IASLC: Pemetrexed-Platinum Duo Called Preferred First-Line Regimen for NSCLC

SEOUL, South Korea, Sept. 5 -- Pemetrexed (Alimta) may have toxicity advantages over gemcitabine (Gemzar) in first-line combination chemotherapy for advanced non-small-cell lung cancer, researchers said here

In two studies presented at the International Association for the Study of Lung Cancer meeting here, there were no overall differences in outcomes between pemetrexed and gemcitabine in combination with carboplatin (Paraplatin) in one trial and cisplatin (Platinol) in the other.

However, the pemetrexed-containing combinations led to significantly less toxicity in both studies.

A planned subgroup analysis of non-squamous cell tumors also showed significantly improved median survival for the pemetrexed-cisplatin combination (11.8 versus 10.4 months, P=0.03) in the study by Giorgio V. Scagliotti, M.D., of the University of Turin in Italy, and colleagues.

The findings establish pemetrexed-cisplatin chemotherapy as a preferred regimen, at least for adenocarcinoma and large cell lung cancer, asserted Lawrence Einhorn, M.D., of Indiana University in Indianapolis, who was a discussant on Dr. Scagliotti's study.

Pemetrexed is approved for NSCLC only as second-line therapy, but a first-line indication is being sought in both the U.S. and European Union, said a spokesperson for Eli Lilly, maker of pemetrexed.

As part of the package of trials required by the FDA when the drug was approved for second-line NSCLC treatment, Dr. Scagliotti and colleagues conducted a noninferiority trial of 1,725 chemonaive patients in 26 countries who had locally advanced or metastatic disease.

Participants were randomized to 75 mg/m² cisplatin on day one plus either 500 mg/m2 pemetrexed on day one or 1,250 mg/m² gemcitabine on days one and eight of each three-week cycle for up to six cycles.

The researchers found a significant benefit to the pemetrexed combination for transfusions, supportive care, and all drug-related toxicities with the exception of thrombotic events, fatigue, and nausea. Among the findings, they reported:

• Febrile neutropenia (1.3% versus 3.7%, P=0.002).
• Anemia (5.6% versus 9.9%, P=0.001).
• Thrombocytopenia (4.1% versus 12.7%, PAny transfusion (16.4% versus 28.9%, PErythropoiesis-stimulating agents (10.4% versus 18.1%, PGranulocyte- or granulocyte-macrophage-colony stimulating factor (3.1% versus 6.1%, P=0.004).

Outcomes, though, were similar between treatment groups. For pemetrexed-cisplatin versus gemcitabine-cisplatin, the results were:

• Overall response rate (30.6% versus 28.2%, P=0.312).
• Median progression-free survival (4.8 versus 5.1 months, adjusted hazard ratio 1.04, 94% confidence interval 0.94 to 1.15).
• Median overall survival (10.3 months for both, adjusted HR 0.94, 95% CI 0.84 to 1.05).

However, subgroup analysis excluding patients with squamous-cell cancer showed significantly better overall survival among those who received pemetrexed (11.8 versus 10.4 months, P=0.03) whereas the analysis of only squamous-cell cancer patients showed the opposite (9.36 versus 10.8 months, P=0.05).

There is a molecular rationale for this histological difference, Dr. Einhorn noted, because squamous-cell tumors have increased expression of the thymidylate synthase gene compared with non-squamous-cell lung cancers.

"These hypothesis generating findings are worthy of prospective validation in future studies," Dr. Scagliotti said.

The study comparing pemetrexed and gemcitabine in combination with carboplatin likewise found no difference in overall survival (median 7.3 versus 7.0 months, P=0.60) or in quality of life, reported Bjrn H. Grnberg, M.D., of St. Olavs University Hospital in Trondheim, Norway, and colleagues.

In their study, 437 chemonaive patients with stage IIIB/IV disease were randomized to 500 mg/m² of pemetrexed and carboplatin on day one or to 1,000 mg/m² of gemcitabine on day one and eight with carboplatin. Both regimens were repeated every three weeks for up to four cycles.

Despite no advantage for the primary endpoint for health-related quality of life, the pemetrexed-platinum duo again showed significant advantages in tolerability.

Among the transfusion and grade 3/4 toxicity findings for the pemetrexed- and gemcitabine-containing arms, respectively, Dr. Grnberg and colleagues reported:

• Leucopenia (22% versus 44%, PGranulocytopenia (38% versus 48%, P=0.03).
• Thrombocytopenia (24% versus 54%, PBlood transfusions (28% versus 42%, P=0.003).
• Platelet transfusions (3% versus 9%, P=0.007).

"What you are getting more or less is the same survival with all the [platinum-based doublets]," Dr. Scagliotti concluded. "The toxicity is what's making the difference."

Furthermore, pemetrexed has a more convenient dosing schedule than gemcitabine that allows drug infusion once a month rather than twice, Dr. Grnberg noted, though this may be offset by some cost issues.