New SATURN Results Show Survival Benefit From Erlotinib in NSCLC

Barbara Boughton

August 02, 2009

August 1, 2009 (San Francisco, California) — New results from the phase 3 SATURN trial show that erlotinib (Tarceva) maintenance therapy significantly improves overall survival in nonsmall-cell lung cancer (NSCLC) patients. These results, a secondary end point of the trial, were presented here at the 13th World Conference on Lung Cancer (WCLC), organized by the International Association for the Study of Lung Cancer.

Details about the improvement in progression-free survival, the primary end point of this trial, were also released. The initial progression-free-survival results were presented earlier this year at the American Society of Clinical Oncology (ASCO) meeting, as reported by Medscape Oncology at the time.

The SATURN trial involved 889 patients who had not progressed after 4 cycles of platinum-based chemotherapy. Maintenance therapy with erlotinib (150 mg/day) resulted in an increase in progression-free survival time, from 41% to 45%, compared with placebo (hazard ratio [HR], 0.71; P = .000003), researchers announced at the meeting.

Overall survival statistics, a secondary end point of the study, showed that those receiving erlotinib had a significantly longer survival than those receiving placebo (12 months vs 11 months). "When we looked at survival according to [epidermal growth-factor receptor] EGFR status, we found that survival was not driven by this status. There was also a statistically significant benefit for patients with EGFR wild-type tumor," said lead researcher Federico Cappuzzo, MD, professor and vice director of the Instituto Clinico Humanitas in Milan, Italy.

These longer-term (3 year) progression-free-survival results are in contrast with those announced at ASCO, where researchers noted a "huge benefit" for patients with the EGFR mutation compared with other patients in the trial.

Although patients with EGFR mutations fared better than others in terms of progression-free survival, a benefit was also seen for those with other molecular markers, Dr. Cappuzzo told the meeting. For instance, patients with EGFR wild-type tumors receiving erlotinib had a median survival of 11.3 months, compared with 10.2 months for those receiving placebo.

"There was a significant progression-free survival benefit regardless of any tumor marker," said Wolfram Brugger, MD, PhD, coauthor and head of the Department of Hematology, Oncology and Immunology at Schwarzwald-Baar Clinic in Villingen Schenningen, Germany. Although KRAS mutations are a strong negative prognostic factor, they did not have any predictive value for erlotinib therapy in this study, he said.

Survival Benefit Seen Early in Study

Although the survival benefit of 1 month seen in the erlotinib group might not seem like much, Dr. Cappuzzo noted that there was a 10% absolute difference in survival between the treatment and placebo groups at 3 years. During a press conference, he said that the patients who fared best in the study had survived up to 30 months.

Some individual patients may have struck out and others may have hit a home run.

"When you look at these studies, you have to consider individual patients," noted David Gandara MD, WCLC program chair. "Some individual patients may have struck out and others may have hit a home run. For any of these therapies where we see an improved survival or response rate, it's important to find out who these treatments benefit most. That way, we can give treatments to those who will really benefit, [and not expose] others to unnecessary drug toxicity and financial toxicity."

Dr. Gandara added that as the SATURN studies mature, scientists are likely to gain information about what kind of survival benefit erlotinib can provide.

In the SATURN trial, the difference in survival between those receiving erlotinib and those receiving placebo was seen early in the study, Dr. Cappuzzo noted. However, the difference in survival became especially pronounced after 9 months.

Although patients who received erlotinib experienced more adverse events, such as rash and diarrhea, their quality of life was not negatively affected by the drug. "There were no unexpected toxicities," said Dr. Cappuzzo. Using the Functional Assessment of Cancer Therapy-Lung (FACT-L) instrument, the researchers found that those receiving erlotinib experienced little difference in quality of life, compared with those receiving placebo. However, when time to pain and time to analgesic use were considered, those receiving erlotinib benefited more than those receiving placebo.

No "Sea Change" in Practice As Yet

The survival benefit seen with erlotinib in the SATURN trial was announced in a press release from the manufacturer, OSI Pharmaceuticals, 2 weeks ago, and there is an expectation that the data will secure an indication for the drug as maintenance therapy in NSCLC. "But will that matter? It's already [US Food and Drug Administration]-approved as a second-line therapy, so this is effectively moving it a few weeks or months earlier [to becoming] a more proactive second-line treatment, in my mind. It is already approved for use as second-line therapy," said H. Jack West, MD, medical director of thoracic oncology at the Swedish Cancer Institute in Seattle, Washington, writing in his July 19, 2009 Blowing Smoke blog for Medscape Oncology.

Benefit with other maintenance therapy in NSCLC was reported at ASCO — notably, an improvement in overall survival with pemetrexed and an improvement in progression-free-survival with the combination of erlotinib and bevacizumab (the ATLAS trial).

But Dr. West notes that, from his "conversations with various medical oncologists, ranging from broad community-based practice to thoracic oncology specialists, there isn't a sea change happening in the wake of these positive trials."

"Many oncologists seem far more inclined to extend 1 or more agents from first line [therapy] until progression than to switch to a new treatment after 4 lines of therapy," he writes.

"The one setting in which I do think there may be a prioritization of earlier introduction of erlotinib is in patients who happen to have [undergone] EGFR-mutation testing during the first 4 cycles of chemotherapy [with or without bevacizumab] and are found to be positive. These patients had a very, very substantial progression-free-survival benefit (HR, 0.10 on SATURN) compared with placebo," Dr. West writes. "I also think that an oral therapy may be a more appealing maintenance approach for a certain subset of patients who prefer to take a break from IV therapy but not to take a break from treatment."

"It is fair to say, though, that none of the maintenance trials did an ideal job of really isolating the timing of treatment, since all of them ended up treating [less than] two thirds of the patients in the placebo or delayed-treatment arm," Dr. West continued. "In that sense, these trials may really do a better job of just highlighting [the fact] that patients who showed stable disease or a response to first-line chemotherapy are exactly the patients most likely to benefit from later treatment, and that the key difference is that when you give maintenance therapy, nobody misses their opportunity for further benefit."

Dr. Cappuzzo has received honoraria from AstraZeneca, Boehringer, Eli Lilly, and Roche. Dr. Brugger has been a consultant to Roche, Lilly, and AstraZeneca, and a speaker for Roche and Lilly. Dr. Gandara has been a consultant to Response Genetics, Sanofi-Aventis, Bayer, AstraZeneca, Lilly Oncology, Amgen, Genentech, Bristol-Myers Squibb, and Pfizer, and he has received research support from Lilly, Bristol-Myers Squibb, Genentech, Pfizer, and Abbott Oncology.

13th World Conference on Lung Cancer (WCLC): Abstract A2.1. Presented August 1, 2009.