Tyrosine kinase inhibitors (TKIs) that inhibit the EGFR are now standard of care for first-line treatment in patients with metastatic, non-squamous NSCLC whose tumors harbor an EGFR mutation (Figure 1A). Randomized trials have shown that patients experience superior overall response rates (ORR) and progression-free survival (PFS) when treated with EGFR TKIs versus chemotherapy for first-line therapy [erlotinib: EURTAC (4), OPTIMAL (5); gefitinib: NEJGSG_ 002 (6), WJTOG 3405 (7), IPASS (8, 9); afatinib: LUX LUNG 3 (10, 11), LUX LUNG 6 (11, 12)].

Erlotinib and gefitinib are first generation TKIs, while afatinib is a second generation TKI. Second generation TKIs block more ligands of the HER family and are non-competitive inhibitors at the kinase site so confer a longer period to resistance (13). Patient performance status, comorbidities, and age come into play in the decision making. EGFR mutation subtype is also important to consider. Unlike chemotherapy, TKIs are continued past progression as long as there is a clinical benefit to the patient.

LUX LUNG 7, a recently reported randomized phase IIb trial, compared afatinib to gefitinib in patients with advanced NSCLC and common EGFR mutations (14). The coprimary endpoint of PFS hazard ratio (HR) was met for superiority of afatinib, HR = 0.73 (p = 0.0165). This benefit was independent of mutation subtype. Response rate (RR), a secondary endpoint, was 70% versus 56% (HR = 1.873, p = 0.0083) favoring afatinib. Toxicities were as expected, with a preponderance of diarrhea and rash for afatinib and transaminitis for gefitinib. The overall survival (OS) was 3 months longer for afatinib (27.9 versus 24.5 months) but did not meet statistical significance [HR: 0.86 (95% CI: 0.66–1.12), p = 0.2580] (15). ARCHER 1050, a 452 patient phase III randomized trial of first-line treatment of EGFR-positive NSCLC comparing gefitinib with dacomitinib, will shed light on the question of which EGFR TKI is superior (16).

The inhibition of both EGFR and angiogenesis pathways deserves comment. The results of a randomized phase II trial from Japan illustrated a benefit for the combination erlotinib–bevacizumab over erlotinib for common EGFR mutations (17). Median PFS for the combination was 16.0 versus 9.0 months for erlotinib monotherapy, with no statistical difference in RRs or OS (18). In June 2016, the European Commission approved the combined use of erlotinib and bevacizumab for the first-line treatment of EGFR positive NSCLC patients. A larger phase III trial of this EGFR TKI–bevacizumab combination is needed to confirm and quantify the benefit (18).

An acquired mutation in EGFR exon 20, T790M, which leads to drug resistance, may be found in up to 60% of patients progressing on TKIs (19). Repeat testing for mutations is now recommended. Testing plasma cell free (cf) DNA has been suggested as an alternative to repeat biopsy. Different testing platforms are being developed and validated, and concordance between cfDNA and tumor tissue is improving (20–23). Patients who initially test negative for the presence of a T790M mutation by cfDNA testing should undergo a tumor rebiopsy. Biopsy is still considered to be the gold standard for T790M molecular testing.

For patients with a T790M positive disease, third generation EGFR TKIs have demonstrated RRs of over 60% and prolonged PFS, resulting in the approval of osimertinib (AZD9291) in several countries. Pooled results from AURA phase I and II trials was recently presented, which evaluated osimertinib in patients with T790M-positive disease who progressed on previous EGFR TKIs (24). Patients from the pooled cohort (n = 411) had a RR of 66%, and a PFS of 11 months (24, 25).

For patients without a T790M, second-line therapy is a chemotherapy doublet. Patients who are T790M mutation negative who progress on chemotherapy have few other options and may consider a clinical trial.

For patients whose tumors are positive for an ALK rearrangement, crizotinib is superior to standard chemotherapy. The phase III PROFILE 1014 trial randomized 343 treatment-naïve patients with advanced ALK rearrangement positive NSCLC to receive either crizotinib or intravenous chemotherapy (26). The primary endpoint of PFS was significantly longer in patients treated with crizotinib at 10.9 months as compared to those treated with chemotherapy at 7.0 months [HR: 0.45 (95% CI: 0.35–0.60); p < 0.001]. Overall RRs were 74% for crizotinib and 45% for chemotherapy (p < 0.001). Median OS was not reached in either group due to cross-over [HR: 0.82 (95% CI: 0.54–1.26); p = 0.36] (26). Crizotinib was associated with a greater reduction in symptoms and better quality of life. As with other TKIs, crizotinib can be continued past progression if there is continuing clinical benefit to the patient.

New agents are proving valuable as second-line treatments for NSCLC patients with ALK-positive tumors. As the brain is a frequent site of metastasis for patients with ALK-positive tumors, the intracranial activity of these agents is important to consider.

Patients with advanced NSCLC whose tumors do not have EGFR mutations or ALK rearrangements, or who have unknown mutation status, receive the standard of care: a platinum doublet (pemetrexed-based preferred) for four to six cycles (see Figure 2A). The Scagliotti trial demonstrated that NSCLC patients with adenocarcinoma experience greater benefit when treated with cisplatin/pemetrexed than with cisplatin/gemcitabine in the first line [OS: 12.6 versus 10.9 months; HR: 0.84 (95% CI: 0.71–0.99); p = 0.033] (1, 43).

Maintenance therapy is administered after completion of first-line therapy but before disease progression. The PARAMOUNT trial demonstrated that pemetrexed maintenance after first-line chemotherapy significantly reduced disease progression over placebo for patients with non-squamous tumor histology (44). Studies have shown that pemetrexed improves both PFS and OS when administered as maintenance therapy (45). Although erlotinib was also an accepted option for switch maintenance based on the SATURN trial (46), the IUNO trial (HR: 1.02; 95% CI: 0.85–1.22; p = 0.82) did not support these results. As a consequence, erlotinib is no longer considered as a maintenance option for people with negative or unknown tumor mutation status (47).

The most important change in the NSCLC treatment paradigm has been the introduction and success of PD-L1 immune checkpoint inhibitors. The programmed cell death receptor (PD-1) is an inhibitory receptor on T lymphocytes that binds PD-L1 and PD-L2 ligands. When ligands PD-L1 and PD-L2 bind, the immune response is suppressed. PD-L1 overexpression by tumor cells allows them to escape T cell detection. Monoclonal antibodies targeting PD-1 or PD-L1 can lead to reactivation of the T lymphocyte and stimulate the natural immune response against tumor cells. Patients tested for PD-L1 overexpression can be categorized into PD-L1 expressers (≥1% expression) and non-expressers (<1% expression).

Trials evaluating three immunotherapy agents targeting the PD-1 pathway in NSCLC patients have demonstrated durable clinical activity and manageable toxicity (48–51).

Now that checkpoint inhibitors are used in the second line, the previously second-line therapies become third-line options for patients whose tumors are mutation negative or mutation unknown. Options include docetaxel (54), erlotinib (55), and pemetrexed (56). Pemetrexed can only be prescribed if it was not used in first line or maintenance therapy. The REVEL trial showed a benefit of adding the angiogenesis inhibitor ramucirumab to docetaxel, with PFS of 10.5 months for the combination versus 9.1 months for docetaxel alone (HR: 0.86; p = 0.23) (57).

It follows from above that fourth line therapies may include whatever agents were not administered in previous lines. A significant limitation of therapy selection is that no trials have tested these different agents in later lines of therapy. Patients with satisfactory performance status can be considered for clinical trials.

With many investigational agents in development, it is enticing to speculate what future treatment algorithms for patients with non-squamous NSCLC, mutation negative, or unknown mutation status (see Figure 2B).