Combining Trial Data With Clinical Case Studies to Illustrate the Lung Cancer Landscape

In a discussion at the 2019 Spring Session of the Florida Society of Clinical Oncology (FLASCO), speakers provided updates to the treatment landscape for lung cancer and presented a case study from the clinic.

Moderator Edgardo Santos, MD, FACP, FLASCO Program Committee Chairman, of Lynn Cancer Institute and Florida Atlantic University, introduced the main speaker as a lung cancer expert with a long career as a researcher who would give the audience “a view of the new landscape in the treatment of lung cancer.”

In the last 2 to 3 years, that therapeutic landscape has been “irrevocably altered in that time period, and it’s all really thanks to the new immunotherapy paradigm,” said Corey J. Langer, MD, director of thoracic oncology, professor of medicine, University of Pennsylvania Hospital.

First, the data of 3 years ago found that programmed death 1 (PD-1) and programmed death­—ligand 1 (PD-L1) inhibitors increase overall survival and result in durable progression-free and overall survival in refractory non­–small cell lung cancer (NSCLC).

Since then, these drugs have moved into the first and second lines of therapy. His current paradigm of treatment includes pembrolizumab as the standard of care for patients with PD-L1 expression 50% or higher and what he called the “kitchen sink regimen” of 4 separate drugs for patients who are tyrosine kinase inhibitor (TKI)-refractory. However, he emphasized that each of these recommendations could change at any moment “considering how quickly these studies come in.”

“We almost seem to be practicing by press release” with the constant stream of new trial results and drug approvals, Langer said.

He mentioned the results of the Keynote-042 trial of pembrolizumab versus chemotherapy as an example of clinical trial data impacting practice; without evidence of the “completely unprecedented” improvements in progression-free survival seen in almost all trial subgroups, he believes pembrolizumab would not have received FDA approval. When the data were updated to show a median survival of 30 months, “in one fell swoop that became the standard across the country and now increasingly across the world for those with high levels of PD-L1 expression.”

The survival improvements seen in the Keynote-042 trial were driven by the group with 50% or higher PD-L1 expression, as no overt survival advantage was shown in the group with 1% to 49% expression.

Langer also discussed the various arguments for and against combining checkpoint inhibitors with chemotherapy. In his view, there are more pros than cons to using a combination to promote antitumor immune response.

Next, Langer reviewed the trial data for combinations of pemetrexed, carboplatin, and pembrolizumab. The triplet’s conditional approval in advanced nonsquamous NSCLC may have been premature based on the data available at the time in 2017, but “time has been kind to the study,” and the survival times have actually improved since then.

The rationale for using a single agent versus the triplet is the lower cost and decreased toxicity of a single drug, but the triplet has the advantage of producing higher response rates and progression rates that hold up over time. Beyond the measurable data, delaying disease progression avoids emotional turmoil, Langer said.

“The worst moment in clinic is when we go up to that patient, we show them the films, and we say the disease has progressed. Their quality of life goes down, and I assure you the quality of life of the doctor, and the nurses, and everybody else in the clinic also goes down at that moment,” he explained. “The longer we can put off progression, the better off we all are.”

With that in mind, his practical strategy for treating advanced nonsquamous NSCLC with PD-L1 expression of 50% or higher is to choose pembrolizumab for older or frailer patients and those with lower metastatic burden, fewer symptoms, and significant comorbidity; he would use the triplet in younger and heartier patients with metastatic disease. In those with 1% to 49% PD-L1 expression, he would only use pembrolizumab alone in patients who are even older and frailer and averse to or ineligible for chemotherapy.

Langer also discussed trial data showing a “special synergy” between checkpoint inhibitors and angiogenesis inhibitors for TKI-refractory patients with advanced NSCLC. As an anecdote, he has treated at least 3 such patients with atezolizumab and chemotherapy according to this rationale, and all 3 have responded to the therapy, with toxicity that has been easier to manage than anticipated.

Next, he moved to what he called the elephant in the room: the role of tumor mutational burden (TMB) as a biomarker. Langer discussed the results of the Checkmate-227 trial of nivolumab/ipilimumab in patients with high TMB. While TMB may not yet be ready for prime time as a prognostic marker, Langer believes it could have a potential role if it demonstrates benefit to overall survival in phase 3 trials.

Langer concluded that the therapeutic approach to lung cancer has completely changed with immunotherapy, but there are still open questions, such as how to treat patients with low PD-L1 expression and low TMB, or whether to treat beyond disease progression.

Switching gears, Sonam Puri, MBBS, Moffitt Cancer Center, took the stage to present a case study of a 60-year-old male never-smoker with a large lung mass and PD-L1 expression of 50%. His first line of treatment was the EGFR TKI afatinib, but after discovering new disease progression, brain lesions, and EGFR mutation in 10 months, he was started on second-line osimertinib. While imaging showed evidence of intracranial disease control, he experienced systematic progression of disease within 10 months and a biopsy revealed a new soft mass, which raised concerns that his cancer had converted to small-cell carcinoma.

Langer agreed that the demonstrated intracranial activity of osimertinib can lull physicians into a false sense of security, “but after a year and a half, 2 years, 3 years, they will have progression; by and large, disease progression is inevitable at some point in those with oncogenic drivers.”

He also agreed that small-cell conversion is becoming a problem, and “we need certainly more data and probably more innovative approaches” to treat it.

Further progress in that and other areas will be necessary to build upon the substantial advancements already seen in lung cancer treatment. In response to an audience question about how to manage a particular patient’s situation, Langer answered that the course of therapy would depend on how the patient had progressed.

“It really needs to be individualized, and unfortunately the literature’s not really catching up with our anecdotal experience, at least not yet, and we need to fill in the gaps with our experience,” he said.