1.INTRODUCTION 1.1 Background
2. PREDICTIVE BIOMARKERS OF DRUG SENSITIVITY
Several biomarkers, including EGFR expression as assessed by immunohistochemistry (IHC), changes in EGFR copy-number detected by fluorescent in situ hybridization (FISH) or quantitative PCR, and EGFR mutational status evaluated by sequencing or PCR, were identified and evaluated during the key trials which led to EGFR-TKIs approval in second-/third-line treatment for NSCLC [55]. However, controversial results were observed regarding the role of EGFR expression or gene amplification in the response to TKIs; thus,
their validity as predictive biomarkers in NSCLC patients remains controversial [35,46,56,57]. Conversely, clear evidences on the correlation between EGFR mutational status and EGFR-TKIs sensitivity made it the best predictor of clinical response to these targeting agents.
Table 1. Summary of randomized phase II and phase III trials of first-generation EGFR-TKIs in unselected NSCLC patients
Trial Phase Patients features Treatment ORR
(%)
Median PFS/TTP (months)
Median OS (months) Gefitinib
IDEAL-1
(ref #39) 2 210 patients with 1 or 2 prior CT regimens (at least 1 containing platinum)
Gefitinib 250 or 500
mg/day 18.4 (gef 250)
19.0 (gef 500) 2.7 (gef 250)
2.8 (gef 500) 7.6 (gef 250) 8.0 (gef 500) IDEAL-2
(ref #40) 2 221 patients who received at
least 2 prior CT regimens Gefitinib 250 or 500
mg/day 12.0 (gef 250)
9.0 (gef 500) NA
NA 7.0 (gef 250)
6.0 (gef 500) ISEL
(ref #43)
3 1692 patients who were refractory to or intolerant of their latest CT regimen
Gefitinib (250 mg/day) or placebo
8.0 (gef) 1.3 (pl)
3.0 (gef) 2.6 (pl)
5.6 (gef) 5.1 (pl)
INTACT-1
(ref #44) 3 1093 CT-naïve patients Cis/gem + gefitinib (250 or 500 mg/day) or placebo
50.3 (gef 250) 49.7 (gef 500) 44.8 (pl)
5.8 (gef 250) 5.5 (gef 500) 6.0 (pl)
9.9 (gef 250) 9.9 (gef 500) 10.9 (pl) INTACT-2
(ref #45)
3 1037 CT-naïve patients Carbo/pac+ gefitinib (250 or 500 mg/day) or placebo
30.4 (gef 250) 30.0 (gef 500) 28.7 (pl)
5.3 (gef 250) 4.6 (gef 500) 5.0 (pl)
9.8 (gef 250) 8.7 (gef 500) 9.9 (pl) INVITE
(ref #46) 2 196 CT-naïve patients (age >or=
70 years) Gefitinib (250 mg/day) or
vinorelbine 3.1(gef)
5.1(vin) 2.7 (gef)
2.9 (vin) 5.9 (gef) 8.0 (vin) INTEREST
(ref #47) 3 1466 patients who had 1 or more
prior platinum-based regimens Gefitinib (250 mg/day) or
docetaxel 9.1 (gef)
7.6 (doc) 2.2 (gef)
2.7 (doc) 7.6 (gef) 8.0 (doc) Erlotinib
BR.21
(ref #48) 3 731 patients who had 1 or 2 prior
CT regimens Erlotinib or placebo 8.9 (erl)
<1 (pl) 2.2 (erl)
1.8 (pl) 6.7 (erl) 1.8 (pl) TITAN
(ref #49)
3 424 patients who progressed after up to four cycles platinum-based CT
Erlotinib or CT (docetaxel or pemetrexed)
7.9 (erl) 6.3 (CT)
6.3 weeks (erl) 8.6 weeks (CT)
5.3 (erl) 5.5 (CT) SATURN
(ref #50)
3 889 patients with non-progressive disease following platinum-based CT
Erlotinib or placebo 11.9 (erl) 5.4 (pl)
12.3 weeks (erl) 11.1 weeks (pl)
12.0 (erl) 11.0 (pl) TRIBUTE
(ref #51)
3 1059 CT-naive patients Carbo+pac+ erlotinib or placebo
21.5 (erl) 19.3 (pl)
5.1 (erl) 4.9 (pl)
10.6 (erl) 10.5 (pl) TALENT
(ref #52) 3 1172 CT-naïve patients Cis+gem+ erlotinib or
placebo 31.5 (erl)
29.9 (pl) 23.7 weeks (erl)
24.6 weeks (pl) 43 weeks (erl) 44.1 weeks (pl) Carbo, carboplatin; cis, cisplatin; CT, chemotherapy; doc, docetaxel; erl, erlotinib; gef, gefinib; gem, gemcitabine; NA, not available; pac, paclitaxel; pl, placebo; vin, vinorelbine.
To date, several somatic EGFR mutations have been observed in NSCLC [58,59]. Importantly, multiple aberrations in the region of the EGFR gene encoding the TK-domain (exons 18-24) have been associated with the therapeutic response to EGFR-TKIs [59-61]. The exon 21 missense point mutation L858R and the in-frame deletions in exon 19 are the most frequently observed EGFR alterations in NSCLC. These mutations, also known as activating mutations, confer tumor cell dependency on EGFR signaling and are the most commonly studied predictive biomarkers of response to gefitinib and erlotinib [53,54,62] being observed in 15 to 40% of cases in several published studies [34,63-66]. Of note, sensitizing EGFR mutations are frequently found in certain subsets of patients such as females, Asian individuals, and non-smokers [34].
Other recurrent but less frequent EGFR mutations correlated with response to EGFR-TKIs include the point mutation G719S in exon 18 and the L861Q mutation in exon 21 [67].
Even though the ISEL study failed to demonstrate survival benefit with the use of gefitinib compared to best supportive care (BSC) in unselected patients, preplanned subgroup analyses revealed a significant increase in OS in both Asians (9.5 vs. 5.5 months; HR = 0.66; CI: 0.48-0.91; P = 0.010) and never-smokers (8.9 vs. 6.1 months; HR = 0.67; CI: 0.49-0.92; P = 0.012) when treated with gefitinib [43]. These results identified Asians and never-smokers as individuals who are more likely to benefit from EGFR-TKIs. The following Iressa Pan-Asia Study (IPASS) was designed in order to optimize gefitinib clinical response, comparing the TKI with carboplatin/paclitaxel as upfront treatment in lung adenocarcinoma patients who were light or never-smokers [61] (Table 2). This study enrolled more than 1200 patients and PFS was its primary endpoint. No significant difference in PFS was observed between the treatments. Interestingly, the retrospective EGFR mutation analysis revealed that mutations-positive patients took advantage from gefitinib treatment either in terms of RR (71.2% vs. 47.3%; P < 0.0001), and PFS (9.5 vs. 6.3 months; HR = 0.48; CI:
0.36-0.64; P < 0.0001). Of note, patients presenting wild-type EGFR who were treated with the TKI showed significantly lower RR (1.1% vs. 23.5%; P = 0.001) and worse PFS (1.5 vs. 5.5 months; HR = 2.85; CI: 2.05-3.98; P < 0.001). Therefore, IPASS results provided the missing link between EGFR mutational status and clinical response to EGFR-TKIs and represent a milestone toward personalized medicine. Based on the results of this trial, gefitinib has been recently approved in Europe as first-line treatment of patients harboring EGFR activating mutations. Furthermore, although no difference was observed between the treatments (OS, 18.8 months [gefitinib] vs. 17.4 months [carboplatin/paclitaxel]; HR = 0.90; P = 0.109), EGFR mutation-positive patients had longer OS independently from the received treatment (EGFR mutation-mutation-positive: 21.6 months [gefitinib] and 21.9 months [carboplatin/paclitaxel]; EGFR mutation-negative: 11.2 months [gefitinib]
and 12.7 months [carboplatin/paclitaxel]) [68]. Thus, the IPASS trial demonstrated that EGFR mutation-positive cases are a clinically distinct entity with a better prognosis compared to non-mutated NSCLCs.
Ultimately, despite the large and unpredictable inter-individual variability in toxicity, the IPASS trial demonstrated a more favourable tolerability profile for gefitinib when compared to chemotherapy [69].
Multiple trials enrolling patients selected on the basis of molecular and clinical characteristics were launched after the identification of patient features and EGFR mutational status as predictive biomarkers. A randomized phase II clinical study comparing erlotinib as single agent or in combination with carboplatin/paclitaxel in adenocarcinoma patients who were light or never-smoker, demonstrated the non-inferiority of the TKI alone, when compared to the combination, in terms of PFS (5.0 vs. 6.6 months, respectively; P = 0.1988). Of note, toxic effects (grade 3 to 4 hematologic and non-hematologic toxicity) were greater in the arm treated with the combination of erlotinib with chemotherapy. Similar to IPASS, this study identified EGFR mutation-positive patients as the most likely to benefit from both the treatments [70].
Recently, results from several phase III trials comparing gefitinib or erlotinib to standard chemotherapy as first-line setting for NSCLC patients with activating EGFR mutations have been reported (Table 2). In agreement with the IPASS findings, the randomized trials WJTOG3405 [71] and NEJ002 [72], comparing gefitinib to platinum-based chemotherapy as upfront treatment in prospectively identified EGFR-mutated NSCLC patients, reported advantage derived from the TKI treatment in terms of RR and PFS for this selected population. Similarly, erlotinib prolonged PFS and increased RR when compared to platinum-based chemotherapy in selected EGFR-mutated patients in the OPTIMAL [73] and EURTAC [74] prospective trials.
These results definitely validate the IPASS findings sustaining the efficacy of EGFR-TKIs in this setting.
Table 2. First-generation EGFR-TKIs versus chemotherapy as first-line treatment for NSCLC patients with activating EGFR mutations
Trial Patients features Treatment ORR
(%)
Median PFS/TTP (months)
Median OS (months) Gefitinib
IPASS
(ref #61,#68) 261 patients EGFR-mutation positive Gefitinib or carbo+pac 71.2 (gef)
47.3 (CT) 9.5 (gef)
6.3 (CT) 21.6 (gef) 21.9 (CT) WJTOG3405
(ref #71)
172 patients EGFR-mutation positive Gefitinib or cis+doc 62.1 (gef) 32.2 (CT)
9.2 (gef) 6.3 (CT)
30.9 (gef) NA NEJSG002
(ref #72) 230 patients EGFR-mutation positive Gefitinib or carbo+pac 73.7 (gef)
30.7 (CT) 10.8 (gef)
5.4 (CT) 30.5 (gef) 23.6 (CT) First-SIGNAL
(ref #75)
313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma
Gefitinib or cis+gem 55.4 (gef) 46.0 (CT)
5.8 (gef ) 6.4 (CT)
22.3 (gef) 22.9 (CT) Erlotinib
OPTIMAL (ref #73)
165 patients EGFR-mutation positive Erlotinib or carbo+gem
83.0 (erl) 36.0 (CT)
13.1 (erl) 4.6 (CT)
NA NA EURTAC
(ref #74) 174 patients EGFR-mutation positive Erlotinib or carbo/cis +
doc/gem 58.0 (erl)
15.0 (CT) 9.7 (erl)
5.2 (CT) 19.3 (erl) 19.5 (CT) Carbo, carboplatin; cis, cisplatin; CT, chemotherapy; doc, docetaxel; erl, erlotinib; gef, gefinib; gem, gemcitabine; NA, not available; pac, paclitaxel; pl, placebo.
Moreover, given the reduced toxicity, the improved quality of life and the rapid symptoms relieve with single agent TKI when compared to chemotherapy, the use of first-generation EGFR-TKIs has become the new standard of care for the upfront treatment of EGFR mutation-positive NSCLC patients. However, the recent South Korean randomized phase III trial First-SIGNAL comparing gefitinib to first-line chemotherapy in 309 Korean never-smokers with lung adenocarcinoma, failed to demonstrate any OS advantage (22.3 vs.
22.9 months, respectively; HR = 0.932; CI: 0.716-1.213; P = 0.604) derived from TKI treatment in this selected population [75] (Table 2).
In contrast, the Chinese study INFORM, comparing gefitinib to BSC as maintenance therapy in unselected NSCLC patients, reported a significantly longer PFS in the TKI treated arm with respect to placebo (4.8 vs. 2.6 months, respectively; HR = 0.42; P < 0.0001). Of note, consistent with other trials, EGFR-mutation positive patients took advantage the most from gefitinib maintenance treatment (median PFS: 16.6 vs. 2.7 months; HR = 0.16), but no difference in term of OS was reported [76]. On the other hand, maintenance therapy with erlotinib in the SATURN study achieved significantly improved PFS and OS among the overall patients. Interestingly, erlotinib was able to improve PFS in both EGFR mutated (HR = 0.10; CI: 0.04-0.25; P < 0.0001) and wild-type (HR = 0.78; CI: 0.63-0.96; P = 0.0185) patients [50]. Taken together, the results from INFORM and SATURN trials suggest that EGFR wild-type patients may benefit from EGFR-TKI maintenance therapy on the basis of the specific EGFR-TKI used.
Even though a large number of trials firmly established the predictive role of EGFR mutations as biomarkers of response to gefitinib or erlotinib, a small group of wild-type EGFR NSCLC patients also significantly benefits from the treatment with the EGFR-TKIs [77]. These findings suggest the existence of additional mechanisms involved in sensitivity or resistance to these agents in EGFR mutation-negative patients.