Breast cancer doctors got it right a long time ago when they began characterizing malignancies with classifications such as hormone-receptor and HER2 status, according to Alexander Spira, MD, PhD, FACP, Medical Oncologist, Virginia Cancer Specialists, Fairfax.
“We have to start thinking about lung cancer as a multitude of malignancies, considering it in terms of PD-L1 scores and genetic mutations,” he said. “If we think about it that way it will be a better paradigm, and better for our patients.”
Over the past 6 or 7 years, the treatment of patients with non–small-cell lung cancer (NSCLC) has changed dramatically. Understanding PD-L1 expression levels and mutation profiles has allowed for more effective and targeted treatments in NSCLC, particularly regarding immune checkpoint inhibitors and targeted therapies. At the virtual 2020 Community Oncology Alliance (COA) Community Oncology Conference, Dr Spira provided an overview of the current state of immunotherapy options for patients with these malignancies and touched briefly on targeted therapies.
PD-L1 has become an established biomarker for predicting which patients will respond to immune checkpoint inhibition, and patients with high levels of PD-L1 typically respond more favorably. The KEYNOTE-189 clinical trial—which now informs therapy in the first-line and later settings—compared treatment with carboplatin plus pemetrexed (Alimta) to treatment with carboplatin plus pemetrexed and pembrolizumab (Keytruda) in patients with adenocarcinoma. Patients who received the immunotherapy drug combination had significantly better survival, but the results according to PD-L1 status were even more striking, Dr Spira noted.
“We expected it to work in PD-L1–high patients, and it did; the curves diverged and this is about as good a hazard ratio and as good a survival curve as you would ever see in patients with lung cancer,” he said. In patients with high PD-L1 expression, approximately 80% were alive at 12 months, which is a survival rate that was unheard of in patients with lung cancer only 5 or 6 years ago.
“But what shocked me was the patients with a PD-L1 score of less than 1%,” Dr Spira added. “These are patients you’d think would have a very low chance of responding, yet they performed almost as well as those with high levels of PD-L1.”
He pointed out this result could suggest a synergistic effect of immunotherapy when given in combination with chemotherapy, but it highlights the need for more precise therapeutic biomarkers in patients with NSCLC.
What Treatment Is Best for PD-L1–High Patients?
A 2016 study in the New England Journal of Medicine, which was the first study to really show the benefit of immunotherapy, compared chemotherapy to immunotherapy in treatment-naïve patients with NSCLC and PD-L1 expression of ≥50%.1
Patients who received pembrolizumab had a better response than patients who received chemotherapy, which led to the understanding that patients with high PD-L1 expression should receive pembrolizumab monotherapy as first-line treatment. However, analysis of the literature reveals that 1-year survival in patients receiving monotherapy with an immune checkpoint inhibitor is similar to survival of patients receiving combination treatment with chemotherapy and immunotherapy, said Dr Spira.
“The question is, what do you do with PD-L1–high patients? Do you give them chemotherapy with pembrolizumab or pembrolizumab by itself?” he asked. “We all understand we’re not supposed to do cross-trial comparisons, but it’s unclear whether or not the addition of chemotherapy improves outcomes for patients with high PD-L1 expression in the first-line setting. So, this is where you get a bit more into the art of treatment rather than the science of it, because there is no good data.”
When determining the course of treatment for patients with PD-L1 expression >50%, Dr Spira urges providers to consider factors such as the patient’s symptoms, the potential toxicity of treatment, the cost of treatment, and the likelihood of that patient making it to second-line therapy (still only approximately 50%-60% likelihood across the board in adenocarcinoma). Also keep in mind that the closer a patient is to 100% PD-L1 expression, the higher the likelihood of response to immunotherapy alone. However, Dr Spira added that he still sees a major role for chemotherapy in these patients.
The Future of Combination Immunotherapy
“Combination immunotherapy is probably in the very foreseeable future, and is important because, for the first time we might be talking about no role for chemotherapy in the first-line setting,” noted Dr Spira.
The recently published CheckMate-227 clinical trial of more than 1700 patients compared combination checkpoint inhibitor therapy with nivolumab (Opdivo) and ipilimumab (Yervoy) to chemotherapy in patients with advanced NSCLC.2
Across the board, and in all important prespecified subgroups, patients in the immunotherapy arm performed better than those in the chemotherapy arm, including patients with a PD-L1 expression level of <1%. Among all patients in the trial, the median duration of overall survival was 17.1 months with nivolumab plus ipilimumab and 13.9 months with chemotherapy.2
“This [immunotherapy combination] is not FDA-approved, but we do expect it to be approved shortly,” Dr Spira said. Indeed, just after his presentation on May 15, 2020, the FDA approved the combination of nivolumab plus ipilimumab as first-line treatment of metastatic NSCLC and ≥1% PD-L1 expression in patients with no FGFR or ALK genomic tumor aberrations.
A Note About Targeted Therapies
PD-L1 is not the only important biomarker in NSCLC. Testing for genetic mutations such as EGFR, ALK, ROS1, BRAF, and MET informs targeted therapy, but according to Dr Spira, a common challenge is determining whether treatment should be held until the results of a patient’s mutation analysis are known.
For example, patients who start treatment with pembrolizumab plus chemotherapy and later test positive for EGFR mutation are frequently switched to treatment with the EGFR inhibitor osimertinib (Tagrisso), which often leads to high rates of pneumonitis and other immune-related adverse events. However, receiving treatment in the reverse order of an EGFR inhibitor followed by a checkpoint inhibitor is associated with none of these adverse effects.
“This is my plea to wait for next-generation sequencing or mutation analysis results, especially in patients with a high likelihood of having an EGFR mutation, like nonsmokers,” said Dr Spira. “It’s always okay to wait for checkpoint inhibitors and start with chemo first. And if you don’t think you’re going to have enough tissue or you’re not sure about the timing of it, strongly consider liquid biopsy.”
- Reck M, Rodríquez-Abreu D, Robinson AG, et al; for the KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375:1823-1833.
- Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020-2031.