Corey Langer, MD

Less than 3 years after the first checkpoint blockade immunotherapies were introduced for non—small cell lung cancer (NSCLC), the treatment paradigm is poised for dramatic changes in frontline care for patients with metastatic disease.

The FDA has granted priority reviews for 2 applications for first-line regimens for patients with metastatic nonsquamous disease: pembrolizumab (Keytruda) in combination with standard chemotherapy and atezolizumab (Tecentriq) plus bevacizumab (Avastin), carboplatin, and paclitaxel. Adding to the interest are recent study results for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with squamous or nonsquamous histology with high tumor mutational burden (TMB), an emerging biomarker.

The flurry of research developments is noteworthy even amid the rapid advancements in the lung cancer field that have occurred in less than a decade. The emerging combinations, if approved, would expand the use of the PD-1 immune checkpoint inhibitors pembrolizumab and nivolumab and the PD-L1 inhibitor atezolizumab, which already have lung cancer indications. Ipilimumab, which targets the CTLA-4 checkpoint, currently is approved only in melanoma settings.

Table. Key Findings in Frontline Lung Cancer Studies

Pembrolizumab Findings

The potential for expanding the use of these agents in NSCLC was showcased at this year’s American Association for Cancer Research (AACR) Annual Meeting in April (Table). Additional results for atezolizumab were reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in June. The study findings pave the way for greater opportunities to personalize care for patients, according to several experts who put the findings into perspective in interviews with OncologyLive®. In the KEYNOTE-189 trial, investigators found that pembrolizumab with pemetrexed (Alimta) and either cisplatin or carboplatin showed a much greater benefit than chemotherapy alone, reducing the risk of death by over 50% in patients with nonsquamous NSCLC without EGFR or ALK mutations.1,2 At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1%-56.2%) in the control group (HR, 0.49; 95% CI, 0.38-0.64; P <.001).

The HR of 0.49, indicating the reduced risk of death in the pembrolizumab arm, is “absolutely astounding,” said Corey J. Langer, MD, director of thoracic oncology at the Hospital of the University of Pennsylvania Abramson Cancer Center in Philadelphia. In patients with a PD-L1 expression score of 50% or greater (% of tumor cells with membranous staining), the HR was even lower at 0.42. “In more than 30 years of being a clinical researcher I have never seen results like that in thoracic oncology. I’ve just never seen that profound a benefit, ever,” he said. “In my mind this really makes that triplet regimen, if not the standard care, certainly a strong standard care.”

Langer was the lead investigator on the KEYNOTE-021 cohort G trial, which showed significant increases in objective response rate (ORR) and progression-free survival (PFS) with the pembrolizumab triplet, and he said his practice has been using the treatment since it received FDA accelerated approval a year ago.3 The new results, which now form the basis of the application for permanent approval in this setting, cement the change and may compel skeptics to use the combination, he said.

Jessica R. Bauman, MD, a thoracic oncologist at Fox Chase Cancer Center in Philadelphia, said she held off changing her practice after the small KEYNOTE- 021 study (N = 123) came out but is now starting to administer the triplet therapy. She said KEYNOTE-189 (N = 616) shows there is “clear synergy” of immunotherapy with chemotherapy, with “vast improvement” at all endpoints including ORR and PFS, as well as benefit to patients in all PD-L1 expression level groups. She said physicians must now consider when to use the triplet for patients with high-PD-L1—expression and when to stick with pembrolizumab monotherapy. The latter which has been a standard frontline treatment for patients without EGFR mutations or ALK translocations since the KEYNOTE-024 trial results were published in 2016.4

“Interestingly, the response rate in that earlier trial was about 45% for patients with 50% or greater PD-L1 expression, and the response rate in the current trial in that population was 61.4%. So it does raise the question, is the chemotherapy adding that much more benefit in this population in particular? It’s certainly adding at least a little bit more toxicity, considering single-agent pembrolizumab is so well tolerated. For that population specifically, we may still consider pembrolizumab alone. But more data will be helpful, as well as longer term follow-up,” Bauman said. It is hard to compare response rates across studies but the difference merits further investigation, she added.

Although the ORR for patients with high-PD-L1 expression differs between the 2 trials, the PFS rates were similar. In practice, the choice between pembrolizumab alone and the triplet will depend on patient preference and other factors, said Ticiana A. Leal, MD, a clinical assistant professor of medicine at the University of Wisconsin Carbone Cancer Center in Madison.

“For a patient with bulky disease who needs a more rapid response, you could consider using the triplet combination to get more tumor shrinkage, which potentially could provide them better symptom relief and disease control. Whereas perhaps with somebody who has cardiac or other important comorbidities, and who has more risk of [adverse] effects, including infection and neutropenia that are associated with chemotherapy, you might want to consider the pembrolizumab monotherapy,” Leal said. Patients who choose frontline monotherapy can still receive chemotherapy later if necessary, she said.

The triplet study excluded patients with EGFR and ALK mutations, for whom targeted therapy remains the standard of care. However, if a patient with high PD-L1 expression has a high metastatic burden and is very symptomatic, Langer said he may give them pembrolizumab monotherapy or the triplet right away rather than waiting weeks for results of a next-generation sequencing panel for oncogenic drivers. “We’re sometimes caught in this dilemma: If someone’s 80% PD-L1, a former smoker, maybe not a heavy smoker, and there’s a chance they might be EGFR- or ALK-positive, then do you wait or do you act? I don’t think we have good answers for that,” he said. Bauman said she has also seen patients who needed immediate treatment, but she noted that single-marker tests are available that provide ALK and EGFR status within days.

A number of other trials exploring the use of pembrolizumab in lung cancer have been recently completed or are under way. The phase III KEYNOTE-042 trial found that single-agent treatment with the PD-1 inhibitor improved OS versus chemotherapy as a frontline treatment for patients with squamous or nonsquamous NSCLC and PD-L1 expression of 1% or greater.5

At the AACR conference, Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, mentioned the current INSIGNA study of patients with 1% or greater PD-L1, which includes 3 arms: pembrolizumab triplet induction followed by pembrolizumab-pemetrexed maintenance, pembrolizumab monotherapy as first-line therapy followed by second-line treatment with the triplet, and pembrolizumab monotherapy s first-line therapy followed by second-line treatment with pemetrexed-carboplatin.

Atezolizumab Benefits

“Trials like this are what we need. We now need to use trials to figure out how to bring this into practice with biomarker results,” Herbst said. He noted researchers must focus on combining pembrolizumab with antiangiogenic agents and other drugs, resistance, and using the PD-1 inhibitor as adjuvant and neoadjuvant therapy in squamous cancer, small cell lung cancer, and in oncogene-driven tumors. “We’re doing well, and we can do even better if we personalize this therapy,” Herbst said. The latest first-line atezolizumab findings show survival improvements across a broad range of subgroups. In the IMpower150 study, investigators are evaluating the addition of atezolizumab to chemotherapy and bevacizumab in patients with chemotherapy-naïve advanced nonsquamous NSCLC. The chemotherapy doublet used in the study, carboplatin and paclitaxel, already is approved in combination with bevacizumab, which attacks angiogenesis by inhibiting VEGF, for the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC.

Findings from the study showed that the 4-drug regimen resulted in a significant OS improvement for patients in the intention-to-treat (ITT) population with wild-type tumors (n = 696), the coprimary endpoint of the study.6 Patients who received the atezolizumab-containing combination had a median OS of 19.2 months compared with 14.7 months with bevacizumab and chemotherapy (HR, 0.78; 95% CI, 0.64, 0.96; P = .016).

Additionally, the median OS benefit for the atezolizumab regimen compared with chemotherapy plus bevacizumab translated across key subgroups: EGFR mutations or ALK translocations (not reached vs 17.7 months; HR, 054); liver metastases at baseline (13.2 vs 9.1 months; HR, 0.54); PD-L1—high expression (22.5 vs 16.4 months; HR.,0.77); and high expression of a T-effector gene signature (25.0 vs 16.7 months; HR, 0.83).

The survival findings, reported at ASCO, are the latest positive results that have been released for IMpower150. Previously released data indicate that the atezolizumab-containing regimen translated to a 38% reduction in the risk of progression or death (HR, 0.62; 95% CI, 0.52-0.74; P <.0001).7

“These data suggest that atezolizumab plus bevacizumab plus chemotherapy provides a new treatment option for these key patient populations,” study coauthor Mark A. Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando, said in discussing the findings at AACR.

IMpower150 is the only first-line trial that has recruited EGFR- and ALK-positive patients, Socinski said in an interview with OncologyLive®. Of the 800 patients in the ITT population, 108 had a sensitizing EGFR mutation or ALK translocation (14%). “It was the first time that we saw the impact of immunotherapy in this population,” he said. “Historically, these are populations that, at least with immuno-monotherapy, there’s really not been a suggestion of great benefit in the EGFR and/or ALK population.”

Of note, patients with these aberrations who participated in IMpower150 had already “exhausted” tyrosine kinase inhibitor (TKI) therapy and were appropriate candidates for chemotherapy, Socinski said.

As far as the impact of the frontline study results presented at AACR are concerned, Socinski said there has been “more confusion than clarity.” For example, he said the patient populations in the KEYNOTE-189 and IMpower150 trials were different. To be eligible for IMpower150, patients had to be candidates for bevacizumab therapy, which excludes more than half of those who would have gone on the KEYNOTE-189 regimen.

Before the IMpower150 findings, patients who were eligible for bevacizumab therapy would have received that drug plus carboplatin and paclitaxel or pemetrexed. Those who were not bevacizumab candidates would have received carboplatin plus pemetrexed. In light of the new study results, Socinski said, the atezolizumab regimen for patients eligible for bevacizumab and the pembrolizumab combination for those who are not would be the paradigm to consider. Other experts noted the potential impact of IMpower150. “For folks with oncogenic drivers who are TKI refractory, that may be a very attractive go-to regimen,” Langer said. If the full study results bear out the favorable PFS data, they will drive more studies on incorporating immunotherapy in patients with actionable mutations in the resistance setting, Leal said.

Socinski said the combination’s efficacy apparently stems from the enhancement of atezolizumab’s T-cell—mediated tumor cell killing through bevacizumab’s reversal of VEGF-mediated immunosuppression.

Given its effectiveness against tumors with oncogenic drivers, researchers should continue studying how the combination functions and how it may be further refined, Leal said. “What really is driving that benefit? It seems to be the interaction between bevacizumab and atezolizumab. So how much is chemotherapy adding, if that’s correct? Those are things that are going to be important to investigate in future trials,” she said.

Nivolumab Biomarker

One concern that may limit the combination’s uptake, if it is approved, is that it includes 4 drugs—atezolizumab, bevacizumab, carboplatin, and paclitaxel—of which 2 are still under patent. “When you do quadruple therapy as opposed to double or triple, you are absolutely increasing costs associated with them dramatically. We have to consider cost against the real benefits and how we are doing in term of the quality of life of patients. Is it in fact really improving their day-to-day lives, which ultimately becomes one of the most important endpoints?” Bauman asked. The combination of 2 immunotherapies, nivolumab and ipilimumab, also offered intriguing results. The regimen more than tripled the 1-year PFS rate versus chemotherapy for treatment-naïve patients with NSCLC with high TMB.8,9 The 1-year PFS rate was 42.6% for patients with high TMB (≥10 mutations/megabase) assigned to the immunotherapy combination compared with 13.2% for those assigned to platinum-doublet chemotherapy. The median PFS was 7.2 versus 5.5 months, respectively, representing a 42% reduction in risk of disease progression or death (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).

The combination’s prospects remain unclear pending release of survival data and of results for the overall CheckMate-227 study, but the data on the TMB subpopulation have stimulated debate over the biomarker and its utility in guiding immunotherapy treatment. Bauman said it was striking that TMB was predictive of response to nivolumabipilimumab irrespective of PD-L1 status.

“Until now we’ve really been looking to PD-L1, but we know that PD-L1 is an imperfect test. We all have patients who have PD-L1 zero who respond well to immunotherapy and people who have PD-L1 positivity who don’t respond,” she said. “Tumor mutation burden is a new, very different biomarker. It’s showing us another population of patients with lung cancer who may have an individual therapy that might be better for them than standard chemotherapy.”

Langer said he expected TMB will become an increasingly important marker as it is tested in more immunotherapy combinations, particularly if liquid biopsy assays for TMB become available in the next several years.

However, TMB testing also faces skepticism, at least in its current form. David Rimm, MD, PhD, a professor of pathology at Yale University School of Medicine, said TMB testing costs 5 to 10 times as much as immunohistochemistry and requires 10 times as much tissue as a PD-L1 assay.

It is not standardized and perhaps not standardizable, Rimm said. CheckMate-227 used 2 cutpoints, 10 mutations and 13 mutations per megabase, and labs use different assays to determine TMB. He also questioned the marker’s predictive power, pointing out that the CheckMate-026 study found improved PFS from nivolumab compared with chemotherapy but no OS benefit among high-TMB patients.10

“I’d like to raise the possibility that what we’re seeing is going to be seen in many studies as we let overall survival [data] mature,” Rimm said at the AACR conference. “When you have a tumor with a lot of mutational skill, that has a high tumor mutation burden, that tumor can also mutate further to avoid immune therapy or become mutant and thus further become resistant to immune therapy. Is TMB ready for prime time? I don’t believe so. I think it’s not ready yet for use for patient care.”

Langer and others were also cautious about using the nivolumab-ipilimumab combination, due largely to the toxicity profile of the CTLA-4 inhibitor. Langer said he dug into the supplementary data tables for CheckMate-227 and saw noticeably higher incidences of adverse events (AEs) in the TMB group than in the overall study population. In the overall study population, the incidence of serious grade 3/4 treatment-related AEs in the combination arm was 17.7% with ipilimumab compared with 10.7% with chemotherapy.9 The discontinuation rates due to any grade AE were 17.4% and 8.9% in the combination and chemotherapy groups, respectively.

“This combo is not as easy as people would assume it might be,” he said. “I’d rather deal with the toxicity of pemetrexed-carboplatin over the toxicity of ipilimumab-nivolumab. Once it does get an approval, I’m not sure the uptake’s going to be that brisk.”

Langer said nivolumab-ipilimumab could be useful for patients who categorically refuse chemotherapy or those with zero PD-L1 expression and high TMB. Leal noted that the combination improved PFS across NSCLC histologic subtypes with high TMB and said it could help patients with squamous cell cancer, a group that has not yet benefited from immunotherapy combinations.

Although much more research lies ahead, Langer described himself as not only “bedazzled” by findings from KEYNOTE-189 and other trials but also astounded by the broader advance of immunotherapy from the second line to primary therapy. “A lot of my colleagues said, ‘Well, it will be hard to see a benefit in the frontline,’ but we have a bunch of positive trials now,” he said. “Can you remember a time when we saw so many positive trials in advanced lung cancer?”

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