Jul 2, 2019
This JCO Podcast provides observations and commentary on the JCO article “Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment for Stage IIIA-N2 EGFR-Mutant NSCLC (EMERGING-CTONG 1103): A Randomized Phase II Study” by Zhong et al. My name is Tony Mok, and I am a Professor of Clinical Oncology at the Chinese University of Hong Kong in the Prince of Wales Hospital in Hong Kong. My oncologic specialty is Medical Oncology.
With the advent of molecular targeted therapy, patients harboring driver oncogenes may now survive longer and better than before, and EGFR mutation is the prime example of such achievement. However, evidence for “cure” of patients with metastatic EGFR mutation positive lung cancer remains scanty. In contrast, It may be more reasonable to first attempt cure of patients with earlier stage disease using molecular targeted therapy. CTONG 1103, published in this issue of Journal of Clinical Oncology, is the first randomized study comparing neoadjuvant erlotinib with chemotherapy for patients with stage IIIA EGFR mutation positive lung cancer.
CTONG 1103, the report that accompanies this podcast, is not an easy study to conduct. Between December 2011 and December 2017, investigators from 17 centers across China managed to screen 386 patients with stage IIIA non-small cell lung cancer (NSCLC) and identified only 72 (which is about 19%) eligible EGFR mutation positive patients. They were randomized to receive either erlotinib 150mg daily for 42 days or two cycles of chemotherapy using gemcitabine and cisplatin as neo-adjuvant therapy. After neoadjuvant therapy, 73% of the erlotinib arm, and 63% of the chemotherapy arm, received curative surgery, including two patients in erlotinib arm who received pneumonectomy. The primary endpoint of this study is tumor response rate, which is 54.1% for erlotinib and 34.3% for chemotherapy. However, the odds ratio of 2.26 for tumor response rate was not statistically significant. Two other important and impactful endpoints include major pathological response and progression free survival (PFS). Major pathological response is defined as less than 10% residual viable tumor cell and it occurred only in 10.7% of patients who received erlotinib and none with the chemotherapy. But on the other hand, PFS was significantly better with erlotinib arm, reporting median of 21.5 month comparing with 11.4 months with chemotherapy arm.
In reference to the primary endpoint of tumor response rate, we should conclude that CTONG 1103 is a negative study. Zhong et al has reasonably estimated the sample size based on a presumptive response rate of 70% in the erlotinib arm and 36% in the chemotherapy arm. The reported response rate at 54.1% with erlotinib in this study has significantly fallen short of the expected rate of 70%, which was actually the widely accepted response rate in patients with stage IV disease. The authors selected to offer 42 days of neo-adjuvant erlotinib in order to match the two cycles of neo-adjuvant chemotherapy. While there is no biologic reason to explain the low response rate in earlier stage disease, the shorter duration of treatment may contribute to the relatively lower response rate. The other important outcome is the major pathological response of 10.7% with neo-adjuvant erlotinib, which is supposed to be a surrogate for overall survival. Hellman et al were among the first groups to suggest the predictive power of major pathological response for neo-adjuvant chemotherapy for patients with early stage lung cancer. The lower than expected major pathological response may be considered a surrogate indicator for overall survival but it is more important to wait for the mature survival outcomes.
A negative study can still be impactful. This study has established the feasibility of neo-adjuvant EGFR TKI for patients with potentially resectable EGFR mutation positive lung cancer. The first single arm phase II study on pre-operative gefitinib published in 2009 in the Journal of Clinical Oncology enrolled 36 patients but only 6 harbored the activating EGFR mutations. Tumor response was observed in 4 patients and all were positive for the mutations. Another single arm study published in 2018 in the journal The Oncologist enrolled 19 patients with EGFR mutation positive stage IIIA NSCLC and treated with neoadjuvant erlotinib for 56 days. Tumor response rate was 42.1% and resection rate was 68.4%. Only 5 of the 14 patients (35.7%) with surgical resection had documented pathologic downstaging from N2 to N0/N1 disease. The median PFS and OS was 11.2 and 51.6 months respectively. CTONG 1103 is the first and only randomized comparative study that confirmed the feasibility and efficacy of neo-adjuvant EGFR TKI. Tumor response rate is higher than chemotherapy by 20% although not statistically significant, but toxicity profile is better, which is an established fact from multiple phase III studies on advanced stage disease. The resection rates were similar between the two arms but it was unclear how many of the enrolled patients had unresectable disease prior to neo-adjuvant therapy. Key objectives of neo-adjuvant therapy are to down-stage tumor/nodal disease and to improve resectability. This randomized study may potentially document if erlotinib is more capable of converting unresectable stage IIIA disease to being resectable, however, this data is not currently available.
The authors of the current study have also reported improvement in progression free survival, but we cannot conclude that the improvement is solely due to the neo-adjuvant therapy. As per study protocol, patients from neo-adjuvant EGFR TKI arm did receive 12 months of erlotinib as adjuvant therapy while the chemotherapy arm received only 2 more cycles of similar treatment. Considering the duration of therapy, the adjuvant erlotinib may in fact contribute more to prolongation of progression free survival than the neo-adjuvant therapy. In 2017 in the journal Lancet Oncology, the same group of investigators have reported a randomized phase III study comparing adjuvant gefitinib with chemotherapy and the median disease free survival was 28.7 months and 18.0 months, respectively. All patients enrolled in this study had resectable lung cancer with over 60% of patients having N2 disease, and the authors had concluded on the potential survival advantage of adjuvant EGFR TKI. Thus, the improvement in progression free survival should be explained by both neo-adjuvant and adjuvant erlotinib.
In summary, CTONG 1103 is a negative study but it has significant impact on management of stage IIIA EGFR mutation positive lung cancer. With high screening failure rate at 80%, it took the authors 6 years to enroll 72 patients. This study will remain the only randomized study on this patient group for a long time as similar large scale phase III trials of this strategy will be unlikely. Clinicians are obligated to share and explain CTONG 1103 to patient with stage IIIA EGFR mutation positive lung cancer. For patients with resectable disease at presentation, the benefit of neo-adjuvant EGFR TKI may be debatable. But for patients with un-resectable stage IIIA disease, neo-adjuvant EGFR TKI may potentially downstage the disease status and facilitate resection.
This concludes this JCO podcast. Thank you for listening.