As soon as EGFR-TKIs became available, a series of clinical trials, such as INTACT 1 [5], INTACT 2 [6], TALENT [7], and TRIBUTE [8], were conducted to investigate the effect of chemotherapy alone or in combination with TKIs in non-selected patients with advanced NSCLC. However, the results from these studies were all negative. The reasons may include potential antagonism between platinum drugs and EGFR-TKIs [9] or that cell cycle–specific chemotherapy drugs are difficult to play a role because EGFR-TKIs arrest the tumor cell cycle at G1 phase [10].
Based on these hypotheses and the results from basic research, the combination strategy was largely eschewed for some time. However, in 2013, FASTACT-2, a large phase III randomized controlled trial [11], used a combination therapy protocol known as intercalated therapy to avoid concomitant use of chemotherapy and TKI, thereby preventing cell cycle arrest from impairing the efficacy of chemotherapy. Specifically, a group of Asian patients with advanced NSCLC received 28-day cycles of chemotherapy with gemcitabine (days 1, 8) and carboplatin (day 1), as well as erlotinib on days 15-28. After up to six cycles of chemotherapy, oral erlotinib was given every day until disease progression. The results showed that PFS and OS were significantly longer in the chemotherapy-combined-with-erlotinib group than in the erlotinib-alone group. A similar study, ISCAN [12], reached similar conclusions, although the time point for intercalated chemotherapy was slightly different.
In 2016, JMIT, a phase II randomized controlled trial, was designed based on a different hypothesis, that platinum drugs and EGFR-TKIs are antagonistic [13]. Pemetrexed was given in combination with oral gefitinib (daily, from day 1 of chemotherapy) without using a intercalated strategy. In addition, this was the first trial to enroll patients with advanced NSCLC and sensitive EGFR mutations. The results showed that PFS, the primary endpoint, was significantly longer in the combination group than in the gefitinib-alone group.
In 2018, the initial results of study NEJ009 [14] challenged the presumed mechanism of the clinical benefits observed in FASTACT-2 and JMIT. The trial investigated the efficacy of gefitinib alone or in combination with chemotherapy in patients with advanced non-squamous NSCLC and sensitive EGFR mutations. The chemotherapy regimen was pemetrexed combined with carboplatin, a platinum-based two-drug regimen, and gefitinib was given from day 1 of chemotherapy without a preset interval. The trial achieved the best outcomes with chemo-targeted combination therapy, as this regime extended PFS from 11.9 months to 20.9 months (p < 0.001) and OS from 38.8 months to 50.9 months (p = 0.021) [4], suggesting that intercalated chemotherapy with TKI (based on the theory of TKI-induced cell cycle arrest) or the use of non-platinum-containing chemotherapy in combination with TKI (based on the theory of antagonism between platinum drugs and TKI) was unwarranted. The failure of early clinical trials is likely related to a lack of precise patient selection.
During this period, researchers are also developing a more in-depth understanding of lung cancer with EGFR mutations. High-throughput technology shows that 45% to 55% of patients with EGFR mutations also harbor a concomitant non-EGFR genetic alteration(s), and these patients are far less responsive to EGFR-TKIs than those with pure EGFR mutations [15,16]. This may be related to the resistance that rapidly develop in association with the activation of alternate pathways, and chemotherapy combined with TKI may prevent rapid activation of alternate pathways because the regime works on both EGFR and non-EGFR pathways. Our study indirectly confirms this hypothesis: In the TKI monotherapy group, the ORR was 50%, the median PFS was 5.3 months, which were significant lower or shorter than the historical data of first-line EGFR-TKI therapies. In the combination therapy group, the ORR was 78%, the median PFS was 18.8 months, the HR of disease progression was reduced by 77%, and the HR of death was reduced by 55%. These data indicate that the combination therapy overcomes the shortcomings of TKI monotherapy in patients with both EGFR and concomitant non-EGFR genetic alteration(s), which may be one of the benefit logics of chemo-targeted combination strategy. Answering questions such as whether patients with a pure EGFR mutation will benefit from the combination therapy (and if so, what is the mechanism) and the clinical benefits relative to those observed in patients with both EGFR and non-EGFR alterations will facilitate the precise selection of a treatment protocol.
This study has obvious limitations due to the nature of retrospective analyses and the small sample size. For example, this study showed that approximately 25% of patients harbored two or more non-EGFR mutations in this real-world clinical setting, but according to Cox multivariate regression analysis, the number of non-EGFR mutations was not an independent prognostic factor for PFS. The number of non-EGFR mutations seen in this study may be incorrect, or it may be unbalanced due to the different testing platforms and panels used across studies, which along with the small sample size makes it impossible to draw any definitive conclusion about the relationship between the number of non-EGFR mutations and the efficacy of combination therapy.