New Research Focuses on Benefits of Targeted Agents in the Treatment of Advanced Non-small Cell Lung Cancer

New Research Focuses on Benefits of Targeted Agents in the Treatment of Advanced Non-small Cell Lung Cancer

The use of new targeted agents to treat patients with advanced non-small cell lung cancer (NSCLC) may open new avenues to improved clinical results and better quality of life for patients, if these patients can be appropriately selected for studies. Results of several trials presented at the Lung Cancer–Metastatic Oral Abstract Session yesterday provoked interest and raised questions about the direction of future trials of these agents.

The efficacy of pemetrexed as maintenance therapy following standard treatment was outlined by Chandra P. Belani, MD, of Hershey Cancer Institute (CRA8000). Preliminary results of this study presented at the 2008 ASCO Annual Meeting demonstrated that maintenance therapy with pemetrexed delayed disease progression, but this is the first time a significant improvement in overall survival has been shown in this setting. In this randomized, double-blind, phase III study, patients were treated with pemetrexed (441 patients) or placebo (222 patients), along with best supportive care. All patients had stage IIIB or IV NSCLC (both squamous and nonsquamous subtypes) that had not progressed after four cycles of platinum-based chemotherapy.

Patients treated with pemetrexed had an overall survival of 13.4 months, compared with 10.6 months for patients in the placebo group (p = 0.012). For the nonsquamous subgroup (481 patients), overall survival was 15.5 months for patients receiving pemetrexed, compared with 10.3 months for patients receiving placebo (p = 0.002). Patients with the squamous histology did not seem to benefit from pemetrexed, confirming results seen in previous studies.

Severe (grade 3 or 4) side effects were low, but more common in the pemetrexed group, specifically fatigue (5% in the pemetrexed group vs. 1% in the placebo group) and low white blood cell counts (3% vs. 0%). Side effects did not increase for patients who received pemetrexed for a longer period of time, and there were no drug-related deaths. “Nonsquamous histology is predictive of the improved efficacy of pemetrexed in patients with advanced NSCLC,” said Dr. Belani. “It is very easy to say that a 5-month improvement in overall survival is significant.”

Similar positive results from the addition of erlotinib were seen in the Sequential Tarceva in Unresectable NSCLC (SATURN) Trial, presented by Federico Cappuzzo, MD, of the Instituto Clinico Humanitas IRCCS, Italy (Abstract 8001). This trial hypothesized that erlotinib, given immediately following first-line chemotherapy, would delay disease progression.

For this study, 1,949 patients with advanced NSCLC were treated with a platinum-based doublet regimen; 889 patients with no progressive disease after this treatment underwent mandatory tumor sampling and were then stratified by epithelial growth factor receptor (EGFR) immunohistochemistry (IHC); stage (IIIB vs. IV); Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1); chemotherapy regimen; and smoking history. Patients were randomly assigned to one of two arms: placebo or erlotinib, until disease progression.

Progression-free survival was significantly improved for all patients receiving erlotinib (p < 0.0001) and for patients who were EGFR IHC-positive (p < 0.0001). The disease control rate (complete response plus partial response plus stable disease of at least 12 weeks) was 40.8% with erlotinib and 27.4% with placebo (p < 0.0001). “The clinical benefit of erlotinib was seen across the majority of patient subgroups, irrespective of histology, race, or smoking status,” said Dr. Cappuzzo.

The important question raised by these studies is one that a patient might ask: “Does the earlier initiation of these agents in my care result in my living longer or living better?” said Nasser H. Hanna, MD, of Indiana University, in reviewing these studies. He noted that, although there are more grade 3 and 4 toxicities — albeit at low rates — with pemetrexed described in Abstract 8000, “in my view, grade 1 and 2 hematological toxicities are not trivial. There was no reported difference in quality-of-life deterioration between pemetrexed and placebo arms.” Although agreeing that the study reinforces the efficacy and activity of pemetrexed, he did not think this study proved that the maintenance strategy was the cause of improved survival.

“Improved progression-free survival alone is less meaningful unless it also results in patients’ experiencing decreased cancer symptoms, fewer complications of their cancer, and improved quality of life,” he said. “None of that has been demonstrated in these studies.”

Physicians can personalize treatment by offering patients supportive care that eases symptoms; however, patients’ life expectancy is very short, and exposing them to even mild toxicities of treatment may not be worthwhile.

The next study (CRA8003) showed that the use of vandetanib, an oral inhibitor of vascular endothelial growth factor receptor, EGFR, and rearranged during transfection (RET) signaling, when added to treatment with docetaxel, resulted in a significant improvement of progression-free survival for patients with previously treated advanced NSCLC. Roy S. Herbst, MD, PhD, of M.D. Anderson Cancer Center, noted that the results of the Zactima in Combination with Docetaxel in Non-small Cell Lung Cancer (ZODIAC) trial show that vandetanib is the first oral targeted therapy in phase III trials to show significant evidence of clinical benefit when added to standard chemotherapy for these patients. These results had been seen already in phase II studies of vandetanib and docexatel.

In this study, 1,391 patients who had been treated previously with chemotherapy were randomly assigned to receive either docetaxel combined with vandetanib (vandetanib 100 mg/day plus docetaxel 75 mg/m2 every 21 days for a maximum of six cycles), or docetaxel and placebo. The median progression-free survival was 4 months in the vandetanib arm compared with 3.2 months in the control arm (p < 0.001); the overall response rate for patients in the vandetanib arm was 17%, compared with 10% in the placebo arm (p < 0.001). Time to deterioration of symptoms, based on the FACT-L Lung Cancer Subscale, also was significantly improved for patients receiving vandetanib (p < 0.001). Similar progression-free survival benefits were observed for patients with adenocarcinoma and squamous histologies.

This trial showed that vandetanib improved response rate, progression-free survival, and quality of life, but it did not show a difference in overall survival, said Martin J. Edelman, MD, of the University of Maryland Greenebaum Cancer Center. In his critique of the study, Dr. Edelman suggested that progression-free survival may not be a valid endpoint for a definitive trial. Overall survival is a clear endpoint with an exact measurement; its disadvantage may be that there could be “contamination” from subsequent therapy. However, progression-free survival is a subjective endpoint with varying definitions; its only advantage may be that it is a “pure assessment” of a drug’s activity.

Results of the ZODIAC trial and others involving targeted agents are showing researchers and physicians that there may be only a subset of patients who benefit from these agents, although there could be a group that is harmed as well. “There is a very real possibility that tumor growth is enhanced by some of these agents,” said Dr. Edelman. “Phase III trials in unselected populations may lead to erroneous conclusions about the lack of drug activity or, even when positive, fail to identify those most likely to benefit and expose a large proportion of patients to ineffective treatment.” Vandetanib improves progression-free survival and quality of life, but the specific population that is most likely to receive the maximum benefit from this agent remains to be definitively identified.

Figure: Overall survival and progression-free survival.