oncologist/hematologist, University of California, Irvine, explained how the use of immunotherapy has improved survival for patients with advanced squamous cell NSCLC.

OncLive: Could you discuss the data from the IMpower131 and KEYNOTE-407 trials in squamous NSCLC?

Zhu: Both trials are randomized phase III studies exploring the use of immunotherapy in combination with carboplatin and paclitaxel or carboplatin and nab-paclitaxel as frontline therapy in patients with advanced squamous NSCLC. In the IMpower131 trial, the coprimary endpoints were investigator-assessed PFS, as well as OS in the intent-to-treat (ITT) population. Results indicated a 0.9-month improvement in median PFS with the addition of atezolizumab to carboplatin and nab-paclitaxel compared with carboplatin and nab-paclitaxel alone. The OS data are not statistically significant yet. Therefore, we are continuing to follow the OS outcomes.

In the KEYNOTE-407 trial, there was a 4.6-month improvement in median OS with the addition of pembrolizumab. The OS outcomes were observed regardless of PD-L1 subgroup. PFS, as well as the objective response rate (ORR), were also statistically significant, and they were also observed regardless of PD-L1 subgroup. Due to the robust OS improvement observed in KEYNOTE-407, the FDA approved the regimen for use in the first-line treatment of patients with metastatic squamous NSCLC.

Was PD-L1 expression indicative of response to either regimen?

Both the IMpower131 and KEYNOTE-407 trials allowed patients with any PD-L1 expression level to be enrolled. For KEYNOTE-407, benefits were seen regardless of PD-L1 expression. For IMpower131, although the PFS benefit was seen in the ITT patient population, the benefit was enriched in the PD-L1—high subgroup.

Pending further OS data with atezolizumab, how will clinicians choose between the frontline regimens?

That's a very good question because the trial designs for both studies are very similar, in which patients received a frontline triplet therapy followed by maintenance immunotherapy. We still don't know if there is a difference between different immunotherapeutic agents.

Are there any drawbacks to the triplet regimen with pembrolizumab?

Not necessarily. Traditionally, we had no good treatment regimens available for patients with squamous cell NSCLC. Their first-line treatment was basically a platinum doublet. We simply cannot use pemetrexed in patients with squamous cell histology. We can either use paclitaxel or nab-paclitaxel. I personally favor nab-paclitaxel, but I don't use the “textbook” weekly dosing. I use the breast cancer regimen, which is every 3 weeks followed by growth factors. Neuropathy is a big concern, particularly for elderly patients. However, I am really pleased to see that the addition of immunotherapy has further improved outcomes for our patients.

What questions are we seeking to answer in current research?

We don't commonly see many driver mutations in squamous NSCLC. There are so many targeted therapies available or in clinical trials for patients with driver mutations. We know that they have better outcomes if they are treated with targeted therapies as compared with chemotherapy. If your patient with squamous cell NSCLC is a never-smoker, if the biopsy specimen is small—meaning you may miss the adenocarcinoma component—or if the histology is mixed like adenosquamous, you should still try to do comprehensive molecular profiling. By doing that, we may be able to identify a very small subset of patients who may have driver mutations.

Regarding the triplet therapy, if patients progress on a combination of chemotherapy and immunotherapy then we have wonder what we're going to offer next. That is what everybody is exploring right now.

Should clinical trials focus on enhancing the activity of frontline regimens or work towards defining better second-line therapies?

If you have resources you should do both, but [advances in] first-line treatment are critical in terms of improving overall outcomes. Oftentimes, patients may not be able to move onto second-line treatment or beyond; that’s why you see clinical trials designed for first-line treatment more often than later lines. On the other hand, a drug that is being looked at for safety data is often tested in refractory patients first. With immunotherapy, you see it being explored more in the adjuvant setting and the neoadjuvant setting to further improve patient outcomes.

You also spoke on emerging biomarkers at the State of the Science SummitTM. Beyond EGFR and ALK, what are we seeing in this space?

I covered a variety of topics, including NTRK, RET, MET, HER2, and TMB. I pointed out a few emerging targeted therapies that are either approved or being explored in this territory. In terms of NTRK, larotrectinib (Vitrakvi) has already been FDA approved regardless of tumor origin. This approval came in the fall of last year based on 3 studies that had been pooled together. A total of 122 patients with TRK fusion—positive tumors were enrolled. The ORR was 81%, and the drug was found to be very well tolerated.

The next target is RET, for which we have some very exciting ongoing clinical trials. Both LOXO-292 and BLU-667 were designed to be potent and specific RET inhibitors in comparison with multikinase inhibitors. Both clinical trials are still enrolling. The preliminary results were very exciting, and both drugs have demonstrated central nervous system activity. I anticipate both agents will eventually be submitted for FDA approval.

For HER2, there are a variety of agents now being studied in clinical trials, including neratinib (Nerlynx) plus trastuzumab (Herceptin). At the University of California, San Diego, and the University of California, Irvine, we have a trial with poziotinib, pyrotinib, as well as tarloxotinib. These studies are ongoing, and patients with HER2 exon 20 insertion—positive lung cancer or rare HER2-mutated lung cancers are encouraged to participate.

Crizotinib (Xalkori) already received breakthrough therapy designation from the FDA for [the treatment of patients with] MET exon 14 skipping alteration—positive lung cancer after failing platinum-based chemotherapy. This designation was based on the original PROFILE 1001 study showing an ORR around 30%, with an estimated PFS around 7 months. Hopefully, crizotinib will eventually be approved for this indication.

Lastly, TMB is an emerging biomarker that may predict response to immunotherapy. However, there is no consensus in terms of how to define a TMB-high population. National Comprehensive Cancer Network (NCCN) guidelines list both CheckMate-227 and CheckMate-026, for [reference] for patients with TMB-high lung cancer.

CheckMate-227 explored the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) compared with nivolumab plus chemotherapy or chemotherapy alone. If you look at the PFS in the TMB-high subgroup, which was defined as 10 [mutations/megabase] or higher, you see an improvement in PFS. However, the OS data were not determined to be statistically significant. This is why we haven’t seen an FDA approval application for this regimen.

The NCCN, however, do list this regimen. The KEYNOTE-026 trial was essentially a negative study that compared nivolumab with chemotherapy in patients with PD-L1 expression ≥5%. If you look at the subgroup analysis of patients with TMB-high tumors, there was an improvement in PFS. This is why the NCCN lists nivolumab as a possible treatment option for patients with TMB-high lung cancer.

Is there a comprehensive panel that accounts for all of these biomarkers or do you specify which alterations to look for when you order the test?

That's an excellent question. Most of these drivers are extremely rare; we're talking about 1% to 3% of the lung cancer patients. If you send for a next-generation sequencing panel, you really need to know if the panel covers everything. That depends on which testing platform you use.

Has any work been done regarding the interplay between PD-1/PD-L1 inhibitors and driver mutations?

Most of these studies are still ongoing. Immunotherapy is not as straightforward in this setting because some PD-L1—negative patients benefit from immunotherapy. There are other emerging biomarkers as well; the work is ongoing.

What is your advice for treating physicians regarding these emerging biomarkers, and what do you envision the future to look like?

I always favor comprehensive molecular profiling for all patients with stage IV adenocarcinoma. I do not like testing patients sequentially. By doing so, you may exhaust very precious tumor tissues. I also favor using liquid biopsies upfront to perhaps catch some of these rare mutations when your tissue sample is limited. Many of the rare mutations that are being explored right now, had no trials looking into [them as] biomarkers 1 or 2 years ago. When you see something that seems to suggest a driver mutation, look up potential trials on and try to refer your patients.

Is there any value in re-biopsying?

Absolutely. Re-biopsy has a role, particularly in patients with, for example, EGFR-, ALK-, or ROS1-positive lung cancers because there are many available targeted therapies for these patients. In general, next-generation TKIs tend to cover some of the acquired resistance mutations. For instance, in ALK-positive lung cancer, once patients progress on a TKI, we almost always favor repeat biopsy whether it be liquid biopsy or tissue biopsy. The idea is that we can identify an acquired resistance mutation. For example, G2032R for ROS1 and G1202R for ALK. This knowledge helps us select the next TKI with activity against the resistance mutation.


  1. 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 15; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.
  2. Socinski MA, Rittmeyer A, Shapovalov D, et al. IMpower131: progression-free survival (PFS) and overall survival (OS) analysis of a randomised phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel in 1L advanced squamous NSCLC. Ann Oncol. 2018;29(suppl 8, abstr LBA65). doi: 10.1093/annonc/mdy424.077.