ECOG Seeks New Agents to Make Greater Headway Against Advanced Non–Small-Cell Lung Cancer

NASHVILLE, Tennessee—Conceding that treatment of advanced non–small-cell lung cancer (NSCLC) has made only limited progress in the past decade, members of the Eastern Cooperative Oncology Group (ECOG) have vowed to pursue newer chemotherapeutic agents aggressively. ECOG’s focus has changed, according to David H. Johnson, MD, director of hematology and oncology with the Vanderbilt-Ingram Cancer Center, Nashville. Investigators now see the promise in new biological agents with novel mechanisms of action that might be integrated into current chemotherapeutic regimens.

“We in ECOG really feel like shifting around the deck chairs on the Titanic is not what we want to be doing in the next decade,” Dr. Johnson said. “So we are anxious to look at some of these newer agents. Everybody is saying they want to do it now, but the reality is somebody has to take the bull by the horns and actually do it, and that’s what we are looking to do.”

To find candidates, ECOG will be drawing on their own research and looking to the results of other groups. Two promising candidates, Dr. Johnson reported, include recombinant humanized monoclonal antibody to vascular endothelial growth factor (rhuMAb-VEGF) and trastuzumab (Herceptin).

Studies With rhuMAb-VEGF

A phase-II study, presented earlier this year at the annual meeting of the American Society for Clinical Oncology (ASCO), suggested that rhu-MAb-VEGF, an antiangiogenic approach, plus chemotherapy may provide a survival benefit for patients with stage IIIB/IV disease.

The study compared rhu-MAb-VEGF plus carboplatin (Paraplatin)/paclitaxel (Taxol) with carboplatin/paclitaxel alone. Investigators found that rhuMAb-VEGF at a high dose seemed to increase overall response rate and time to progression, albeit with a higher incidence of hemorrhage, possibly related to squamous cell carcinoma histology.

Based on these findings, ECOG has proposed a phase III investigation of chemotherapy with or without rhuMAb-VEGF and excluding patients with squamous histology.

Trastuzumab Enhances Survival

Another tack is to draw upon the progress that has been made in related fields, such as breast cancer. Current investigations show that trastuzumab enhances survival when used with chemotherapy in HER2/neu-positive patients with advanced breast cancer. (Overexpression of HER2/neu is seen in approximately 30% of adenocarcinomas among NSCLC cases.)

Preliminary results from an ECOG study on trastuzumab in non–small-cell lung cancer suggest that this agent added to the carboplatin/paclitaxel combination may provide similar benefit in NSCLC. Accordingly, another phase III trial has been proposed, in which HER2/neu-positive patients would be randomized to chemotherapy plus trastuzumab or chemotherapy alone, with an endpoint of overall survival.

Natural Progression

The move to biologic agents represents a natural progression from ECOG experience dating as far back as the late 1970s and early 1980s, when cisplatin plus etoposide (VePesid) was identified as the least toxic and most consistent combination in NSCLC in terms of consistency in 1-year survival rate.

In subsequent trials using cisplatin/etoposide as a reference arm, investigators found median survivals of approximately 25 weeks, with 1-year survival typically no more than 20%. While disappointing, these early studies elucidated the role of performance status in NSCLC; namely, poor performance status (ie, PS ³ 2) correlated with higher risk of serious toxicities and shorter median survivals.

The search continued for new drugs with good activity, using chemotherapy-naïve patients with good performance status and measurable stage IV non–small-cell lung cancer.

Variety of Agents

The first trial was E1583, which compared both single-agent iproplatin and carbo-platin to several combinations containing cisplatin. Carboplatin’s overall response rate was only 9%, but yielded the best median survival, though 1-year survival did not differ from that achieved in earlier ECOG combination chemotherapy trials in stage IV patients.

Over the next 10 years, ECOG conducted phase II trials in stage IV patients looking at a variety of agents, including everything from gallium nitrate to teniposide (VM-26, Vumon) to trimetrexate (Neutrexin).

Paclitaxel Shows Benefit

Of the agents studied, the only one found to have acceptable activity was paclitaxel, which, as researchers did not expect, also seemed to confer a 1-year survival advantage of approximately 40% vs historical data. This finding was corroborated by M. D. Anderson investigators who reported “virtually identical results,” Dr. Johnson said.

A subsequent 574-patient phase III trial showed that cisplatin plus paclitaxel provided significantly greater survival than cisplatin plus etoposide. Thus, cisplatin/paclitaxel was chosen to be the reference arm for ECOG 1594, the much-anticipated 1,200-patient phase III trial reported at the ASCO 2000 meeting, which compared four current regimens head to head: cisplatin/paclitaxel vs cisplatin/docetaxel (Taxotere), cisplatin/gemcitabine (Gemzar), and carboplatin/paclitaxel.

In ECOG 1594, no regimen emerged as better than the reference arm in survival; overall median survival was 8 months. The response rate of carbo-platin/paclitaxel was lower than in the reference arm. In addition, updated data presented at the World Conference on Lung Cancer showed survival at 2 years was 15.7% in the gemcitabine arm, compared with survival ranging from 10.5% to 11.5% in the other three arms.

Dr. Johnson said that he is excited by the opportunity to explore new routes of enhancing efficacy, not only with trastuzumab and rhuMAb-VEGF, but with other emerging strategies such as tyrosine kinase inhibition.

“We are seeing a lot of enthusiasm for exploring new combinations that hopefully will retain the efficacy of platinum-based regimens but with less toxicity,” Dr. Johnson said. “It’s almost mind boggling. For a decade or more, we worked with five drugs, none of which worked very well. Now it’s really become almost like kids in a candy shop.”