First-Line Erlotinib Triples Progression-Free Survival in NSCLC in Chinese Population

Becky McCall

October 10, 2010

October 10, 2010 (Milan, Italy) — Progression-free survival tripled in patients receiving first-line erlotinib (Taraceva; Genentech) who had advanced non–small cell lung carcinoma (NSCLC) carrying endothelial growth factor receptor (EGFR)-activating mutation, according to new trial results.

Dr. Caicun Zhou

Caicun Zhou, MD, from Shanghai Pulmonary Hospital, Tongji University, China, was principal investigator for the OPTIMAL study, which was a prospective phase 3 study evaluating first-line erlotinib vs gemcitabine–carboplatin in patients with NSCLC. He presented the results here at the 35th European Society for Medical Oncology Congress.

"The study shows us that erlotinib does much better than standard regimens in patients with EGFR-activating mutations," he said. "Progression-free survival tripled in patients on erlotinib. It should therefore be considered in preference to first-line chemotherapy in patients with this distinct disease."

He added that hazard ratios were also very significant in this study, and they represent the degree of benefit compared with standard treatment. "Our hazard ratio with erlotinib was 0.16, so the risk of disease progression was found to have decreased by 84% compared to standard therapy," Dr. Zhou told Medscape Medical News.

Progression-Free Survival Significantly Longer

The study was carried out in a Chinese population who had not received previous chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0 to 2 and measurable disease. Patients were randomly assigned to receive either erlotinib at 150 mg/day until unacceptable toxicity or progressive disease (n = 82) or combination chemotherapy (n = 72) of gemcitabine and carboplatin (gemcitabine, 1000 mg/m2, on days 1 and 8, plus carboplatin [area under the curve, 5] on day 1, every 3 weeks for up to 4 cycles).

Approximately one third (34%) of patients with advanced NSCLC had an EGFR receptor mutation, and 52% of these patients had exon 19 deletion type of EGFR-activating mutation in contrast to exon 21 L858R mutation.

Data analysis showed progression-free survival, the primary endpoint, was significantly longer in patients receiving erlotinib vs those receiving the gemcitabine–carboplatin combination (13.1 vs 4.6 months, respectively; hazard ratio, 0.16; 95% confidence interval, 0.10 - 0.26; P < .0001).

Progression was defined as disease worsening by 20% or more in lesions or development of new lesions. The objective response rate was significantly improved in patients receiving erlotinib vs gemcitabine–carboplatin (83% vs 36%, respectively; P = .0000). In addition, the disease control rate was also more favorable with erlotinib (disease control rate — complete response + partial response + stable disease — was 96% vs 82%; P = .002).

Dr. Zhou reported a lower incidence of adverse events and serious adverse events with erlotinib vs the gemcitabine–carboplatin combination. No unexpected adverse events or interstitial lung disease-like events were reported in either group.

Dr. Zhou explained that the overall EGFR mutation rate in the white population with NSCLC is about 10%, but in the Chinese population, that figure increases to 30%. Of the 549 patients screened for this study, the mutation rate was 34%.

A similar study in the white population, known as the EURTAC study, is currently ongoing.

In conclusion, Dr. Zhou suggested that erlotinib should be the treatment of choice in these patients. "The impact of using erlotinib is great when moved to front-line treatment in patients with EGFR mutation," he said. "This is a big step forward, and the hazard ratio of 0.16 could be the new benchmark for studies.

"I think erlotinib should be preferred over conventional chemotherapy in these particular populations," he added.

Separate Analysis

In a separate abstract also drawn from the OPTIMAL study and also presented here, a number of mutations were analyzed as biomarkers for treatment response. Namely, KRAS, EGFR T790M, HER2, BRAF, PIK3CA, and PTEN from pretreatment samples were examined using polymerase chain reaction and direct DNA sequencing.

Yi-long Wu, MD, from Guangdong General Hospital and Guangdong Academy of Medical Sciences in China, reported these results.

He noted that in terms of EGFR mutation type, progression-free survival did not differ significantly whether exon 19 deletion or L858R (erlotinib hazard ratio, 0.58; P = .057; gemcitabine–carboplatin hazard ratio, 1.23; P = .41). Patients with tumors carrying exon 19 deletions (52%) had a progression-free survival of 15.3 months compared with 12.5 months for the exon 21 L858R mutation.

The analysis, however, did not reveal any additional biomarkers. An EGFR T790M mutation was detected in 1 patient in the erlotinib group. No other mutations were identified in either group.

"Other gene mutations identified in lung cancer appear to be rare in tumours with EGFR activating mutations. Baseline c-MET amplification status was not predictive for the efficacy of erlotinib or [gemcitabine–carboplatin] in this setting," Dr. Wu said in a statement.

Exciting Therapy, But More Data Needed

"This adds to a growing body of data which shows that selection of patients by EGFR-activating mutations means you can avoid chemotherapy first-line and treat them with a pill," commented David Spigel, MD, director of the thoracic oncology program at the Sarah Cannon Research Institute in Nashville, Tennessee.

"I think this is a very exciting therapy, which many in the United States now adopt as standard of care," said Dr. Spigel, who was approached by Medscape Medical News for an independent commentary. "It will be interesting to see if this will result in an absolute survival. So far, at least, it is a good approach to controlling disease over a long period of time with, hopefully, minimal toxicity."

Fortunato Ciardiello, MD, PhD, professor at the Division of Medical Oncology, Seconda University of Naples, Italy, compared erlotinib with gefitinib (Iressa; AstraZeneca). "I cannot tell you if these results are superior, inferior, or similar to gefitinib, but more than 1 year [of] progression-free survival is really very good," said Dr. Ciardiello, who was not involved in either study.

"Of course these are 2 different drugs with 2 different toxicity profiles, and we are awaiting results of the European study, which is very similar to this study but mainly in Spanish patients comparing erlotinib to chemotherapy to see if these data are comparable," he said.

The study was funded by Genentech. Dr. Zhou has received sponsorship from Roche Pharmaceutical Company China Ltd and Eli Lilly. Dr. Wu has declared honoraria from Roche, AstraZeneca, Eli Lilly, and Pfizer. Dr. Spigel is an unpaid consultant to Roche. Dr. Ciardiello has disclosed no relevant financial relationships.

35th European Society for Medical Oncology Congress: Abstract LBA14. Presented October 9, 2010.