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The frontline standard of care for patients with EGFR-mutant non–small cell lung cancer remains an EGFR TKI, most commonly osimertinib in the United States.
Heather Wakelee, MD
The frontline standard of care for patients with EGFR-mutant non—small cell lung cancer (NSCLC) remains an EGFR TKI, most commonly osimertinib (Tagrisso) in the United States, according to a presentation by Heather Wakelee, MD, at the 2019 International Lung Cancer Congress.
A number of studies have explored the addition of other agents to EGFR TKIs, without the demonstration of a clear improvement in long-term outcomes. EGFR inhibitors and angiogenesis inhibitors have been combined, with promising progression-free survival (PFS) findings but not a clear improvement in overall survival (OS), Wakelee noted. Chemotherapy has also been combined with EGFR inhibitors, with promising OS findings, but limited study data. Additionally, it remains unclear how to best incorporate immunotherapy.
"If someone has an EGFR activating mutation, we know they're going to do better with an EGFR TKI than with chemotherapy, this has been proven over and over again in multiple trials," said Wakelee, professor of medicine, oncology, Stanford University. "In this era, where we often get other test results back, such as PD-L1 first, remember that if that EGFR mutation is there, you are not helping your patient by starting off with chemo. You're better off waiting another week or two."
Newly Approved Frontline EGFR TKIs
In April 2018, the FDA approved osimertinib as a frontline treatment for patients with EGFR-mutant NSCLC, based on impressive findings from the phase III FLAURA trial. Following this approval, osimertinib quickly became the frontline standard of care in the United States.
In FLAURA,1 the median PFS was 18.9 months with osimertinib compared with 10.2 months for erlotinib or gefitinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001). The 18-month OS rate was 83% with osimertinib versus 71% for erlotinib and gefitinib. Although OS data were not yet mature, there was already a 37% reduction in the risk of death shown with osimertinib (HR, 0.63; 95% CI, 0.45-0.88; P = .007). “It has been 2 years and we still do not have median OS. This is a good sign for our patients,” said Wakelee.
For most adverse events (AEs), osimertinib was better tolerated than erlotinib or gefitinib. Grade 3/4 AEs occurred in 32% of patients in the osimertinib group compared with 41% of those receiving erlotinib or gefitinib. The most common all-grade AEs were rash or acne (58% vs 78%, for osimertinib and standard EGFR TKI, respectively), diarrhea (58% vs 57%), and dry skin (36% in each group).
"In general, osimertinib has fewer toxicities than first-generation drugs, but we do need to be mindful of some of the cardiac toxicity," Wakelee said. "Overall though, there is less rash and less diarrhea."
Shortly following the approval of osimertinib, in September 2018, the FDA approved dacomitinib (Vizimpro) as a first-line treatment for patients with EGFR-mutant metastatic NSCLC, based on findings from the phase III ARCHER 1050 trial. Notably, however, this trial did not include patients with brain metastases, Wakelee stressed.
In this study,2 the median PFS with dacomitinib was 14.7 months compared with 9.2 months for participants who received gefitinib (HR, 0.59; 95% CI, 0.47-0.74; P <.0001). With 31.3 months of median follow-up, the median OS was 34.1 months with dacomitinib versus 26.8 months for gefitinib (HR, 0.76; P = .0438). The OS rate at 30 months was 56.2% in the dacomitinib arm and 46.3% in the gefitinib arm.
Substantially more patients required a dose reduction in the dacomitinib arm compared with gefitinib (66.5% versus 8.0%), primarily related to AEs. The most frequent grade ≥3 AEs in the dacomitinib arm were dermatitis acneiform (13.7%), diarrhea (8.8%), paronychia (7.5%), rash (4.4%), and stomatitis (3.5%). The most frequent grade ≥3 AEs with gefitinib were ALT increase (8.5%) and AST increase (4.0%).
"This is a drug that is a little bit more toxic, which is expected," said Wakelee.
Intriguing data have been presented from the JO25567 and NEJ026 trials showing an improvement in PFS with the combination of bevacizumab (Avastin) and erlotinib for patients with EGFR-mutant NSCLC. However, early PFS results with the combination did not translate to an improvement in OS in the JO25567 trial, and data for OS are still pending from NEJ026.
In the JO25567 study,3 the median PFS with the combination was 16.4 months compared with 9.8 month with erlotinib (HR, 0.52; 95% CI, 0.35-0.76; P = .0005). This was similar in NEJ026,4 with a PFS of 16.9 months with the combination versus 13.3 months with erlotinib alone (HR, 0.605; 95% CI, 0.417-0.877; P = .01573). The OS in JO25567 was 47.0 months with erlotinib plus bevacizumab compared with 47.4 months with erlotinib alone (HR, 0.81; 95% CI, 0.53-1.23; P = .3267).
Findings from the RELAY study were presented at the 2019 ASCO Annual Meeting showing potential for the combination of ramucirumab (Cyramza) and erlotinib.5 At a median follow-up of 20.7 months, the median PFS by investigator assessment was 19.4 months with the ramucirumab combination compared with 12.4 months with erlotinib alone (HR, 0.591; 95% CI, 0.461-0.760; P <.0001).
Adding to these data, a phase I/II study examined the combination of osimertinib plus bevacizumab. In findings presented at the 2019 ASCO Annual Meeting,6 the objective response rate with the combination was 80% and the median PFS was 18.4 months. A larger study is planned to further explore the combination of osimertinib with or without bevacizumab for patients with EGFR-mutant NSCLC.
Other EGFR Combinations
EGFR inhibitors have been examined in combination with chemotherapy and more recently in addition to immunotherapy. When looking at first and second-line treatment together, PFS data with chemotherapy plus EGFR inhibition were similar; however, there was a survival advantage noted. Additionally, the combination of immunotherapy and EGFR inhibition has led to AEs, warranting caution, Wakelee noted.
In the phase III NEJ009 trial,7 carboplatin and pemetrexed were added to gefitinib, with a median PFS1 in the first-line of 20.9 months compared with 11.2 months with gefitinib (HR, 0.493; 95% CI, 0.390-0.623; P <.001). In the second-line, however, the PFS2 leveled out, at 20.7 months in the gefitinib alone arm compared with 20.9 months with the combination (HR, 0.966; 95% CI, 0.766-1.220; P = .774). The median OS was 52.2 months with the combination versus 38.8 months with chemotherapy alone (HR, 0.695; P = .013).
"There is a signal of improved overall survival," said Wakelee. "There was a second trial, that was very similar, done in India...There was a PFS benefit and a clear overall survival benefit."
For the combination of immunotherapy and an EGFR TKI, an initial phase II study sought to enroll 25 patients but only accrued 11 for the combination of pembrolizumab and an EGFR inhibitor.8 Of these patients, there were no relevant responses, and 2 of the patients died within 6 months, 1 with pneumonitis. Additionally, in the TATTON study,9 38% of patients treated with the combination of an EGFR inhibitor and a PD-L1 inhibitor developed interstitial lung disease.
"You need to be particularly mindful if you have a newly diagnosed patient, and they have high PD-L1 and they might have an EGFR mutation but you don't know, if you start them on immune therapy first waiting for the EGFR result, you might actually be hurting them, especially if they get hepatotoxicity," cautioned Wakelee.
Although the dataset is small, there is potential to utilize the combination of atezolizumab (Tecentriq) plus bevacizumab, carboplatin, and paclitaxel (ABCP), based on an improvement in OS seen in the Impower150 study,10 Wakelee noted. In patients with previously treated EGFR-mutant NSCLC, the median OS was not yet reached with ABCP compared with 17.5 months with bevacizumab, carboplatin, and paclitaxel (HR, 0.31; 95% CI, 0.11-0.83).
Wakelee concluded by noting that more research is needed into potential resistance mechanisms. Moreover, she noted a need for further exploration into immunotherapy for patients with EGFR-mutant NSCLC.