Clinical trial evidence is building for moving checkpoint blockade immunotherapy forward in the treatment timeline for non–small cell lung cancer, but improving patient selection for these therapies remains a key challenge.
Benjamin P. Levy, MD
Clinical trial evidence is building for moving checkpoint blockade immunotherapy forward in the treatment timeline for non—small cell lung cancer (NSCLC), but improving patient selection for these therapies remains a key challenge, according to an OncLive Peer Exchange® panel of international experts.
Although advancements have reshaped the landscape for metastatic NSCLC, changes in the paradigm for treating patients with locally advanced disease have been slower to develop, noted Benjamin P. Levy, MD, who moderated the panel. “[It’s] a space where we’ve really been begging for new therapies,” he said. “Immunotherapy first landed in the advanced-stage setting in the second line, but it’s being moved up to the first line, and now we’re seeing emerging data with the use of immunotherapy in the locally advanced setting.”
During the Peer Exchange, which took place during the International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer (WCLC 2018), a panel of thoracic oncology experts from the United States and Europe discussed new checkpoint inhibitor data in the stage III and IV NSCLC setting. The panelists provided insights on how they are using various immunotherapy approaches in their clinical practices to improve patient outcomes.PACIFIC Trial
The experts started with a review of the landmark PACIFIC trial, which helped open the door to the use of PD-L1 inhibition in patients with locally advanced, unresectable stage III NSCLC. A planned interim analysis of progression-free survival (PFS) from the trial showed a statistically significant improvement in PFS with the PD-L1 inhibitor durvalumab (Imfinzi) compared with placebo (16.8 months vs 5.6 months, respectively).1
“[A] benefit of almost 11 months of PFS, reaching 17 months, [is] something that we are not used to observing in NSCLC,” Solange Peters, MD, PhD, said. Based on PACIFIC PFS data, in February 2018, the FDA approved durvalumab in patients with unresectable stage III NSCLC that had not progressed following concurrent platinum-based chemotherapy and radiation therapy; however, questions remained about its survival benefit.2
At WCLC 2018, a PACIFIC trial update also published in the New England Journal of Medicine, revealed a statistically significant benefit in overall survival (OS) with durvalumab versus placebo (HR, 0.68; 99.73% CI, 0.469-0.997; P = .00251).3,4 The OS rate was 83.1% at 12 months and 66.3% at 24 months with durvalumab versus 75.3% at 12 months and 55.6% at 24 months with placebo. Median OS was not reached in the durvalumab group and was 28.7 months in the placebo arm. The PFS benefit remained similar to that reported in the interim analysis (17.2 months for durvalumab vs 5.6 months for placebo).3,4
“Based on [PACIFIC data], I think we have the final confirmation that there’s something there. I would even say the magnitude of benefit is showing that there’s something interesting in trying to combine various modalities,” Peters said. She emphasized that these data were in an intention-to-treat (ITT) population and not restricted to patients with enhanced PD-L1 expression. “I know it’s going to be a matter of debate about PD-L1 and accessibility of tissue, but basically, this trial was aiming at looking at a simple question: In an ITT population, is survival better or not? And the answer is yes,” she said.
In late September 2018, the European Commission approved durvalumab in patients with locally advanced, unresectable NSCLC whose disease has not progressed following chemoradiation, but with the caveat that patients’ tumors must express PD-L1 on ≥1% of tumor cells.5 This approval considered PACIFIC trial PFS and OS data, as well as findings from a posthoc subgroup analysis by PD-L1 expression, which was requested by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).6
“I think [restriction to the PD-L1—positive patient] will be a big issue,” David Planchard, MD, PhD, said. “We are not convinced that PD-L1–negative patients do not benefit on this type of treatment,” he added. Levy said that data on PD-L1–low disease (<1% PD-L1 expression) are forthcoming and will provide more definitive information.Several studies have assessed whether consolidation chemotherapy could be curative in patients achieving disease control with chemoradiotherapy, but this strategy has been ineffective.3 Following chemoradiation, approximately 15% to 30% of patients are alive at 5 years, with the median OS being approximately 28 months. With the addition of consolidation chemotherapy, median OS has been lower, reaching no more than 23 months.3 “I would say the enthusiasm for consolidation therapy was waning away piece by piece because of incremental evidence that it really doesn’t help,” Suresh S. Ramalingam, MD, said. However, the PACIFIC trial showed that consolidation therapy with durvalumab is different.
“There is a greater than 30% reduction in the risk of death as a result of receiving consolidation durvalumab. I think that’s unprecedented,” Ramalingam said. “We [now] have a treatment that improves survival, so I think it’s an easy change in the paradigm when patients get chemoradiation,” he said. Consolidation chemotherapy was not allowed in the PACIFIC trial.
The panelists proceeded to discuss when to initiate consolidation durvalumab. Levy mentioned that the PACIFIC trial indicated a greater benefit when the drug was started earlier following chemoradiation. Ramalingam said he generally starts durvalumab consolidation 4 weeks after chemoradiotherapy completion. “Our multidisciplinary team believes that you’ve got to wait a few weeks after chemoradiation before you get a good readout for the degree of benefit with chemoradiotherapy,” he explained. “Once [patients] recover from acute toxicities within the 4- to 6-week period, they would then go on to receive durvalumab.”
The panelists remarked that despite some toxicity concerns with initiating immunotherapy immediately after radiation, no excess toxicity was observed in the PACIFIC trial. Of particular concern was pneumonitis, a known complication of both radiation therapy and immunotherapy; it was thought that layering these treatments might result in excess lung toxicity, but this was not observed.
“It’s not the case in most of the trials where we try to combine radiation on the lung and immunotherapy. Decidedly, the mechanisms behind them are not cumulative or not synergistic,” Peters said.Levy asked the panelists whether the PACIFIC regimen would change how they approach patients who are deemed surgically resectable, such as the patient with stage IIIA disease. Ramalingam said that although this regimen has the potential to improve outcomes, a clinical trial is needed to provide definitive answers in this setting.
“I think to move this paradigm into the resectable setting at this point would be premature,” he said. “Even though there is a little bit of overlap, the surgically unresectable stage III and resectable stage III cases are distinctly biologically different groups of patients, and we need to treat them as such.”
In contrast, Peters thought that the availability of the PACIFIC regimen might have some important implications for European patients. She explained that in Europe, there is a tendency to favor surgery over radiation, with surgeons being more liberal in their definition of resectable, which often includes patients who are just borderline resectable due to very bulky disease or multistation involvement. “I think it really offers us a very promising new strategy to maybe spare some patients from very invasive, very large surgery, and that’s something that is probably a positive move for Europe,” she said.EGFR mutations have been reported in up to 50% of Asian patients with lung adenocarcinomas and 10% to 15% of white patients with this form of NSCLC.7 Levy mentioned that patients with these mutations were not found to have a statistically significant benefit from the PACIFIC regimen. “We know that EGFR mutations may not do well with at least single-agent checkpoint blockade,” he said, and he asked the panelists whether durvalumab could still be considered for a patient with EGFR mutation—positive disease who completes concurrent chemoradiation.
The panelists agreed that, until more definitive data prove otherwise, these patients should not be excluded from consideration for the PACIFIC regimen. “At the end of the day, it’s a subset, an unplanned analysis of a relatively small number of patients with wide confidence intervals and a point estimate showing some benefit. There aren’t enough data to withhold that treatment from that group,” Sanjay Popat, BSc MBBS, FRCP, PhD, said. Additionally, Peters explained that, unlike checkpoint inhibition alone, a combination of chemotherapy and radiation may create an environment where some immunogenicity is gained. Another option for patients with locally advanced NSCLC may flow from a pending FDA decision on a supplemental biologics license application (sBLA) for the PD-1 inhibitor pembrolizumab (Keytruda). The agency is reviewing an sBLA for single-agent pembrolizumab as a frontline treatment of patients with locally advanced or metastatic nonsquamous or squamous NSCLC with a PD-L1 expression (tumor proportion score [TPS]) level of ≥1% and no EGFR or ALK genomic tumor aberrations. A decision is expected by April 11, 2019.8
The application is based on data from the phase III KEYNOTE-042 trial, in which the median OS was 16.7 months with frontline pembrolizumab monotherapy compared with 12.1 months with standard chemotherapy in patients with advanced or metastatic NSCLC and TPS of ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P = .0018). Across all patients with PD-L1 TPS of 1% to 49%, which was an exploratory analysis, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11). 9
Of the 1274 patients who participated in the study, 160 (12.6%) had locally advanced disease. The HR among patients in this group with TPS ≥1 was 0.74 (95% CI, 0.49-1.13), according to findings presented at the 2018 American Society of Clinical Oncology Annual Meeting.9Multiple immunotherapies have been approved in the second-line setting for patients with advanced NSCLC, but fewer than 50% of patients receive second-line therapy, because disease progression often leads to rapid clinical deterioration.10 Subsequently, identifying efficacious first-line therapies in this setting is exceedingly important, and the panelists noted that this is where the focus has now shifted.
This emphasis is reflected in the recent pace of FDA approvals for first-line immunotherapies in the metastatic setting.
In August 2018, based on KEYNOTE-189 data, the FDA granted approval to the combination of the PD-1 inhibitor pembrolizumab (Keytruda) plus standard-of-care chemotherapy (ie, pemetrexed [Alimta] plus cisplatin or carboplatin) in the first-line setting for patients with stage IV nonsquamous NSCLC and no EGFR or ALK genomic tumor aberrations.11 The combination was approved for the same indication by the European Commission in September 2018.12
In the study, the median OS was not reached in the pembrolizumab—chemotherapy arm compared with 11.3 months in the chemotherapy-alone (control) arm (HR for death, 0.49; 95% CI, 0.380.64; P <.001).10
Additionally, in October 2018, the FDA approved first-line pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for patients with metastatic squamous NSCLC. The approval is based on results from the phase III KEYNOTE-407 trial, in which combining pembrolizumab with chemotherapy reduced the risk of death by 36% compared with chemotherapy alone in this population. The median OS was 15.9 months (95% CI, 13.2—not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017).13
In December 2018, the combination strategy for treating NSCLC was expanded into a 4-drug regimen. The FDA approved the PD-L1 inhibitor atezolizumab (Tecentriq) in combination with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) for the first-line treatment of patients with metastatic nonsquamous NSCLC. The indication excludes patients with EGFR or ALK aberrations.
The approval is based on findings from the phase III IMpower150 trial, in which the ABCP resulted in a median OS of 19.2 months (95% CI, 17.0-23.8) compared with 14.7 months (95% CI, 13.3-16.9) with bevacizumab and chemotherapy (HR, 0.78; 95% CI, 0.64-0.96; P = .0164).14The Peer Exchange panelists agreed that there are many nuances and gray zones when selecting among the available first-line treatments in stage IV NSCLC, a heterogenous disease for which a variety of targeted therapies is also available in the setting of various driver mutations. An example provided was the never-smoker with low tumor mutational burden (TMB) and a BRAF mutation. Peters suggested that in such cases, the addition of some chemotherapy might be beneficial. Ramalingam agreed but suggested that in patients with driver mutations, targeted agents are likely to provide the best possible outcomes, which he said has already been demonstrated with EGFR-directed therapies. “I would venture to say that even for BRAF- and ALK-positive patients, what we see with more and more exciting targeted agents coming down the road is that they should get targeted therapy. When we run out of targeted therapy options, we go with immune checkpoint inhibition, no matter how high the PD-L1 expression is,” he said.
The panelists also emphasized the importance of next-generation sequencing in treatment decision making. “PD-L1 might be a good biomarker, but it’s not a good biomarker alone,” Planchard said, noting he would never start an immune treatment alone without conducting other medical testing, including for EGFR, BRAF, ALK, and ROS1 aberrations, particularly in a never-smoker. He explained that clinical trials have not proved that immune treatment is better than the other treatments for never-smokers, which is why he tries to find a molecular alteration to target to improve these patients’ outcomes. Furthermore, he said, starting a targeted agent after immunotherapy increases the risk of toxicities, even if immunotherapy was stopped early. “It’s at least 4 weeks or 6 weeks of half-life with an immune treatment, and you cannot stop treatment for 2 or 3 months before you start any specific targeted therapy. We have to take this into account,” he said.Another promising development the panelists discussed involves using dual checkpoint blockade in the first-line treatment of stage IV NSCLC, rather than adding chemotherapy as a backbone. One trial assessing this approach is CheckMate-227, which is comparing the combination of the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) with histology-specific chemotherapy among patients with high TMB (≥10 mutations per megabase).15
Updated data have revealed an OS benefit with dual checkpoint blockade of 23.03 months versus 16.72 months with chemotherapy in patients with high TMB. A subgroup analysis of patients with less than 10 mutations per megabase also showed benefit with the combination, with a median OS of 16.20 months versus 12.42 months for chemotherapy.16 The FDA is reviewing a SBLA for the combination, an action date of May 20, 2019.16
The panelists suggested that understanding of TMB is still in its infancy but that one important revelation has been that patients with high TMB are not the same as those with high PD-L1 expression. “There’s a direct discordance in who is high PD-L1 versus high TMB. What I think TMB does is help you select a subgroup of patients who don’t have high PD-L1 but who could still benefit from immune checkpoint inhibition,” Ramalingam said.In their concluding thoughts, the panelists emphasized the importance of truly understanding patients’ molecular profiles. “You’ve really got to get a proper comprehensive molecular analysis of the patients so that you know what the key drivers are—you know what the PD-L1 status is, and you might even know what the TMB status is—to enable the best decisions for patients to be made up front,” Popat said. The panelists made it clear that as new treatments join the ever-expanding arsenal, molecular profiling and other strategies for improving treatment selection will take on increasing importance.