Brahmer Highlights Immunotherapy Breakthroughs in Metastatic NSCLC

Julie R. Brahmer, MD, provides an overview of the landscape of metastatic non–small cell lung cancer, specifically addressing the combination immunotherapy studies with the greatest impact.

Julie R. Brahmer, MD

Immunotherapy advances in the treatment paradigm for patients with metastatic non—small cell lung cancer (NSCLC) could eventually lead to a cure for this disease, said Julie R. Brahmer, MD.

“Never before have we had these type of treatment choices for our patients,” explained Brahmer, associate professor of Oncology, co-director of the Upper Aerodigestive Department, Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medicine. “Life is changing for them. Certainly, we have a further way to go to the point of curing patients with stage IV disease, but I hope some of these studies may open that avenue for patients.”

Immunotherapy and chemotherapy combinations continue to move the needle forward. In August 2018, the FDA granted a full approval to frontline pembrolizumab (Keytruda) in combination with standard chemotherapy for patients with metastatic nonsquamous NSCLC without EGFR or ALK mutations, based on data from the phase III KEYNOTE-189 trial. An accelerated approval was granted in May 2017.

Findings showed a 51% reduction in the risk of death with the addition of pembrolizumab to pemetrexed and either cisplatin or carboplatin in the first-line setting. The median overall survival (OS) had not been met in the pembrolizumab arm compared with 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. The median progression-free survival (PFS) was 8.8 months (95% CI, 7.6-9.2) and 4.9 months (95% CI, 4.7-5.5) in the immunotherapy and control arms, respectively (HR, 0.52; 95% CI, 0.43-0.64; P <.001).1,2

Moreover, the IMpower150 trial exploring the 4-drug regimen of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel is showing promise in patients with advanced wild-type nonsquamous NSCLC. Brahmer noted that this trial did not exclude patients with EGFR or ALK mutations, suggesting that this approach could be a possibility for these populations as well.

OncLive: What do we know about immunotherapy in stage IV disease?

In an interview during the 2018 OncLive® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Brahmer provided an overview of the landscape of metastatic NSCLC, specifically addressing the combination immunotherapy studies with the greatest impact.Brahmer: When looking at a patient with metastatic NSCLC, we first look at what type of histology they have—nonsquamous versus squamous–driver mutations they may have, specifically whether or not they have EGFR or ALK or PD-L1 status. Immunotherapy may or may not be an option for most patients with driver mutations, specifically EGFR and ALK. The first-line clinical trials did not include these patients. Right now, therapies such as tyrosine kinase inhibitors (TKIs) are recommended for first-line treatment of these patients.

For the majority of patients, the options are wide-ranging now. If you have PD-L1 staining of ≥50%, pembrolizumab as a single agent is still an option. We know this based on 2 studies. The KEYNOTE-024 study specifically looked at those with PD-L1 expression ≥50% and showed a survival advantage in those patients who received pembrolizumab. Also, the KEYNOTE-042 study looked at patients whose tumor proportion score (TPS) was 1% or greater and showed a survival advantage if they received pembrolizumab. My opinion is a lot of the benefit was mainly seen in patients with high PD-L1 expression, and that may have carried the survival benefit.

The bulk of the advances is in combining these kinds of agents with chemotherapy. The KEYNOTE studies of adding pembrolizumab to chemotherapy backbones showed an advantage to platinum-based doublets by itself in patients with metastatic disease.

Data from KEYNOTE-189 in nonsquamous cell histologies combining pembrolizumab with pemetrexed and carboplatin or cisplatin showed a survival advantage in patients compared with chemotherapy. KEYNOTE-407 combined carboplatin, paclitaxel, or nab-paclitaxel (Abraxane) with pembrolizumab versus a carboplatin-based doublet in squamous cell histology. It also showed a survival advantage when pembrolizumab was added to chemotherapy. Based on that, most of us would recommend the combination with chemotherapy.

Now, we have IMpower150 in which atezolizumab was combined with 3 other drugs: bevacizumab, paclitaxel, and carboplatin. That was compared with chemotherapy plus bevacizumab. While PFS was improved, OS was not improved. Most of us are quite interested in the fact that this is the only study that included EGFR-mutated disease and showed an improvement in PFS in that group of patients when adding atezolizumab to chemotherapy and bevacizumab. It's quite intriguing, but we need to see larger studies with that subgroup of patients to feel comfortable combining that 4-drug regimen together in that patient population.

For patients with EGFR mutations, we know that the first-line data with osimertinib (Tagrisso) compared with the first-generation TKIs improves PFS, and certainly PFS when it comes to central nervous system progression. That was the basis of osimertinib’s approval in that group of patients. The ALEX study showed an improvement in PFS in patients with ALK translocations who received first-line alectinib (Alecensa) versus those who received crizotinib (Xalkori).

What are the unanswered questions from these studies?

We now also have approval of dabrafenib (Tafinlar) and trametinib (Mekinist) in combination for patients with NSCLC who have BRAF V600E mutations. Crizotinib is also approved for first-line use in ROS1-positive disease.The aspects of the studies in the first-line setting that remain unaddressed are whether we can just use a single-agent PD-1 blockade in some patients and have the same outcome. Does chemotherapy do anything detrimentally to long-term survival for these patients? The biggest question is with the immunotherapy combinations. Are there some patients who may do better with 2 drugs compared with chemotherapy?

How have you incorporated genetic testing into practice?

Is there potential for neoadjuvant immunotherapy?

Is there a scenario where you would give immunotherapy to patients with low PD-L1 expression?

What is the biggest challenge you have encountered in clinical practice?

That gets us into the nivolumab (Opdivo) and ipilimumab (Yervoy) combinations in patients with high tumor mutation burden (TMB). It's been shown that there is an improvement in PFS in those patients with a high TMB. They may do better with that combination versus chemotherapy. Those are the biggest questions that are still out there. Additionally, what is the best biomarker to predict response or outcome in these patients? That's a moving target. I don't think we have the best biomarker yet.In our practice, we have next-generation sequencing, as well as PD-L1 staining right off the bat in patients with metastatic nonsquamous cell histology. In squamous cell histology, we're incorporating TMB into our practice, though that is still very controversial.Yes. We discussed trying to move immunotherapy to earlier stages. We now have durvalumab (Imfinzi) approved for use after concurrent chemotherapy and radiation therapy for consolidation treatment. Also, we're looking to see whether or not we can see an improvement in disease control and outcomes in those who receive this type of treatment before surgery. Those phase III studies are ongoing.Right now, I don't feel completely comfortable giving first-line pembrolizumab in those patients with a PD-L1 TPS of 1% to 49%. I prefer to combine that with chemotherapy.My biggest challenge is getting to the chance of cure. Since the majority of our patients are coming in with metastatic disease, it can be disheartening to tell them that cure is just not on the table. Another challenge is the fact that we're seeing so many patients come in with metastatic disease, and you know based on their demographics that they should have undergone screening. That might have made a difference, since most of our patients are previous smokers or current smokers. We do have an increase in younger women, so that certainly is becoming a challenge, as well. The question is: “Why?” It's outside of the fact that women have not quit smoking at the same rates as men.


  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. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
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