By: Nick Turner, PhD, Senior Director Activating mutations in the EGFR gene are found in about 10-12% of all non-small cell lung cancer (NSCLC) cases and around 50% of cases in East-Asian patients. Cancer in patients with mutations is driven by constitutive activation of EGFR-signaling pathways due to acquired mutations in the catalytic domain of the receptor rendering them amenable to EGFR-tyrosine kinase inhibition1.
Although poorly active in all-comer pivotal trials, first- and second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKI; erlotinib, gefitinib, afatinib, dacomitinib) elicit anti-tumor responses in approximately 75% of patients harboring activating mutations2. In Phase III trials in this subset of patients, EGFR-TKIs show superiority over platinum-based chemotherapy, with median progression-free survival (mPFS) of 9-15 months compared to 4-6 months2. The question of whether EGFR-TKIs extend overall survival (OS), however, remains contentious.
An OS benefit was not established in pivotal trials of first-generation agents, which has been attributed to crossover from the chemotherapy arm2. Whether second-generation inhibitors improve survival is also unclear. Although the second-generation afatinib did show an OS benefit in a combined analysis of the Phase III LUX-Lung 3 and 6 trials, it was in a subset of patients with activating del19 mutations and did not translate across to the broader EGFR-mutation-positive population3. An OS benefit was also reported for dacomitinib, although the comparator arm was the first-generation agent gefitinib and the p value of 0.044 is not particularly robust4.
Thus, the question of whether EGFR-TKIs improve OS compared to chemotherapy is unsettled, but better tumor responses, a significant PFS advantage over platinum-based chemotherapy, improved quality of life and a median OS of 27 months establish EGFR-TKIs as the standard of care in EGFR-mutation-positive NSCLC. Unfortunately, all patients will eventually develop resistance to first- and second-generation EGFR-TKIs, most commonly due to a T790M somatic mutation2.
The third-generation agent osimertinib was developed to address this resistance mechanism and couples high potency against both EGFR activating mutations and T790M resistance. It has shown impressive clinical efficacy in EGFR-driven NSCLC that has progressed on first-generation agents, reducing the risk of disease progression by 70% compared to platinum-based chemotherapy (mPFS of 10.1 months vs. 4.4 months, hazard ratio (HR) 0.3)5. The FLAURA trial also recently established osimertinib as a first-line agent, showing superiority to gefitinib on PFS (mPFS of 18.9 months vs. 10.2 months; HR 0.46, p<0.0001). The OS data are still immature, but the trend is positive (HR 0.63 NS)6.
Although these data could make osimertinib the treatment of choice in the first-line setting, they lead to a conundrum regarding the best sequencing of EGFR-directed therapy:
- Should treatment always be initiated with the most effective front-line agent (i.e., osimertinib)?
- Is afatinib the preferred agent in patients with EGFR del19 mutations?
- Should osimertinib be reserved for T790M-resistant disease?
- Does a first- or second-generation agent followed by osimertinib offer greater survival outcomes than osimertinib in the first line?
The last question remains a matter of debate, but there is some guidance in the literature:
- Pooled OS data from the AURA trials in patients who had progressed after first-line EGFR-TKI therapy showed that osimertinib resulted in a mOS of 26.8 months7. With mPFS on first- and second-generation agents averaging around 11 months2, this implies that the potential OS on gefitinib, erlotinib or afatinib followed by osimertinib is around 38 months.
- Similarly, a small hypothesis-generating study looking at survival after first-line afatinib reported that mOS had still not been reached in subjects who received subsequent osimertinib after more than 4 years of follow-up8.
Whether osimertinib front-line can rival or beat this extension of survival will become clear when final OS data from FLAURA report, possibly in 2019.
The counter-argument is that, outside of the clinical trial setting, only a minority of patients may move onto subsequent lines of therapy. This favors front-line use of the most effective agent – osimertinib. A key consideration for this opinion may be whether patients progressing on first-line osimertinib will have limited subsequent treatment options compared to patients progressing on first- or second-generation agents. It will therefore be important to determine whether responses to first- and second-generation agents are preserved in patients who progress on first-line osimertinib. Theoretically, as osimertinib targets the T790M resistance mutation, escape from inhibition is likely to follow a different path. To date, this seems to be linked to EGFR C797S mutation or MET amplification9. One might, as a result, anticipate that first-generation agents will have activity in osimertinib resistance, but this needs to be confirmed in clinical trials.
With respect to a potential role for immune checkpoint inhibition in EGFR-mutation-driven NSCLC, supporting data are scant, as the majority of pivotal trials have specifically excluded patients with EGFR/ALK mutations. Interest arises, however, from a subgroup analysis of Roche’s IMpower150 trial implying that mortality was reduced by 46% in subjects with EGFR/ALK mutations treated with the PD-L1 blocker atezolizumab in combination with bevacizumab and chemotherapy, compared to subjects that did not receive atezolizumab10. Although this has been used to suggest atezolizumab in combination with bevacizumab and chemotherapy could have clinically meaningful efficacy in EGFR/ALK-mutated NSCLC that has progressed after first-line TKI, the data fall a long way short of supporting the combination as an alternative to osimertinib. At the very least, these data require confirmation.
The findings from IMpower150 are also controversial in the sense that they run counter to the body of evidence indicating an inverse relationship between EGFR mutations and PD-L1 expression. Meta-analysis has shown that EGFR-mutant NSCLC is less likely to be PD-L1-positive and more likely to have lower PD-L1 expression than EGFR-wild-type disease11. Similarly, high tumor mutational burden (TMB), also proposed as a biomarker for PD1/PD-L1 response, is negatively associated with clinical outcomes to EGFR-TKIs in EGFR-mutant NSCLC12, while low TMB is associated with longer duration of response to EGFR-TKIs13. Thus, high PD-L1 expression and high TMB, which predict response to PD1/PD-L1 inhibitors, appear to be negative markers for response to EGFR-TKIs.
A recent meta-analysis of second-line pembrolizumab, nivolumab or atezolizumab supports this conclusion, showing checkpoint inhibitors do not beat chemotherapy on efficacy in EGFR-mutated NSCLC, in contrast to their effect in wild-type patients14. Similarly, response rates to EGFR-TKIs are lower in patients with strong PD-L1 expression11.
Although IMpower150 has been used to propose a role for atezolizumab in NSCLC with driver mutations, confidence intervals are wide and supporting evidence is lacking. At this point, all that can be said is that atezolizumab in combination with bevacizumab and chemotherapy does not appear to have a negative impact on OS in EGFR/ALK-mutation-driven NSCLC.
Taken together, the body of evidence so far does not support a role for PD1/PD-L1 inhibitor therapy in EGFR-mutation-driven NSCLC.
- Gazdar, A.F. “Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.” Oncogene, Vol. 28 (2009): S24-S31.
- Girard, N. “Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?” Future Oncology, Vol. 14 (2018): 1117-1132.
- Yang, J.C-H., et al. “Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.” Lancet Oncology, Vol. 16 (2015): 141-151.
- Mok, T.S., et al. “Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer and EGFR-Activating Mutations.” Journal of Clinical Oncology, Vol. 36 (2018): 2244-2250.
- Mok, T.S., et al. “Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer.” New England Journal of Medicine, Vol. 376 (2017): 629-640.
- Soria, J.C. “Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer.” New England Journal of Medicine, Vol. 378 (2018): 113-125.
- Mitsudomi, T. “Overall survival (OS) in patients (pts) with EGFR T790M-positive advanced non small cell lung cancer (NSCLC) treated with osimertinib.” ESMO 2017, Abstract 1348P.
- Sequist, L. “Subsequent therapies post-afatinib among patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC in LUX-Lung (LL) 3, 6 and 7.” ESMO 2017, Abstract 1349P.
- Rekamp, K.L. “Optimal Sequencing of EGFR TKI Therapy – 3rd Generation First.” WCLC 2018, Abstract PC04.02.
- Socinski, M.A., et al. “Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.” New England Journal of Medicine, Vol. 378 (2018): 2288-2301.
- Soo, R.A., et al. “Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer: Current controversies and future directions.” Lung Cancer, Vol. 115 (2018): 12-20.
- Cheng, M.L., et al. “Does TMB Impact the Effectiveness of TKIs in EGFR-Mutant NSCLC?” Clinical Cancer Research, published online on November 13, 2018.
- Offin, M.D., et al. “Tumor mutation burden and efficacy of targeted therapy in patients with EGFR mutant lung cancers.” ASCO 2018, Abstract 9042.
- Lee, C.K., et al. “Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non–Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis.” JAMA Oncology, Vol. 4 (2018): 210-216.