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UDC: 618.11-006.6
Tillyashaikhov Mirzagoleb Nigmatovich
Doctor of Medical Sciences. Professor Director of Republican specialized scientific practical Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan, Tashkent.
DOI: 10.24411/2520-6990-2019-11008 REVISITING UP-FRONT CHEMOTHERAPY IN EGFR-MUTATED NON-SMALL-CELL LUNG
CANCER
Тилляшихов Мирзаголеб Нигматович
Доктор медицинских наук. Профессор. Директор Республиканского специализированного научно-практического Республиканского специализированного научно-практического медицинского центра онкологии и радиологии Министерства здравоохранения Республики Узбекистан, г. Ташкент.
ПЕРЕСМОТР ОБНОВЛЕННОЙ ХИМОТЕРАПИИ В EGFR-МУТИРОВАВШЕМ НЕМЕЛКОКЛЕТОЧНОМ РАКЕ ЛЁГКИХ
Abstract
In this article, the authors present data on revision of up-front chemotherapy in EGFR-muted non-small-cell lung cancer (NSCLC). Аннотация
В данной статье автор приводит данные по пересмотру обновленной химиотерапии в EGFR-мутировавшем немелкоклеточном раке лёгких (НМРЛ).
Key words: lung cancer, chemotherapy, EGFR. Ключевые слова: рак легких, химиотерапия, EGFR.
The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has transformed the management of advanced non-small-cell lung cancer (NSCLC) bearing an activating EGFR mutation, offering improved survival and tolerability when compared with the use of up-front cytotoxic chemotherapy.[1-3] Although response rates reach as high as 80% to the third-generation EGFR TKI osi-mertinib, [4] response durations are limited, and subsequent disease progression is near inevitable. This has led to evaluation of combination therapy strategies up front and at disease progression with the intent to offer improved outcomes.
Early efforts to combine EGFR TKIs and cyto-toxic chemotherapy for advanced NSCLC occurred before understanding the importance of activating EGFR mutations in predicting TKI benefit and were limited by their enrollment of molecularly unselected patient populations. Several large phase III studies failed to demonstrate a survival advantage in this un-selected population, including studies evaluating the addition of erlotinib or gefitinib to the chemotherapy backbones of carboplatin and paclitaxel (TRIBUTE and INTACT 2) and platinum and gemcitabine (Tarceva Lung Cancer Investigation Trial, INTACT 1, and FASTACT-2). [5-9] Efforts to enrich for a more TKI-sensitive population by enrolling patients with limited smoking history similarly did not reliably result in improved outcomes (CALGB 30406), even in the subset of the EGFRmutant patient popula-tion.[10,11] The overall lack of survival benefit seen in these early studies was accompanied by greater toxicities in patients receiving chemotherapy plus TKI combinations compared with patients receiving TKI
therapy alone. Interest in this approach waned, and nonchemotherapy combinations dominated the field.
The 2 articles that accompany this editorial have revisited the role chemotherapy may play when given first line in combination with EGFR TKI therapy in the era of molecular testing. Noronha et al12 report the results of a phase III study of gefitinib given in combination with carboplatin and pemetrexed chemotherapy versus gefitinib alone for newly diagnosed, advanced, EGFR-mutated NSCLC. In this single-center study conducted at a tertiary care hospital in India, the chemotherapy plus gefitinib arm, versus gefitinib alone, demonstrated substantial increases in both progression-free survival (PFS; median, 16 v 8 months, respectively; hazard ratio [HR], 0.51; 95% CI, 0.39 to 0.66) and overall survival (OS; median, not reached v 17 months; HR for death, 0.45; 95% CI, 0.31 to 0.65). The use of less stringent inclusion criteria, including the enrollment of a sizable fraction (21%-22%) of patients with an Eastern Cooperative Oncology Group performance status of 2, renders the continued demonstration of survival benefit notable and suggests continued applicability outside of the setting of the relatively healthy demographic of clinical trial participants. Likewise, Hosomi et al [13] report the results of NEJ009, which evaluates the same randomized comparison of gefitinib with or without carboplatin and pemetrexed chemotherapy for first-line treatment of patients with EGFR-mutated NSCLC. In this multicenter study conducted in Japan, the investigators also observed substantial increases in PFS and OS with the addition of platinum doublet chemotherapy to gefitinib versus gefitinib alone (PFS:20.9 v 11.9 months, respectively; HR, 0.49; 95% CI, 0.39 to 0.62; OS:
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50.9 v 38.8 months, respectively; HR, 0.72; 95% CI, 0.55 to 0.95). The highly significant improvements in OS observed in these studies with the addition of chemotherapy have reinvigorated interest in the use of TKI plus chemotherapy combinations for this patient population.
Although these results initially seem surprising in the context of prior work in this area, there have been prior indications that this approach could hold promise. A phase II study enrolling a high proportion of never smoking, East Asian patients did report small improvements in PFS with the addition of erlotinib to pemetrexed versus either therapy alone in the sec-ondline setting, consistent with a presumed significant enrichment for an EGFR-mutated population within this demographic.[14] A phase II study conducted in Asia enrolling patients with EGFR-mutated NSCLC reported improved PFS with first-line combination gefitinib plus pemetrexed compared with gefitinib monotherapy (15.8 v 10.9 months, respectively; HR, 0.68; 95% CI, 0.48 to 0.96), with a trend toward improved OS (43 v 37 months, respectively; HR, 0.77; 95% CI, 0.5 to 1.2).[11,15] Analysis of the subset of patients with EGFRmutated NSCLC within the FASTACT-2 phase III study of platinum plus gem-citabine with or without intercalated erlotinib demonstrated increases in PFS (16.8 v 6.9 months, respectively) and OS (31.4 v 20.6 months, respectively) similar to those seen in the more recent studies discussed here. [8] As in these earlier studies, the use of an EGFR TKI backbone, the identification of EGFR activating mutations, and the availability of pemetrexed as a better tolerated chemotherapy partner may all help to drive the positive outcomes observed in the 2 recently reported studies.
It remains to be fully understood why up-front combination therapy offers superior OS compared with TKI monotherapy with subsequent availability of standard-of-care chemotherapy. Current understanding of oncogene-driven NSCLC suggests significant sub-clonal tumor heterogeneity, both in the treatment-naive setting and as an acquired feature of tumor progression under the selective pressure of targeted therapies, [16] which may be facilitated by the survival of residual, quiescent, drug-tolerant populations.[17] The use of combination targeted therapies may be one strategy to address this problem, but it has faced challenges related to tolerability when applied using earlier generation EGFR TKIs and, in the up-front setting, related to the difficulties of addressing the breadth of potential EGFR TKI resistance mechanisms. In comparison, the nonspecific activity of cytotoxic chemotherapy may offer advantages in the setting of this heterogeneity, permitting more effective targeting of residual tumor cell populations. It will be interesting to understand whether the addition of chemotherapy fundamentally changes the spectrum of acquired resistance mechanisms to gefitinib (ie, EGFR T790M) or merely delays their appearance. The use of platinum plus pemetrexed chemotherapy, which has some reported CNS activity, may also be improving outcomes by improving CNS control when added to ge-fitinib, which has limited expected CNS activity.
The observed survival benefit may also partially reflect greater access to cytotoxic chemotherapy when received in the up-front setting. In the study by Noro-nha et al, 44% of patients treated with gefitinib mono-therapy up front received chemotherapy after disease progression. This may in part reflect real-world barriers to implementation of testing for resistance mechanisms, initiation of later line therapies, declining performance status, and drug access after disease progression in the first-line setting, and the rate of 44% is within the range of previously published rates of crossover to second-line systemic therapy after progression on first-line EGFR TKIs, reported as between 38% and 62% of patients.[1,3] Moving chemotherapy to the first-line setting once more for this population may increase the fraction of patients who are able to receive it in clinical practice. Despite this, the persistence of an OS benefit in the study by Hosomi et al, in which 95% of patients received second-line systemic therapy (77% received a platinum doublet), does suggest that the observed survival benefit is not entirely driven by receipt of second-line therapy.
The availability of the third-generation EGFR TKI osimertinib, which has demonstrated superiority to treatment with earlier generation EGFR TKIs and which is now standard-of-care first-line therapy within the United States for treatment of NSCLC with an EGFR activating mutation, also raises the question of how to apply these studies to clinical practice. In both studies discussed here, there was limited access to osimertinib in the second-line setting, potentially in part driven by global variation in drug access and practice patterns. Despite an expected approximately 50% EGFR T790M-positive rate of resistance,29 for which osimertinib would be indicated, it was received at progression by only 15% and 22% of patients in the studies by Noronha et al and Hosomi et al, respectively. In comparison, in the FLAURA study evaluating first-line use of osimertinib for EGFR-mutated NSCLC, in the comparator arm, 43% of patients who began treatment with an earlier generation EGFR TKI subsequently received osimertinib at disease progression. The recent update demonstrating an OS benefit to osimertinib over standard-of-care EGFR TKI (gefitinib or erlotinib) in the first-line randomized trial comparing these approaches further complicates interpretation of the comparison of gefitinib plus chemotherapy versus gefitinib alone.
Several studies are currently evaluating the addition of platinum plus pemetrexed chemotherapy to osimertinib in the first-line setting (FLAURA2/NCT04035486 and UMIN000024438). Improved tolerability, longer duration of response, and improved CNS activity compared with earlier generation EGFR TKIs may all limit the potential benefits of adding up-front chemotherapy to osimertinib, but if the findings seen with earlier generation TKIs are replicated, this would have potentially practice-changing implications for the treatment of EGFR-mutated NSCLC. In this scenario, magnitude of benefit and comparative treatment toxicities will be critical to understanding how best to incorporate combination therapy into patient care. The potential for response to
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osimertinib monotherapy to last several years, with 28% of patents currently continuing on treatment at 3 years, the generally well-tolerated nature of osimertinib monotherapy, and the palliative nature of treatment in the metastatic setting suggest that there will be a need to carefully consider how to integrate these data into clinical practice. Improved understanding of which patients are likely to derive less durable responses to osimertinib monotherapy may facilitate prioritization of patients for an up-front combination therapy approach, and additional research is needed in this area.
For patients currently without access to first-line osimertinib, the magnitude of OS benefit demonstrated in these 2 studies establishes a new standard of care of upfront gefitinib with carboplatin plus pemetrexed chemotherapy for first-line treatment of NSCLC with an EGFR activating mutation. For patients with access to osimertinib, the data are provocative but have not yet demonstrated superiority to first-line osimertinib monotherapy. We anticipate that the understanding of optimal first-line treatment in this setting will continue to evolve as data become available from the ongoing studies in this area, which are eagerly awaited. The applicability of these findings to other oncogene-driven subsets of NSCLC also remains to be explored.
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