Selection of non-small cell lung cancer patients for intercalated chemotherapy and tyrosine kinase inhibitors

Soon after the discovery of activating mutations of epidermal growth factor receptor (EGFR) and of their crucial role in determining sensitivity to tyrosine kinase inhibitors (TKIs), several trials confirmed the advantage of TKIs in comparison to chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations.1-5 Due to higher response rate, longer time to progression and less toxicity, monotherapy with TKIs has been approved as the preferred first-line treatment for these patients. TKIs clearly improve short-term prognosis of patients with EGFR mutant lung cancer. Still, after a median interval of around one year, patients on treatment with TKIs develop resistance and experience disease progression.6 New treatments, either as first-line or at progression are needed.7

After huge disappointment due to four large negative trials of chemotherapy alone versus chemotherapy combined with continuous application of gefitinib or erlotinib8-11, the idea of combining TKIs with chemotherapy never fully recovered. Many research groups simply concluded that the two categories of drugs should not be used together and most of current pre-clinical and clinical research focuses on new drugs designed to overcome primary or acquired resistance to TKIs.12-14 The fact that the four trials were unselected regarding histology and smoking status received little attention. For a quarter of patients in the TRIBUTE trial, the status of EGFR mutations was later determined: when treated with the combination in comparison to chemotherapy alone, EGFR mutant patients had higher response rate and a trend towards longer progression-free survival (PFS), but no advantage in overall survival (OS).15

In spite of prevailing disappointment, some researchers insisted that the negative message of the four large trials should be accepted as new knowledge rather than ignored and developed the concept of intercalated treatment. The reasoning was clear: when applied concomitantly with chemotherapy, TKIs induce G1-phase cell-cycle arrest, due to which cell-cycle dependent chemotherapeutic agents will not be effective.16 Chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib was confirmed in vitro.17 Time separation with an interval of 6 days without TKIs to restore chemosensitivity of tumor cells should remove this mutual antagonism, so as to benefit from the efficacy of both classes of drugs.18 Additional support for the concept of intercalated treatment came from laboratory experiments and from a clinical trial of sequential application of chemotherapy and TKI: proper sequence starting with cytotoxic drugs, followed by TKIs leads to their synergistic activity.19-23

So far, a few dozen clinical trials on intercalated treatment with chemotherapy and TKIs have been published. A recent review focused on trials with randomization between intercalated schedules and chemotherapy alone.24 While such a review is definitively valuable, a reader is confused when facing a list of trials with a wide range of eligibility criteria, leading to diverging conclusions. This review paper has a different goal. We believe that before proceeding with further clinical research, we should understand which patients will most likely benefit from intercalated treatment. Only after defining the optimal target p opulation, future trials can be designed to compare intercalated treatment to the best standard treatment in those selected patients.

Most surveys and meta-analyses focus on the question of efficacy and/or toxicity of a particular new treatment in comparison with the standard approach. This was also the case with intercalated treatment for advanced NSCLC. On the basis of published randomized trials, a recent meta-analysis concluded that intercalated treatment is superior to the comparator arm.24 While this meta-analysis offered a valuable insight into an area which is not in the main stream of current clinical research, the question of efficacy of intercalated treatment is too complex to be answered by a simple comparison.

A critical look at all published trials reveals great heterogeneity in eligibility criteria including treatment-naive patients or those in progression after first-line therapy. In addition, we see a whole spectrum of biologically divergent disease: all histologic types or only non-squamous histology; exclusively EGFR-mutant disease, only EGFR-wt tumors or, in most trials, both groups. On such a heterogeneous basis and without considering the optimal standard therapy for a particular population of patients, the value of a new approach cannot be assessed. Is the intercalated treatment superior to chemotherapy alone for EGFR-wt patients or superior to TKI alone for EGFR-mutant patients? To be more concrete: it comes as no surprise that intercalated treatment was superior to chemotherapy alone for a population which included a substantial proportion of EGFR-mutant patients;26,29, 30,34,37,39,42 and superior to TKIs alone for a population of predominantly EGFR-wt patients.36,40 It is not the intercalated approach, but inclusion of an effective drug into the schedule which may be responsible for the positive experience in these trials. We believe that on the basis of randomized clinical trials published so far, the question of superiority of intercalated schedules over the standard treatment cannot be answered.

Our estimate on the proportion of EGFR mutant patients, as used in the analysis, includes a considerable degree of uncertainty. Only half of trials (14/29) included information on the proportion of EGFR-mutant vs. EGFR-wt tumors for more than 50% of patients. Other trials reported results of EGFR analysis for a minority of patients, or (in 8 publications) no such information. We therefore made an estimate, based on histologic types of tumors (available for 28/29 trials), on proportion of never-smokers (available for 27/29 trials) and on the country where a trial was performed, using tables from a recent meta-analysis.25 This approach led us to the best possible estimate, but the results should nevertheless be regarded as exploratory and tentative. In future, precise molecular diagnostics should minimize these uncertainties.

Our survey does not include analysis of toxicity of different schedules of intercalated treatment. This aspect was clearly presented in a recent review: apart from the expected skin toxicity and diarrhea, intercalated schedules do not present a disproportional burden to patients.24

Relation between selection criteria and effectiveness of intercalated treatment is shown in Figure 2. On the basis of pooled data on median PFS from randomized and single-arm trials, it is clear that pre-treated patients are not good candidates for a treatment which includes a modality to which resistance has already developed. While the proportion of patients with non-squamous histology and of never-smokers determine efficacy of intercalated treatment, EGFR mutations are clearly the strongest predictive factor for longer PFS. By far the greatest benefit was for treatment-naive patients with activating EGFR mutations. According to trials in which this group of patients was reported separately, their median PFS after intercalated treatment ranged between 13.3 and 23.4 months; median PFS for the pooled data was 18.4 months. This figure is substantially above PFS of 9 to 13 months, as reported for TKIs as monotherapy for EGFR-mutant NSCLC.26,55-58 Response rate was also very high: 83.1%, with a substantial proportion of complete remissions. Our survey is in accordance with a recent editorial and with a meta-analysis, which pointed to intercalated regimens as the most promising first-line treatment for EGFR- mutated NSCLC.59,60

With the introduction of liquid biopsy from peripheral blood, the category of patients with undetermined EGFR mutant status should be very small.61 In case this new technique is not available, previously untreated never-smokers with non-squamous histology for whom EGFR status cannot be determined should also be considered for trials testing the role of intercalated treatment. Depending on ethnicity, approximately half of them have EGFR mutant tumors, in which case addition of TKI to cytotoxic drugs would be clearly beneficial; the other half with EGFR negative tumors should benefit from cytotoxic drugs included in the intercalated schedule.

In future trials of intercalated treatment, pemetrexed with platin appears as the preferred option for the cytotoxic component. Regarding the choice of TKI, virtually all current experience is limited to erlotinib and gefitinib. Still, in view of recent very favorable experience for patients who developed resistance mutations, osimertinib intercalated with chemotherapy deserves to be considered either in first-line setting or for patients in progression after first-generation TKIs.62

In two recent phase II randomized trials, patients with treatment-naive advanced EGFR- mutant NSCLC were treated with continuous gefitinib in combination with chemotherapy. As the comparator arm, sequential gefitinib and chemotherapy or gefitinib alone were applied.63, 64 In both trials, patients on the combination with continuous gefitinib and chemotherapy experienced longer PFS. These reports support the advantage of combined treatment with chemotherapy and TKIs and re-open the dilemma between their concomitant and intercalated application. Combination of TKIs with bevacizumab is another possibility which deserves further attention.65

We are perfectly aware that the correlation we have reported between the proportion of patients with EGFR mutation positive tumor and the median PFS obtained with the intercalated treatment could be reasonably observed also with EGFR inhibitors alone. The only way to assess the real added value of intercalated treatment is a randomized trial with comparison to TKI alone and overall survival as the principal endpoint.

In conclusion, intercalated treatment with cytotoxic drugs and TKIs is a promising approach for patients with previously untreated advanced NSCLC with activating EGFR mutations, as well as for never-smokers with adenocarcinoma and undetermined EGFR status. For these patients, randomized trials with comparison to the optimal standard treatment, or possibly to a third arm with continuous application of TKIs in combination with chemotherapy should define the preferred treatment approach.