Erlotinib Boosts PFS in EGFR+ NSCLC But Trial Misses Primary Endpoint

Treatment with erlotinib (Tarceva) significantly extended progression-free survival (PFS) in patients with stage IIIA-N2EGFR-mutant non—small cell lung cancer (NSCLC) compared with a combined chemotherapy regimen of gemcitabine plus cisplatin, according to clinical trial results published recently in theJournal of Clinical Oncology.

The median PFS was significantly longer with erlotinib at 21.5 months compared with 11.4 months in the chemotherapy (HR, 0.39; 95% CI, 0.23-0.67;P<.001). However, PFS was a secondary outcome in this trial.

The primary outcome of objective response rate (ORR) was not met, but slightly more than half of the patients receiving erlotinib (54.1%) and one-third of patients receiving chemotherapy (34.3%) did respond to treatment (odds ratio, 2.26; 95% CI, 0.87-5.84;P= .092). No patient had a pathologic complete response (pCR), but 3 patients (9.7%) in the erlotinib arm had a major pathologic response.

&ldquo;To our knowledge, this study is the first to demonstrate PFS superiority for erlotinib over gemcitabine/cisplatin chemotherapy in the neoadjuvant/adjuvant setting of stage IIIA-N2EGFR-mutant NSCLC,&rdquo; wrote the authors, led by Wen-Zhao Zhong, MD, of Guangdong Provincial People&rsquo;s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. &ldquo;The near doubling of PFS with erlotinib versus GC chemotherapy (21.5 vs 11.4 months; HR, 0.39) was notable, which provides support for the EGFR TKI [tyrosine kinase inhibitor] neoadjuvant/adjuvant therapy strategy in patients with N2EGFR-mutant NSCLC.&rdquo;

Known as CTONG 1103, this phase II, open-label, randomized trial was conducted at 17 centers in China. After screening 386 patients, investigators enrolled and randomized 72 patients 1:1 to receive erlotinib or chemotherapy (both neoadjuvant and adjuvant therapy). The safety analysis population consisted of 71 patients as one patient declined chemotherapy and withdrew informed consent.

A large majority of the study population was female (74%), never-smokers (83%) and had adenocarcinoma pathology (90%). Slightly more than half of the patients (53%) had anEGFRexon 19 mutation and 47% an exon 21 mutation. In the erlotinib arm, 43.2% of patients had stage T2 NSCLC, while 57.1% in the chemotherapy arm did. Slightly more than one-third of the patients on erlotinib (35.1%) received confirmation of an N2 diagnosis via PET/CT scan while 28.6% in the chemotherapy group did.

Patients in the erlotinib arm received neoadjuvant erlotinib 150 mg daily for 42 days, followed by adjuvant erlotinib postoperatively for 12 months or until disease progression or unacceptable toxicity. The chemotherapy arm received neoadjuvant gemcitabine 1250 mg/m²(days 1 and 8) plus cisplatin 75 mg/m²(day 1) every 3 weeks for 2 cycles. They repeated the same regimen for 2 cycles following complete resection or until disease progression or unacceptable toxicity. In the erlotinib arm, the median duration of neoadjuvant treatment was 42 days (range, 20-48), while nearly all the chemotherapy patients (n = 32, 91.4%) were able to complete 2 cycles of neoadjuvant chemotherapy.

In addition to the primary endpoint of ORR and the secondary endpoint of PFS, other secondary endpoints in this trial included downstaging rates of pathologic lymph nodes, complete resection rate, pCR rate, overall survival (OS), safety, and tolerability.

Following neoadjuvant therapy, 31 patients in the erlotinib arm and 24 in the chemotherapy arm underwent surgery. In the erlotinib arm, 73% of patients received R0 resection and 10.8% achieved lymph node downstaging. In the chemotherapy arm, 63% of patients had R0 resection and 2.9% of patientsachieved lymph node downstaging.

After surgical resection, 28 patients (75.7%) in the erlotinib arm received postoperative adjuvant therapy, while 22 patients (62.9%) in the chemotherapy arm did. The median duration of erlotinib treatment was 12 months (range, 5.1 to 13.0 months).

As of data cutoff in November 2018, 61 patients (84.7%) achieved the PFS endpoint, and 38 patients (52.8%) achieved the OS endpoint. Median PFS follow-up was 14.1 months (95% CI, 0.03-68.6). Median OS follow-up was 32.5 months (95% CI, 0.03-78.1). OS was not significantly different between the 2 arms (45.8 vs 39.2 months; HR, 0.77; 95% CI, 0.41-1.45;P= .417).

Adverse events (AEs) were as expected for the respective treatment therapies. Overall, 60 patients (84.5%) developed AEs in the neoadjuvant setting. Of these, nearly one-third (n = 21, 29.6%) experienced grade &ge;3 toxicities with neoadjuvant/adjuvant therapy. No grade 3/4 toxicities occurred in the erlotinib arm, but 29.4% of patients in the chemotherapy group developed &ge;1 such toxicity.

In the adjuvant setting, 70.3% of the erlotinib group and 58.8% of the chemotherapy group developed AEs. More grade 3/4 toxicities were seen in the erlotinib arm (13.5% vs 0.0% in the chemotherapy arm) arm in the adjuvant versus neoadjuvant setting.

Regarding disease progression, Zhong et al reported that 83.8% (31 of 37) and 85.7% (30 of 35) of patients in the neoadjuvant/adjuvant erlotinib and chemotherapy arms, respectively, experienced disease progression or died after a median duration of erlotinib treatment of 12 months (range, 5.1-13) or 2 cycles of chemotherapy.

Zhong et al noted several trial limitations, including a relatively small sample size and slow rate of accrual. They also speculated that longer neoadjuvant erlotinib duration and exposure time to erlotinib might have achieved higher clinical efficacy.

&ldquo;Neoadjuvant erlotinib therapy is appealing but challenging. Reasons for the low accrual rate in our study included both a small patient population having both N2 andEGFRmutations and the challenge of enrolling patients in a neoadjuvant study,&rdquo; they wrote. &ldquo;Although enrollment of the current population harboring the most commonEGFRmutations took 6 years, this preliminary study has proven the feasibility and safety of neoadjuvant TKIs and validated the novel concept of initiating targeted therapy for early-stage disease. With consideration of the low enrollment rate and smaller population, it may be feasible to apply an umbrella trial design and target other relatively uncommon driver mutations.&rdquo;

Reference:

Zhong W-Z, Chen K-N, Chen C, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2EGFR-Mutant Non—Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study [published online June 13, 2019].J Clin Oncol. doi: 10.1200/JCO.19.00075.