In an article published in 2016 in World Journal of Research and Review one of the conclusions was that “because of a veritable cascade of the new drugs (small molecules, immunotherapeutic agents), used in non-small cell lung cancer, the combinations of chemotherapy with tyrosine kinase inhibitors agents was in our opinion neglected, and the final results wait to be find. The incentive combinations are now cytotoxic agents with immunotherapy or targeted therapy with immunotherapy”(1).
In this short review, I want to present again the issue of the association between tyrosine kinase inhibitors (TKIs) and chemotherapy in advanced non-small cell lung cancer (NSCLC).
New evidence of the efficacy of TKIs and chemotherapy combination
The impact of combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy as first-line therapy for patients with advanced NSCLC remains controversial. Therefore, randomized trials that compared this combined regimen with chemotherapy or EGFR-TKIs monotherapy were included for a meta-analysis performed in 2013. There were used published hazard ratios (HRs), if available, or derived-treatment estimates from other survival data. Pooled estimates of treatment efficacy of the combined regimen in the entire unselected population and selected patients by EGFR-mutation status and smoking history were calculated. Eight trials eventually entered into this meta-analysis, including 4585 patients. Overall, the combined regimen significantly delayed disease progression (HR=0.81; 95% CI; 0.69-0.95, P=0.01); the subgroup analysis showed significantly higher progression-free survival advantages in Asian patients (P<0.001), with sequential combination of TKIs and chemotherapy (P=0.02). In selected patients by EGFR-mutation, both mutation-positive (HR=0.48; 95% CI; 0.28-0.83, P=0.009) and mutation-negative (HR=0.84; 95% CI; 0.72-0.98; P=0.02), patients gained progression-free survival benefit from the combined regimen, albeit the magnitude of benefit was marginally larger in mutation-positive patients (P=0.05). In selected patients by smoking history, never/light smokers achieved a great progression-free survival benefit from the combined regimen (HR=0.51; 95% CI; 0.35-0.74, P=0.0004). Unfortunately, the combined regimen had no significant impact on overall survival, irrespective of ethnicity, dose schedules or EGFR-mutation status. Severe anorexia (RR=2.01; 95% CI; 1.11-3.63; P=0.02) and diarrhea (RR=2.70; 95% CI; 1.94-3.76; P<0.001) were more frequent in the combined regimen arm. This strategy of combining EGFR-TKIs and chemotherapy deserves to be considered in the future, although at the moment it is not approved for advanced NSCLC(2).
Another meta-analysis was done, including nine randomized controlled trials, with a total of 3599 patients included. Compared to chemotherapy alone, chemotherapy plus erlotinib was superior in progression-free survival (HR=0.76; 95% CI; 0.62-0.92, P=0.006), and no statistically significant difference was observed in overall survival (HR=0.94; 95% CI; 0.86-1.03; P=0.16). Intercalated erlotinib plus chemotherapy demonstrated improvements in progression-free survival (HR=0.67; 95% CI; 0.50-0.91; P=0.009) and overall survival (HR=0.82; 95% CI; 0.69-0.98, P=0.03). Continuous erlotinib plus chemotherapy treatment failed to demonstrate improvements in progression-free survival (HR=0.91; 95% CI; 0.80-1.04; P=0.16) and overall survival (HR=0.98; 95% CI; 0.89-1.09; P=0.75). The association of chemotherapy plus erlotinib with improvement in progression-free survival was significant in never smoking patients (HR=0.46; 95% CI; 0.37-0.56; P<0.00001), but not in smoking patients (HR=0.70; 95% CI; 0.49-1; P=0.05). Among patients with EGFR-mutant tumors, chemotherapy plus erlotinib demonstrated significant improvements in progression-free survival (HR=0.31; 95% CI; 0.17-0.58; P=0.0002) and overall survival (HR=0.52; 95% CI; 0.30-0.88; P=0.01). Among patients with EGFR wild-type tumors, no statistically significant difference was observed, with respect to progression-free survival (HR=0.87; 95% CI; 0.70-1.08; P=0.21) and overall survival (HR=0.78; 95% CI; 0.59-1.01; P=0.06).
The combination of chemotherapy and erlotinib is a viable treatment option for patients with NSCLC, especially for patients who have never smoked and patients with EGFR mutation-positive disease. In addition, intercalated administration is an effective combinatorial strategy(3).
Another attempt to resolve this issue of TKIs and chemotherapy combination was the review published in 2018. E.H.A. Sim et al. searched for relevant trials up to 17 February 2017(4). There were a total of 35 studies conducted between 2000 and 2017, evaluating 12,089 participants, from different countries, including North America, Europe and Asia. This review showed that patients with advanced lung cancer did not live longer when treated with gefitinib, when compared with no other treatment or chemotherapy. In patients whose lung cancer worsened after the initial therapy, gefitinib may prolong the time before the cancer progresses further, but only in a selected group of patients of Asian ethnicity or with EGFR mutations. Combining gefitinib with chemotherapy probably increases the interval to cancer progression over either gefitinib, or chemotherapy alone. For EGFR-mutation positive patients who are stable after chemotherapy, ongoing gefitinib has been shown to improve survival when compared to placebo. Severe side effects – such as low red and white blood cell counts and nerve symptoms – occurred more frequently in patients with chemotherapy compared to those with gefitinib. The side effects caused by gefitinib included skin rash, diarrhoea and liver dysfunction. The quality of life may be improved in favour of gefitinib when compared with chemotherapy.
The authors concluded that combining gefitinib with chemotherapy appears to be superior in improving progression-free survival to either gefitinib or chemotherapy alone; however, further data and phase III studies in these settings are required(4). To explain the behaviour of the tumors response to epidermal growth factor receptor (EGFR) inhibitors and chemotherapy, when they are associated, there were performed some basic studies. In one of this study(5), the aim was to detect the EGFR gene type at pre- and post-chemotherapy, in order to evaluate the impact of platinum-based chemotherapy on EGFR gene mutations and to provide a theoretical foundation for clinical treatment.
Y. Wang et al. concluded that: “Around 40 serum DNA samples were collected from advanced non-small cell lung cancer, patients who received platinum-based chemotherapy as first-line treatment in our hospital, from August 1st, 2014 to June 1st, 2015. The EGFR gene exons 19 and 21 were amplified by polymerase chain reaction (PCR) and detected by direct sequencing. The outcomes were analyzed with SPSS 17.0. Out of the 40 patients, 38 were included in the analysis. An EGFR gene mutation was detected in 17 cases (44.7%) at pre-chemotherapy, compared with 19 cases (50%) at post-chemotherapy. The EGFR gene mutation differences were not statistically significantly (P=0.165) during pre- and post-chemotherapy. The EGFR gene type was consistent in 26 cases (68.4%). Among the 12 discordant cases, 5 cases changed from mutant type to wild type, while 7 cases changed from wild type to mutant type. EGFR mutation-positive patients had a disease control rate (DCR) of 88.2% (15/17), whereas it was only 57.1% in EGFR mutation-negative patients, which was statistically significant (P=0.01), indicating a better curative effect in EGFR mutation positive patients”(5). The conclusion was that platinum-based chemotherapy may change the serum EGFR gene type in advanced lung adenocarcinoma(5).
At present, EGFR mutation is the strongest predictive biomarker for the efficiency of EGFR-TKIs. However, analyzing relevant research of the past 20 years, researchers found that the prognostic and predictive value of EGFR mutation status in NSCLC remains uncertain, and it is difficult to understand the precise mechanism by which cytotoxic agents influence EGFR-mutant and wild-type tumors differently.
In conclusion, the authors believe that the presence of EGFR mutations has an intrinsic relationship with the outcomes in patients with NSCLC. With improvements in technology for detecting gene mutations, some novel mutations in EGFR have been reported to be sensitive to TKIs, such as p.V765A, p.T783A, p.V774A, p.S784P and p.V769A. The role of EGFR should be evaluated in more detail in prospectively designed research, so that we can have a deeper understanding of the association of EGFR mutation with the curative effect and survival benefit of chemotherapy in the future(6).
An interesting study was published in August 2016, in the Journal of Clinical Oncology, by Cheng and colleagues. The study was analyzed by Antonio Rossi. This phase II study enrolled EGFR mutation-positive chemotherapy-naïve Asiatic advanced non-squamous NSCLC patients, with a 2:1 ratio, to receive concurrent pemetrexed, at the dose of 500 mg/m2 on day 1, every 3 weeks, plus continuous gefitinib, at the dose of 250 mg/day (n=129), versus gefitinib alone (n=66). The primary endpoint was progression-free survival, while secondary endpoints were TTP, overall survival, ORR, duration of response and toxicity. Most of the patients were women, never-smokers, with stage IV disease; 55% of the patients had exon 19 deletions, and 39% had exon 21 L858R point mutations – only 6% had uncommon mutations. The median progression-free survival was 15.8 months with the combination therapy versus 10.9 months in the gefitinib arm (HR=0.68; 95% CI; 0.48-0.96; P=0.029). The median TTP was 16.2 months for the combination arm and 10.9 months in the gefitinib arm (HR=0.66; 95% CI; 0.47-0.93; P=0.018). The ORR was 80% versus 74%, with a median duration of response of 15.4 versus 11.3 months (HR= 0.74; 95% CI; 0.50-1.08; P=0.122), respectively. The analyses of all these outcomes in the main subgroups were consistent with the intention-to-treat results. Overall survival was still immature. Grade ≥3 side effects were more frequent in the combination arm (mainly diarrhea, increased transaminases and dermatitis acneiform in the combination arm, and diarrhea, dermatitis acneiform and dry skin in the gefitinib-alone arm), being 42% versus 19% (P=0.001), respectively, with two toxic deaths (pneumonitis and interstitial lung disease) reported in the combination arm. The authors concluded that the combination of pemetrexed and continuous gefitinib may offer EGFR mutation-positive patients a new treatment option compared with the current standard of care(7). A common deletion polymorphism within B-cell chronic lymphocytic leukemia-lymphoma like 11 gene (BIM) was studied and deemed to be a genetic cause leading to compromised kinase inhibitor therapeutic efficacy in cancer individuals.
Hou-Qun Ying et al. published a comprehensive meta-analysis containing 12 eligible studies, including 1,532 Asian patients, conducted to investigate a steady and reliable conclusion. The results showed that BIM deletion polymorphism was significantly associated with tyrosine kinase inhibitor (TKI) clinical efficacy in term of response rate (Ph=0.349; HR=0.438; 95% CI=0.274-0.699) and disease control rate (Ph=0.941; HR=0.370; 95% CI=0.202-0.678) in EGFR-mutated NSCLC population, not in chronic myeloid leukemia (CML) and hepatocellular cancer (HCC) subgroups. Additionally, EGFR-mutated NSCLC patient harbored BIM deletion polymorphism was associated with a shorter progression-free survival (PFS) than in those with BIM wild polymorphism (Ph=0.580, adjusted HR=2.194, 95% CI; 1.710-2.814)(8).
Sixty-five patients were enrolled. Thirty-six of them received EGFR-TKIs and 29 received EGFR-TKIs plus chemotherapy. EGFR-TKIs plus chemotherapy had significantly higher ORR than TKIs alone (65.5% versus 38.9%, P=0.046). Median progression-free survival was significantly longer in EGFR-TKIs plus chemotherapy group than in TKIs group (7.2 versus 4.7 months; P=0.008). Median overall survival was numerically longer in EGFR-TKIs plus chemotherapy group than in TKIs alone (18.5 versus 14.2 months; P=0.107). EGFR-TKIs plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKIs alone.
In conclusion, the authors point out that EGFR-TKIs plus chemotherapy conferred a significantly higher ORR, prolonged progression-free survival and numerically longer overall survival in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism. Further prospective studies are needed to validate these findings(9). Analyzing these studies, it can be concluded that the association of TKIs and chemotherapy is not yet well defined, although many discoveries have been made, especially about molecular genetics, that have led to a more in-depth understanding of the possibilities of combining these therapies.
Conflict of interests: The author declares no conflict of interests.