Benefits of Erlotinib Maintenance in NSCLC: SATURN Results Published CME

News Author: Nick Mulcahy
CME Author: Charles Vega, MD

May 20, 2010 — Results from the phase 3 Sequential Tarceva in Unresectable NSCLC (SATURN) trial are now published online in The Lancet Oncology.
The results show that, compared with placebo, erlotinib (Tarceva, Genentech/OSI Pharmaceuticals) maintenance therapy significantly improves progression-free survival (hazard ratio [HR], 0.71; median, 12.3 vs11.1 weeks) and overall survival (HR, 0.81; median, 12.0 vs 11.0 months) in patients with advanced nonsmall-cell lung cancer (NSCLC).
The data were first presented at the 2009 World Conference on Lung Cancer and reported by Medscape Oncology at the time.
The most dramatic outcomes with erlotinib were seen in a small subset of patients in the trial — those with an epidermal growth-factor receptor (EGFR) mutation — but these patients accounted for only 22 of the 438 (5%) erlotinib-treated patients.
"Erlotinib was associated with an unprecedented hazard ratio of 0.10 (P < .0001) for patients with an EGFR mutation," said Thomas E. Stinchcombe, MD, and Suresh S. Ramalingam, MD, in an editorial that accompanies the study results.
However, this unprecedented result for progression-free survival did not translate into a statistically significant improvement in overall survival, probably because most of the patients on placebo with an EGFR mutation received treatment with erlotinib upon progression, note Dr. Stinchcombe, from the University of North Carolina at Chapel Hill, and Dr. Ramalingam, from Emory University in Atlanta, Georgia.
This crossover effect on overall survival does not diminish the impressiveness of the improvement in progression-free survival in patients with an EGFR mutation — even if it is a small, limited group, suggest the editorialists.
"It has become clear that robust responses and prolonged [progression-free survival] outcomes with EGFR tyrosine-kinase inhibitors (TKIs) are limited to patients with an EGFR mutation," they summarize.
EGFR TKIs, which include gefitinib (Iressa, AstraZeneca), are well suited for maintenance therapy in this setting, the editorialists point out.
"Their proven efficacy, ease of administration, and favorable tolerability profile make them ideal for maintenance therapy," they write, adding that the quality-of-life indices in SATURN did not show any "significant differences" between the treatment and placebo groups.
In SATURN, the most common grade 3 or higher adverse events were rash (9% in the erlotinib group vs0% in the placebo group) and diarrhea (2% vs0%), report the study authors, led by Federico Cappuzzo, MD, from Ospedale Civile di Livorno in Italy.
Pemetrexed or Erlotinib for Patients With Wild-Type EGFR?
Maintenance therapy for NSCLC is defined as the use of an effective agent in the absence of disease progression following platinum-based combination chemotherapy, the editorialists explain.
An outstanding question for clinicians is whether or not erlotinib is the best choice for maintenance therapy in patients with wild-type EGFR.
Patients with wild-type EGFR accounted for 45% and 42% of the treatment and placebo groups, respectively, in the 889-patient SATURN trial.
But the trial results indicate that erlotinib was not highly effective in NSCLC patients with wild-type EGFR.
"The benefit of maintenance erlotinib compared with placebo in terms of progression-free survival and overall survival was modest for such patients," write Drs. Stinchcombe and Ramalingam, referring to the wild-type patients.
Pemetrexed is a better choice for maintenance therapy in patients with wild-type EGFR, suggest the editorialists.
Pemetrexed is "likely to be the preferred agent in patients with nonsquamous histology, based on the improvement in median survival of 5 months seen with pemetrexed compared with placebo," they opine, suggesting that patients with squamous cell carcinomas are unlikely to have the mutation.
Both pemetrexed and erlotinib are approved by the US Food and Drug Administration as maintenance therapies for patients with advanced NSCLC.
The editorialists remind clinicians that they should remain mindful that maintenance therapy is not for all patients with advanced NSCLC who have stable disease after chemotherapy.
"The decision to administer maintenance therapy should take into consideration the disease burden, extent of symptoms, the toxicities associated with first-line therapy, and patient preferences. While maintenance therapy might be appropriate for some patients, it might be less preferable for others," write Dr. Stinchcombe and Dr. Ramalingam.
The SATURN trial was funded by F. Hoffman-La Roche. Dr. Stinchcombe reports being on the speakers' bureau of Lilly and Genentech. Dr. Ramalingam reports working as a consultant for Genentech, Imclone, Syndax, Astellas, Amgen, and GlaxoSmithKline. Dr. Cappuzzo reports receiving honoraria from Roche, Eli-Lilly, AstraZeneca, and Boehringer; and receiving payment for development of educational presentations, including service on speakers' bureaus, from Roche, Eli-Lilly, AstraZeneca, and Boehringer.
Lancet Oncol. Published online May 20, 2010.

Clinical Context

The mainstay of treatment of advanced NSCLC is platinum-doublet chemotherapy, which is associated with a median overall survival duration of 8 to 11 months. Although most patients with advanced NSCLC will achieve some clinical response with first-line chemotherapy, the majority of these patients will also experience progressive disease within 2 to 3 months of the discontinuation of chemotherapy.

Unfortunately, prolonged treatment with platinum-based chemotherapy may result in higher toxicity with little survival benefit. Erlotinib, an oral EGFR TKI, may help to prolong survival duration after chemotherapy for advanced NSCLC, with less toxicity. The current study tests this hypothesis.

Study Highlights

• The study was completed at 110 sites in 26 countries. All study participants were at least 18 years old and had unresectable or metastatic NSCLC. Patients who previously received anti-EGFR agents or who had uncontrolled brain metastases were excluded from study participation.
• All participants completed 4 cycles of standard platinum-doublet chemotherapy.
• Study subjects without disease progression during chemotherapy were randomly assigned to receive erlotinib 150 mg/day or placebo. Study treatment was continued until disease progression, unacceptable toxicity, or death.
• The main study outcome was progression-free survival. Secondary outcomes included overall survival and quality of life.
• 1949 patients underwent screening and received first-line chemotherapy. The most common chemotherapy regimens were carboplatin plus gemcitabine, cisplatin plus gemcitabine, and carboplatin plus paclitaxel.
• 889 patients had stable disease or improvement during first-line chemotherapy, and these patients received erlotinib or placebo. The mean age of these participants was 60 years, and three quarters of subjects had stage IV cancer. The pathologic features of cancers were nearly equally divided between adenocarcinoma/bronchoalveolar carcinoma and squamous cell carcinoma.
• The median follow-up time was 11.4 months in the erlotinib group and 11.5 months in the placebo group.
• Median progression-free survival times were 12.3 and 11.1 weeks in the erlotinib and placebo groups, respectively, a significant difference (HR, 0.71).
• On examination of patients with EGFR-positive tumors only, erlotinib remained superior to placebo in progression-free survival (median, 12.3 vs 11.1 weeks; HR, 0.69).
• The median overall survival times in the erlotinib group and the placebo group were 12.0 and 11.0 months, respectively (HR, 0.81).
• Measurements of quality of life were similar in comparing the erlotinib group vs the placebo group.
• The rate of adverse events associated with erlotinib was similar to that in previous trials. Serious adverse events occurred in 11% of the patients receiving erlotinib and in 8% of patients receiving placebo. The most frequently reported serious adverse event was pneumonia. The most common adverse events overall with erlotinib were rash and diarrhea, which were usually not severe.
• 16% of participants receiving erlotinib required a dose reduction or interruption of treatment because of adverse events vs 3% of participants receiving placebo.

Clinical Implications

• The mainstay of treatment of advanced NSCLC is platinum-doublet chemotherapy, which is associated with a median overall survival duration of 8 to 11 months. The majority of patients with advanced NSCLC will achieve some clinical response with first-line chemotherapy, but progressive disease is common within 2 to 3 months of the discontinuation of chemotherapy.
• The current study demonstrates that maintenance therapy with erlotinib can improve progression-free and overall survival times among patients who respond to first-line chemotherapy of NSCLC. Quality-of-life scores were similar in comparing participants receiving erlotinib vs placebo.