The past year has witnessed an explosion in immunotherapy combinations for patients with lung cancer, accompanied by a growing knowledge of biomarkers such as PD-L1 and tumor mutation burden; however, an exact standard of care remains elusive.
Corey J. Langer, MD
The past year has witnessed an explosion in immunotherapy combinations for patients with lung cancer, accompanied by a growing knowledge of biomarkers such as PD-L1 and tumor mutation burden (TMB); however, an exact standard of care remains elusive, according to a presentation by Corey Langer, MD, at the 19th International Lung Cancer Congress (ILCC).
In May 2017, the FDA approved pembrolizumab (Keytruda) in combination with pemetrexed (Alimta) and carboplatin for the treatment of patients with previously untreated metastatic non-squamous non—small cell lung cancer (NSCLC), based on findings from the open-label phase II KEYNOTE-021 cohort G study. The lack of long-term data at the time rendered this a controversial approval; however, in just a little over a year, multiple phase III trials have reported their findings showing a significant advantage for immunotherapy plus chemotherapy over chemotherapy alone.
"This was a highly controversial conditional approval just 1 year ago for this triplet in non-squamous lung cancer, independent of PD-L1," said Langer, professor of medicine at the Hospital of the University of Pennsylvania. "In the absence of the results of a validated phase III, there was tremendous backlash at the time, but time and circumstances have been kind to cohort G."
In updated long-term findings from the KEYNOTE-021 cohort G trial,1 median overall survival (OS) with the immunotherapy combination was not reached (95% CI, 24.5-NR) compared with 21.1 months (95% CI, 14.9-NR) for carboplatin and pemetrexed alone. The 2-year OS rate was 67% with pembrolizumab compared with 48% in the control arm, representing a 44% reduction in the risk of death with the immunotherapy combination (HR, 0.56; 95% CI, 0.32-0.95).
Findings from the KEYNOTE-189 trial,2 which were published in the New England Journal of Medicine, further confirmed the efficacy of the combination of immunotherapy with chemotherapy. The estimated 12-month 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 median progression-free survival (PFS) in the pembrolizumab group was 8.8 months (95% CI, 7.6-9.2) versus 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43-0.64; P <.001). Median OS was not reached with pembrolizumab versus 11.3 months (95% CI, 8.7-15.1) in the control arm.
With these combination data available, the question is now whether to utilize pembrolizumab as a single-agent or in combination with chemotherapy, Langer noted. For this, he looked to data for the single-agent PD-1 inhibitor from the KEYNOTE-042 trial, which was presented at the 2018 ASCO Annual Meeting.
In this phase III trial,3 OS correlated with greater levels of PD-L1 expression, with those having a tumor proportion score (TPS) ≥50% having the best outcomes. The median OS was 20 months with pembrolizumab versus 12.2 months with chemotherapy (HR, 0.69; 95% CI, 0.56-0.85; P = .0003). However, in an exploratory analysis of patients with PD-L1 TPS of 1% to 49%, 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).
Based on these findings, Langer recommended using the combination for most patients with PD-L1 expression between 1% and 49%. In those with PD-L1 expression ≥50%, he considered single-agent pembrolizumab, particularly for those who were older, with a low metastatic burden, and significant comorbidities. However, in younger patients, with high metastatic burden and aggressive tumors, Langer felt the combination was best.
"KEYNOTE-189 showed a clear advantage for the triplet compared with standard chemo. There's an improvement in OS, PFS, and response rate, validating the cohort G data," he said. "However, single-agent pembrolizumab is still arguably a standard. There's less toxicity and lower costs for single-agent pembrolizumab, it also doesn't preclude the option of going to pemetrexed and carboplatin at the time of progression."
The phase III INSIGNA trial is being planned, which will compare first-line pembrolizumab alone with the agent in combination with chemotherapy for patients with advanced nonsquamous NSCLC. However, the trial will include patients with PD-L1 expression of 1% of higher, which caused Langer consternation. He felt this question was less relevant than a comparison in those with ≥50% expression.
In response to this, Roy S. Herbst, MD, PhD, from Yale Cancer Center, who is helping to design the trial, countered that a broad PD-L1 inclusion criteria would allow for broad subgroup analyses of the results, to potentially answer multiple questions. At this time, the study has not yet started enrolling.Findings from the phase III IMpower150 trial presented at the 2018 ASCO Annual Meeting opened a potential new role for immunotherapy combinations for patients with ALK or EGFR alterations, Langer noted. Prior studies had not included patients with these mutations, given a lack of efficacy seen with single-agent immunotherapy.
In the IMpower150 trial,4,5 across those with wild-type tumors, the combination of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) reduced the risk of death by 22% compared with bevacizumab and chemotherapy (BCP). However, there was a larger advantage seen in those with driver mutations.
Overall, approximately 13% of participants in the trial were EGFR or ALK-positive. Prior to study entry, these patients had received at least 1 prior EGFR TKI. There was a 46% reduction in the risk of death for patients with EGFR/ALK-mutated NSCLC with ABCP (HR, 0.54; 95% CI, 0.29-1.03). The risk of death was reduced by 18% (HR, 0.82; 95% CI, 0.49-1.37) for patients with EGFR/ALK alterations.
"This is the only trial that has looked at angiogenesis inhibitor as well as TKI-refractory patients with ALK or EGFR alterations," said Langer. "Atezolizumab’s T-cell mediated cancer cell killing may be enhanced through bevacizumab’s reversal of VEGF-mediated immunosuppression."
However, Langer noted that the ABCP combination was quite toxic, with 44% of patients experiencing a serious adverse event. Moreover, he noted, the rates of grade 3/4 adverse events were also high with the quadruplet therapy. As a result, Langer wished to see findings for just the combination of bevacizumab and atezolizumab in this population, to see if the adverse events could be avoided.
"There's a significant improvement in PFS, but the separation of the curves is a bit more robust beyond the completion of the chemotherapy," said Langer. "This raises the question of whether there is synergy here between the angiogenesis inhibitor and the immunotherapeutic. I think the question of bevacizumab and atezolizumab alone needs to be addressed in this population."
In a discussion at the meeting, the speakers theorized that a combination of bevacizumab plus atezolizumab could serve as a second-line therapy for patients with EGFR-mutant NSCLC, following frontline osimertinib (Tagrisso) for patients without a mutation that could suggest activity to a first-generation EGFR TKI. However, they all agreed that they wanted to see data for the two monoclonal antibodies together, without chemotherapy.Findings from the phase III IMpower131 study presented at the 2018 ASCO Annual Meeting showed that the addition of atezolizumab to frontline carboplatin and nab-paclitaxel (Abraxane) delayed the risk of progression or death by 29% compared with chemotherapy alone for patients with squamous NSCLC.6
The median PFS was 6.3 months (95% CI, 5.7-7.1) with the addition of atezolizumab versus 5.6 months (95% CI, 5.6-5.7) with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.85; P = .0001). In the atezolizumab arm, the 12-month PFS rate was 24.7% compared with 12% in the chemotherapy arm.
OS data were immature at the time of the analysis, which made it challenging for Langer to draw a conclusion. However, findings for survival were available for the phase III KEYNOTE-407 trial, which explored pembrolizumab in combination with carboplatin plus paclitaxel or nab-paclitaxel in patients with metastatic squamous NSCLC. In this trial, the addition of pembrolizumab to frontline chemotherapy reduced the risk of death by 36% compared with chemotherapy alone.7
Median OS with the addition of pembrolizumab was 15.9 months (95% CI, 13.2-not evaluable) versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49- 0.85; P = .0008). The PFS for the pembrolizumab group was 6.4 months (95% CI, 6.2-8.3) versus 4.8 months (95% CI, 4.3-5.7) with chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70; P <.0001).
"This is the first study in squamous that has shown this degree of difference in survival. This is a game-changer," said Langer. "The benefits are seen across the board, regardless of PD-L1 status."In addition to combinations of immunotherapy and chemotherapy, findings from the CheckMate 227 trial showed intriguing results for the combination of immunotherapies, namely nivolumab (Opdivo) and low-dose ipilimumab (Yervoy). Across all PD-L1 expression levels in those with TMB of ≥10 mutations per megabase, the 1-year PFS rate was 43% with the immunotherapy combination compared with 13% for those assigned to platinum-doublet chemotherapy.8
Patients in the trial were stratified based on TMB and PD-L1 status. Those with PD-L1—negative, TMB-high NSCLC experienced a reduction in the risk of progression or death of 52% with nivolumab and low-dose ipilimumab compared with standard platinum doublet chemotherapy. There was no benefit in the TMB-low arm (HR, 1.17; 95% CI, 0.76-1.81).9
"In this group, there's a significant improvement in PFS, nearly a tripling in PFS," Langer said. "This improvement is independent of histology and independent of PD-L1 expression, you see the same basic findings in both PD-L1—high and –low."
Before drawing conclusions on these data, Langer hoped to see OS data for the combination. He felt that TMB was not yet ready for prime time, until these data were available. However, despite this, in June 2018, the FDA accepted a supplemental biologics license application for the combination of frontline nivolumab and ipilimumab for patients with advanced NSCLC with TMB ≥10 mutations per megabase.
Adding to this, ILCC meeting co-chair David Gandara, MD, from UC Davis Health, noted that Foundation Medicine was already offering TMB testing as part of the FoundationOne assay. However, unlike the CheckMate 227 trial, the FoundationOne test classifies high TMB as ≥20 mutations per megabase.
"The FoundationOne TMB assay has been studied in about 100,000 human genotypes. It is FDA-approved for 17 indications and TMB is part of it. The median turnaround time is 10 days," said Gandara. "This is a highly-validated test. It has been compared with whole exome sequencing, with excellent correlation."Several studies have explored the addition of immunotherapies to targeted therapies for patients with driver mutations. For the most part, these studies have been mired in toxicity concerns with less than impressive response rates. For single-agent immunotherapy, those with EGFR alterations have a response rate of 12% and those with ALK have no response, Sarah B. Goldberg, MD, MPH, said during a talk at ILCC.
Sarah B. Goldberg, MD
Unsuccessful strategies, due to adverse events or low efficacy, include combinations of erlotinib (Tarceva) with atezolizumab, durvalumab (Imfinzi) plus osimertinib (Tagrisso), and crizotinib (Xalkori) with nivolumab. Other studies remain ongoing exploring lorlatinib and avelumab (Bavencio) and results have been recently published for erlotinib plus nivolumab. In this single arm trial,10 the 6-month PFS rate was 48% with erlotinib plus nivolumab in TKI pretreated patients with EGFR-mutant NSCLC. The 1-year OS rate was 70% and the median OS was 18.7 months.
Another positive study looked at alectinib (Alecensa) and atezolizumab as a first-line therapy for ALK-positive NSCLC, said Goldberg, assistant professor of Medicine at Yale Cancer Center. The objective response rate with the combination was 85.7% and the median PFS was 21.7 months. There were no grade 4/5 treatment-related adverse events.11
"Toxicity has been an issue in several trials combining targeted and immunotherapy. Outcomes in first-line trials do not appear to differ from targeted agents alone so far," said Goldberg. "Further studies are needed, especially biomarker-driven studies. Unclear what path these trials will take given the toxicity issues."