Phase I and phase Ⅱ clinical trials of icotinib monotherapy
Before icotinib came into the market, several phase I / Ⅱ clinical trials (Zhao et al. 2011; Liu et al. 2009; Zhang et al. 2009; Ruan et al. 2012; Ren. 2011; Zhou. 2010) have fully investigated its tolerability, safety, human pharmacokinetics, usage and dose exploration and optimization for advanced NSCLC, efficacy and safety, etc. In a phase I clinical trial exploring the safety and tolerability of a single oral dose of icotinib in healthy volunteers, none of the 75 healthy subjects had test drug-related adverse events (AEs), all AEs were below grade Ⅱ and abnormal indicators returned to normal during the observation period. In a single-center, open, three crossover phase I clinical trial exploring the pharmacokinetics of icotinib tablets in healthy volunteers, after 10 days of treatment, only 3 of 12 healthy volunteers had 4 mild, transient AEs. According to the test results, the peak time is about 1–3 hours and the half-life period is about 6 hours, it showed good linear absorption characterization and tolerability between 100mg and 600 mg. In a two-phase, cross, randomized, open stage I clinical trial observing the pharmacokinetic effects of dietary intake on icotinib in healthy volunteers, plasma samples were collected and analyzed after drug administration in fasting and postprandial states respectively, the results showed that postprandial medication can significantly increase absorption, decrease clearance rate, but had no significant effect on peak time, and had good tolerance.
Another included two independent phase I/ Ⅱa clinical trial of safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of icotinib administered repeatedly at two centers in patients with advanced lung cancer (Ren. 2011; Zhou. 2010), a total of 109 patients were enrolled in phase I and Ⅱ clinical trials. After initial confirmation of the safe and effective dose in phase I, the number of participants in this dose group was expanded and the efficacy and safety were observed. The results showed that, icotinib was safe, and its AEs did not exceed grade Ⅱ, only 3 patients had rash of grade Ⅱ or above, and a few patients had transient transaminase increase, which no need for drug withdrawal or clinical treatment. Treatment-related adverse reactions occurred about 1 week after medication, which were transient and lasted about 2–3 weeks. In the known safe and effective dose group, the disease control rate (DCR) was 78.1%, the objective response rate (ORR) was 29.2%, and three patients achieved complete response (CR). Thus, it was shown that icotinib appeared to be safer and more effective than other EGFR-TKIs. The usage of 125 mg, three times daily is recommended for the later clinical trials.
Phase Ⅲ clinical trials and second / third-line treatment
In view of the above phase I / Ⅱ clinical trials, a randomized, double-blind phase Ⅲ, non-inferiority clinical trial ICOGEN (Shi et al. 2013) led by Professor Shi Yuankai was conducted in 27 hospitals nationwide, gefitinib was used as positive control in this trial. A total of 400 patients aged 18–75 years with advanced NSCLC who had previously failed one or more platinum-based chemotherapy were enrolled between February 26, 2009 and November 13, 2009, they were treated with icotinib or gefitinib respectively. The results showed that the PFS of icotinib group is not lower than that of gefitinib group, with a median PFS of 4.6 months versus 3.4 months, p = 0.13. There was no significant difference in median time to progression(TTP) between the two treatments (5.2 months [95% CI 3.6–6.6] in icotinib group vs 3.7 months [2.5-5.0] in gefitinib group, p = 0.065). By December, 2011, 324 patients had died, 56 (28%) in the icotinib group and 70 (36%) in the gefitinib group with progression had received subsequent therapies. Overall survival (OS) was similar for icotinib and gefitinib (166 [83.4%] patients died in the icotinib group vs 158 [80.6%] patients in the gefitinib group). Median OS was 13.3 months (95% CI 11.1–16.2) in the icotinib group versus 13.9 months (11.4–17.3) in the gefitinib group, p = 0.57. Rash and diarrhea were the most common adverse events, with 41%, 22% in the icotinib group and 49%, 29% in the gefitinib group, AEs was lower in icotinib group than gefitinib group (61% vs 70%, P = 0.046 ). In conclusion, icotinib is not inferior to gefitinib and can be used in the second / third line treatment of advanced NSCLC. EGFR mutants were more likely to benefit than non-mutants. Thus, the China Food and Drug Administration approved it for the second-line or later treatment of locally advanced / metastatic NSCLC in which at least one chemotherapy regimen had failed.
After this, Hu Xingsheng et al (Hu et al. 2015) conducted a study designed to evaluate the efficacy and safety of icotinib in the treatment of patients with advanced NSCLC who previously received platinum-based chemotherapy. A total of 128 patients were enrolled from 15 centers nationwide and received 125mg icotinib three times a day. The primary endpoints of the study is PFS, the secondary endpoints are OS, TTP, ORR, safety, etc. The median PFS and TTP was 5.0 months and 5.4 months, the ORR was 25.8%, the DCR was 67.7% and the median OS was over 17.6 months (95%CI 14.2m-NA). The most common treatment-related AEs were rashes (26%), diarrhea (12.6%) and elevated transaminase (15.7%). This study further verifies the safety and effectiveness of icotinib in second / third line treatment for advanced NSCLC with previous chemotherapy failure (Hu et al. 2015), and compared with ICOGEN (Shi et al. 2013), the security is better.
Phase Ⅳ clinical trials and first-line treatment in advanced NSCLC
In view of the previous efficacy and safety validation, a phase Ⅳ clinical trial ISAFE (Hu et al. 2014) for safety monitoring was conducted after the marketing of icotinib, it aims to evaluate the safety and efficacy of icotinib in a wide range of patients with advanced NSCLC. A retrospective study of 6087 advanced NSCLC patients who were inoperable and/or relapsed treated with icotinib. The primary endpoint is safety, the secondary endpoints are ORR and DCR, EGFR mutations and elderly patients were stratified. The results showed that, a total of 5549 patients were evaluated for safety and efficacy, with a median age of 63 years, 28.3% of whom were over 70 years old, and most of them were stage Ⅳ adenocarcinoma without smoking history. The overall incidence of AEs was 31.5%, rash (17.4%) and diarrhea (8.5%) were the most common AEs, and interstitial lung disease occurred in 3 patients. The ORR and DCR of first-line, second-line and third-line, multiline subpopulations were 33.4% and 81.2%, 30.3% and 80.3%, 30.4% and 89.3%, respectively. For all evaluable patients, the ORR and DCR were 49.2% and 92.3%. In addition to extend the experience of applying icotinib to more representative subpopulations, this large phase Ⅳ study of more than 6000 patients also confirmed the acceptable safety and favorable efficacy of icotinib in a broad NSCLC population, further confirmed the results of ICOGEN.
Another phase Ⅲ clinical study CONVINCE(Shi et al. 2017), enrolled 296 patients with EGFR mutation stage Ⅲ/Ⅳ lung adenocarcinoma, the patients were randomly divided into icotinib group (148 cases) and chemotherapy group (137 cases). The treatment regimen was either oral icotinib or cisplatin combined with pemetrexed 3-week chemotherapy for a maximum of 4 cycles, pemetrexed was maintained for patients without progression until disease progression or toxicity intolerance. The primary endpoint is PFS. Results showed that PFS was significantly longer in the icotinib group (11.2 vs 7.9, P = 0.006), there was no significant difference in OS between the total population and EGFR mutation subgroup. The most common grade 3/4 AEs in the icotinib group were rash and diarrhea, the chemotherapy group were nausea, vomiting and blood decline. AEs and treatment-related AEs in the icotinib group were significantly lower than chemotherapy group: 79.1% vs 94.2%, P < 0. 001 and 54.1% vs 90.5%, P < 0.001. This study confirmed that, for patients with EGFR mutation advanced lung adenocarcinoma, icotinib has better efficacy and less side-effects than cisplatin/ pemetrexed plus pemetrexed maintained first-line chemotherapy. Icotinib can be the standard first-line treatment regimen. Thus, icotinib was approved for the first-line treatment of advanced NSCLC with EGFR mutation.
A multicenter randomized controlled trial of the first-line treatment for brain metastasis patients BRAIN (Yang et al. 2017) enrolled 176 patients with EGFR-mutated advanced NSCLC with initial treatment/second-line brain metastases. Patients were divided into icotinib monotherapy group or whole brain radiotherapy (WBRT) combined with synchronous/sequential chemotherapy group, with 85 patients and 91 patients respectively. Stratified according to EGFR status, number of treatment lines, craniocerebral metastasis status and presence of cranial hypertension symptoms. The primary endpoint was intracranial progression-free survival (iPFS), the median follow-up time was 16.5 months. The results showed that, the iPFS of icotinib group and WBRT group were 10 months vs 4.8 months, respectively. Grade 3 and above AEs in icotinib group were significantly less than WBRT group (8% vs 38%). The mortality rate was 49% in icotinib group and 51% in WBRT group, one patient in WBRT group died of chemotherapy-related thrombosis. It shows that, compared with WBRT combines with chemotherapy, icotinib significantly prolonged iPFS and PFS, improved ORR and DCR in NSCLC patients with EGFR-mutant with multiple brain metastases, it can be considered a better first-line choice.
Postoperative adjuvant trerapy
With the publication of research results such as ADJUVANT and EVAN (Zhong et al. 2017; Yue et al. 2018), postoperative adjuvant targeted therapy has gradually been recognized. But it still faces some confusion, such as the order of medication, the time of medication, the timing of medication, etc. The five postoperative adjuvant targeted therapy trials of icotinib are fully covered, and these confusions will be answered in the future.
Exploration of the adjuvant treatment of icotinib monotherapy
A study named EVIDENCE(He et al. 2021) led by Professor Zhou Caicun is aiming to evaluate the efficacy and safety of icotinib in adjuvant treatment of EGFR-mutated NSCLC. A total of 322 patients who were all stage Ⅱ-ⅢA postoperative were enrolled, they were randomly assigned to the icotinib treatment group for 2 years or the control group for 4 cycles standard adjuvant chemotherapy until recurrence, intolerance or death, and the control group crossed over to the icotinib group after recurrence. The primary end point is disease free survival (DFS), the secondary end points are OS and safety. The interim analysis of the study shows 40 (26%) of 151 patients in the icotinib group and 58 (44%) of 132 patients in the chemotherapy group had disease relapse or death. Median DFS was 47.0 months (95% CI 36.4-not reached) in the icotinib group and 22.1 months (16.8–30.4) in the chemotherapy group (stratified hazard ratio [HR] 0.36 [95% CI 0.24–0.55]; p < 0·0001). 3-year DFS was 63.9% (95% CI 51.8–73.7) in the icotinib group and 32.5% (21.3–44.2) in the chemotherapy group. OS data are immature with 14 (9%) deaths in the icotinib group and 14 (11%) deaths in the chemotherapy (HR 0.91 [95% CI 0.42–1.94] in the full analysis set). Treatment-related serious AEs occurred in two (1%) of 156 patients in the icotinib group and 19 (14%) of 139 patients in the chemotherapy group. The interim analysis results suggest that compared with chemotherapy, icotinib significantly improves DFS and has a better tolerability profile in patients with EGFR-mutant stage Ⅱ-ⅢA NSCLC after complete tumour resection. Based on this, the new indication for post-operative adjuvant therapy of icotinib was approved.
Exploration of sequential adjuvant treatment mode between icoctinib and chemotherapy
An ongoing phase Ⅲ clinical trial ICWIP (BD-IC-IV59, NCT02125240) recruited 124 EGFR-mutant stage Ⅱ-ⅢA lung adenocarcinoma patients aged 18–75 years who had previously received complete surgical resection and standard platinum-based dual chemotherapy from June 3, 2014 to November 15, 2018, they received icotinib or placebo for 36 months and were observed for 3 years, the primary endpoint is DFS and the secondary endpoints are 3-year DFS and safety, etc.
Another multicenter, randomized, prospective, open phase Ⅲ clinical study ICTAN (GASTO1002, NCT01996098) initiated by Sun Yat-sen University, was conducted in patients with stage ⅡA-ⅢA EGFR-mutated NSCLC who completed adjuvant chemotherapy (4 cycles platinum-based) after complete resectionis. At present, 318 patients were recruited and randomly divided into two groups in which patients were given icotinib (125mg three times a day) orally for 6 months or 12 months, respectively. DFS, OS, safety and tolerability were observed, the trial is still in progress now, and the results are remarkable.
Exploration of duration of icotinib adjuvant treatment
A multicenter, randomized, controlled, phase II trial BD-IC-IV50 (NCT01929200) conducted by Professor Yang Yue and Professor Lv Chao's team from Peking University Cancer Hospital is about postoperative adjuvant therapy with icotinib for EGFR-mutant NSCLC for 2 years versus 1 year. A total of 120 stage Ⅱ-ⅢA patients after resection were enrolled, the primary end point is PFS and the secondary end point is OS. The first patient was enrolled in September 2013. At present, the enrollment of this study is nearly completed, and more than half of the patients have completed experimental medication and entered the follow-up period.
Study on the safety of icotinib in adjuvant therapy
ICAPE (BD-IC-IV57, NCT02044328), a clinical study to explore the efficacy and safety of icotinib in postoperative adjuvant treatment of stage Ⅱ-ⅢA EGFR-mutant lung adenocarcinoma. Ten units in North China are involved and 80 patients have been enrolled so far. The experimental group: postoperative adjuvant treatment with icotinib for 18 months. The primary endpoint was DFS. Currently, the study enrollment has been completed, and follow-up results are in progress.
The above five studies will answer the difficult questions of adjuvant targeted therapy at the present stage, and the results are expected to be announced!
Effective targeted therapy can regain surgical resection opportunities for some patients with advanced lung cancer. In addition, surgery can provide complete pathological tissue and lay a comprehensive and accurate foundation for subsequent treatment. Targeted neoadjuvant therapy has high feasibility and low cost, and the comprehensive treatment model of combination of the two treatment can increase the chance of curing advanced lung cancer.
A phase Ⅱ clinical study EMERGING-CTONG1103 (Zhong et al. 2019), comparing the efficacy of erlotinib and gemcitabine combined with cisplatin in the neoadjuvant treatment of untreated EGFR-mutant ⅢA-N2 NSCLC, confirmed the feasibility and potential efficacy of neoadjuvant TKI.
In addition, clinical trials related to EGFR-TkIs including icotinib as neoadjuvant therapy are under way, and the results still need to be awaited. Study BD-IC-IV82 (NCT03749213), designed to evaluate the efficacy and safety of icotinib neoadjuvant treatment in patients with EGFR-mutant, radical surgical resection stage ⅢA-N2 NSCLC, 36 patients are expected to be enrolled, with preoperative icotinib for 8 weeks as neoadjuvant therapy and continue receiving icotinib as postoperative adjuvant therapy for 2 years, or disease progression, intolerant toxic side effects. The main observation index is ORR, the secondary indicators are DCR, OS, treatment-related AEs, etc. Another clinical trial BD-IC-IV81 (NCT03349203) designed to evaluate the ORR of lung and metastatic lesions after preoperative treatment with icotinib for EGFR-mutant stage ⅢB or oligometastatic NSCLC. Patients who are likely to undergo radical surgery were given oral icotinib 125mg, 3 times daily for 8 weeks as neoadjuvant therapy, and postoperative adjuvant therapy of icotinib was continued for 2 years. 60 patients are expected to be enrolled, the primary endpoint is ORR and the secondary endpoints are DCR, TTP, treatment-related AEs, etc. There is also an open, multicenter, single-arm phase Ⅱ trial RIPOT1606 (NCT02820116), designed to evaluate the efficacy and safety of icotinib neoadjuvant therapy for EGFR-mutant stage ⅢA-ⅢB NSCLC. A total of 67 resectable patients will be included and preoperative oral icotinib for 8 weeks, postoperative oral icotib for 2 years, or disease progression and toxicity was intolerable. The main observation indicator is complete resection rate, and the secondary indexes are ORR, OS, AEs, etc. The three trials above are ongoing and the results are very promising, they are expected to add new treatment indications.
Consolidate / maintenance therapy
For patients with stage Ⅳ NSCLC, if the efficacy of first-line chemotherapy is complete remission (CR), partial remission (PR) or stable disease (SD), the maintenance treatment can be followed. The INFORM study (Zhang et al. 2012) and the SATURN study (Cappuzzo et al. 2010) established the status of gefitinib and erlotinib as maintenance therapy for advanced NSCLC. A clinical trial of icotinib as consolidation therapy CH-L-069(NCT03396185) is currently underway, the objective of this study is to evaluate the relapse free survival (RFS) of patients with EGFR-mutant stage ⅢA-ⅢB NSCLC who are given icotinib as consolidation therapy after either concurrent or continuous radiotherapy and chemotherapy. 30 patients with unresectable EGFR-mutant stage ⅢA-ⅢB lung adenocarcinoma will be enrolled and treated with icotinib as consolidation therapy after synchronous/ sequential radiotherapy and chemotherapy. The primary endpoint is RFS, the secondary endpoints are OS, treatment-related AEs. The results are also worth looking forward to. It will confirm that advanced NSCLC with EGFR-mutant controlled by first-line chemotherapy may be treated with icotinib as consolidation therapy.
According to CONVINCE, LUX-Lung6, ICOGEN (Zhou et al. 2011; Wu et al. 2014; Shi et al. 2013) et al study, median PFS in NSCLC patients with EGFR 19DEL mutation was longer than that in the 21L858R group. A phase Ⅱ clinical trial INCREASE(Li et al. 2020) aimed to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in patients with NSCLC harboring 21-L858R mutation. A total of 269 patients with treatment-naive, EGFR-mutant (21-L858R or 19 DEL) NSCLC were enrolled, 186 patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125 mg, thrice daily; L858R-RD) or high-dose icotinib (250 mg, thrice daily; L858R-HD), including 86 in L858R-RD group and 90 in L858R-HD group, whereas 77 patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median PFS (mPFS). The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months) and was significantly longer than that in L858R-RD group (12.9 months vs 9.2 months, HR: 0.75; 95% CI 0.53–1.05). A longer but statistically nonsignificant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI, 0.57–1.13). A higher ORR was observed in L858R-HD group compared with L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups. Conclusions: High-dose icotinib improved mPFS and ORR in patients with NSCLC harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population.