The Multitude of Options for First-Line Therapy for EGFR-Mutated Lung Cancer

Speaking as a medical oncologist who cares for patients with lung cancer, the present is filled with much hope. There has been a profusion of studies that report increasingly improved outcomes for patients with lung cancer, both in early and advanced stages. 

Specifically, for a patient with advanced lung cancer with an EGFR-sensitizing mutation, the National Comprehensive Cancer Network and the Pan-Asian Adapted European Society for Medical Oncology Guidelines list seven to eight first-line therapy options.^1,2 These choices may be broadly divided into single-agent oral tyrosine kinase inhibitors (TKIs)—both early-generation oral TKIs such as gefitinib, erlotinib, and afatinib, and newer oral TKIs such as dacomitinib and osimertinib—and combination strategies including an oral TKI with VEGF inhibitors such as ramucirumab and bevacizumab, and an oral TKI with chemotherapy. 

The three early-generation oral TKIs have broadly similar results and outcomes: response rates of approximately 50% to 80%, median PFS rates of approximately 8 to 11 months, and median OS rates of approximately 19 to 35 months.³ All the other options—that is, new-generation oral TKIs and combination strategies, either with VEGF inhibitors or with intravenous chemotherapy—improve the disease control and PFS to a far greater extent compared to monotherapy with the earlier-generation oral TKIs. The caveat to this statement is that these newer options have not been compared to afatinib; however, afatinib has been compared to other first-generation oral TKIs and was shown to have similar activity. The LUX-Lung 7 trial reported a statistically significant but clinically irrelevant prolongation in median PFS from 10.9 to 11 months (HR = 0.73; [95% CI: 0.57-0.95]; p = 0.017), and similarly, a median OS of 27.9 and 24.5 months in the afatinib and gefitinib arms, respectively (median follow-up, 42.6 months; HR = 0.86; 95% CI: 0.66‒1.12, p = 0.258).^4,5 

Out of the newer options, dacomitinib, osimertinib, and the combination of an oral TKI with chemotherapy have all been shown to improve OS.^6-9 Thus, we are now in the enviable position of being able to offer multiple different options to our patients with EGFR-mutated lung cancer, but this raises questions as to what is the optimal treatment and what is the best way to sequence these various therapies. Although the National Comprehensive Cancer Network does not yet include the option of an oral TKI with chemotherapy in their recommendations for the first-line therapy of a patient with EGFR-mutated NSCLC,¹ this approach has the maximum amount of clinical evidence to date. In the modern era, six randomized trials (two in patients with molecularly unselected lung cancer and four exclusively in patients with EGFR-positive lung cancer) have studied this concept in various forms. These forms include the intercalated approach, in which the oral TKI is administered on the days when the patient is not receiving chemotherapy; the sequential alternating approach, in which the oral TKI is given for several weeks followed by some cycles of chemotherapy, and then the cycle is repeated; and finally, the concurrent approach, in which the oral TKI and the chemotherapy are given together. Table 1 gives additional details of the two recent randomized trials that were conducted in a cohort of patients with non-molecularly driven lung cancer; Table 2 provides the details of the randomized trials that have been conducted in patients with EGFR-mutated NSCLC. 

Recent Data    

To summarize the data from these randomized trials, the combination of a first-generation oral TKI with pemetrexed and carboplatin chemotherapy significantly prolonged response rate, PFS, and OS, with an increase in adverse events over oral TKIs alone, but with no worsening in quality of life (QoL). 

Updated results from the FLAURA trial were very impressive,⁷ but a few caveats remain. The FLAURA study is the only randomized phase III study that has proven the efficacy of osimertinib compared to first-generation oral TKIs, whereas the benefit of a combination of an oral TKI with chemotherapy has been proven in six randomized controlled trials. The predefined subset analysis of the FLAURA study suggested that osimertinib may not be as efficacious in Asian patients; for the 347 Asian patients enrolled, the HR for death was 1.00 (95% CI: 0.75, 1.32), whereas for the 209 non-Asian patients, the HR was 0.54 (95% CI: 0.38, 0.77). Both the NEJ009¹⁴ and the Tata Memorial Hospital study⁸ were conducted exclusively in Asian patients, and thus the combination of an oral TKI with chemotherapy has a proven efficacy in the Asian population. The combination of an oral TKI with chemotherapy in the first-line setting also allows the patients to get exposed to multiple effective lines of therapy, especially to osimertinib in the second line. In the FLAURA study, only 18% of the patients in the osimertinib arm received cytotoxic chemotherapy as the first subsequent therapy, whereas 47% of the patients in the comparator group (first-generation oral TKI) received osimertinib as the first subsequent therapy post-progression. However, there are unassailable arguments for osimertinib in the first line, including the convenience of oral tablets, avoidance of intravenous chemotherapy, low toxicity, and maintenance of QoL. Of note, there was no worsening of the QoL in the combination oral TKI with chemotherapy arm as compared to the gefitinib-alone arm in the NEJ009 study.

The major stumbling blocks to the widespread use of osimertinib are accessibility and affordability. As of June 30, 2020, osimertinib in the first-line setting for EGFR-mutated lung cancer is approved in 78 out of 195 countries including the United States, China, Japan, and the European Union. Public funding is available in only 17 of these countries. The exceedingly high cost of the medicine severely limits its use. Recently, the National Institute for Health and Care Excellence did not approve the use of osimertinib for the first-line treatment of patients with EGFR-mutated NSCLC; the Institute ruled that the cost-effectiveness estimates for osimertinib were beyond the resources of the National Health Services.¹⁵ The affordable and widely accessible generics available for the early-generation oral TKIs as well as chemotherapy allows for their use in most countries.

The Pan-Asian Adapted European Society for Medical Oncology Guidelines have included the combination of an oral TKI with chemotherapy in the first-line setting for patients with EGFR-mutated lung cancer.² Thus, this combination, in our view, is ready for primetime use.

Table 1. Randomized Trials Conducted to Evaluate the Addition of an EGFR-Directed Oral TKI to Chemotherapy in Patients With Non-Molecularly Driven Advanced NSCLC

Acronyms: AE, adverse event; AUC, area under the curve; D, day; erlo, erlotinib; GC, gemcitabine + carboplatin; IQR, interquartile range; No., number; OR, odds ratio; ORR, objective response rate; PS, performance status ; PFS, progression free survival, OS, overall survival; QoL, quality of life; TOI, trial outcome index; TRAE, treatment-related adverse events; EGFR, epidermal growth factor receptor; AUC, area under the curve; HR, hazard ratio; CI, confidence interval; NR, not reported; NSCLC, non-small-cell lung cancer; AE, adverse events; FACT-L, Functional Assessment of Cancer Therapy-Lung

Table 2. Randomized Trials Conducted to Evaluate the Addition of an EGFR-Directed Oral TKI to Chemotherapy in Patients With EGFR-Mutated Advanced NSCLC

Acronyms: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; C, concurrent; D, day; erlo, erlotinib; gr, grade; G, gefitinib; GC, gemcitabine plus carboplatin; GCP, gefitinib plus carboplatin plus pemetrexed; IQR, interquartile range; No., number; NR, not reported; ORR, objective response rate; PFS, progression free survival, OS, overall survival; NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor; P, pemetrexed; PS, performance status; Q, every; QoL, quality of life; SA, sequential alternating; TOI, trial outcome index; TRAE, treatment-related adverse events; HR, hazard ratio; CI, confidence interval

References:

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15. National Institute for Health and Care Excellence. Osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer. Accessed July 2, 2020. https://www.nice.org.uk/guidance/TA621/chapter/1-Recommendations