James CH Yang, MD, PhD
Tyrosine kinase inhibitors (TKIs) are effective as single agents in EGFR-positive non-small cell lung cancer (NSCLC), but investigators continue to ask questions about how to improve the results of these agents.
Can TKIs be combined with other drugs to produce better responses in patients? James CH Yang, MD, PhD, professor of medicine and deputy director of the Department of Medical Oncology at National Taiwan University Hospital, tackled that topic July 31, 2014, in a talk at the 15th
Annual International Lung Cancer Conference, in Huntington Beach, California.
Five TKIs are approved for use in NSCLC: EGFR TKIs gefitinib, erlotinib, and afatinib, and ALK-targeting TKIs crizotinib and ceritinib, Yang pointed out. Those drugs confer a response rate of 60% to 70%, a disease control rate of 85% to 95%, and progression-free survival (PFS) of 9 to 14 months, according to Yang.
“If we want to combine any drugs with single-agent TKIs and beat single-agent TKIs in patients with specific mutations, it would be a very difficult job,” Yang said.
In Yang’s view, hopes for achieving that lie in chemotherapies, anti-angiogenic agents, HSP90 drugs, EGFR monoclonal antibodies, and PD-1/PD-L1 antibodies for patients with corresponding mutations. Many of these have been studied in combination with EGFR TKIs; fewer studies have been conducted with ALK TKIs, although more are expected down the road, according to Yang.TKIs With Chemotherapy
Adding chemotherapy to EGFR TKIs is nothing new. “We had trials with an EGFR TKI (gefitinib or erlotinib) plus chemotherapy (a platinum doublet) compared to chemotherapy alone in unselected patients as a frontline [therapy]. In the TALENT study,1
we used 4000 patients to prove that these drugs do not add anything to chemotherapy [as far as overall survival],” Yang said. “CALGB just published study 30406 showing there was no [PFS] benefit to adding carboplatin/paclitaxel to erlotinib in never-smokers.”2
However, there were PFS and overall survival (OS) benefits demonstrated with this strategy in the FASTACT 1 and 2 studies, especially in patients with EGFR mutations, according to Yang. FASTACT 2 used a strategy of intercalating the drugs, or interspersing them, rather than giving them concurrently, because these drugs were thought to work antagonistically when given together, Yang explained.
While FASTACT 2 demonstrated a better PFS when erlotinib was added to gemcitabine and cisplatin3
compared with the chemotherapy doublet alone, Yang found fault with the study’s design. “These are EGFR mutation-positive patients, so the control should be erlotinib, not chemotherapy,” he said. “This is a problem of this study.”
Some benefit was also reported this year in the Lux-Lung 5 study of afatinib plus paclitaxel versus chemotherapy alone in patients with metastatic NSCLC who had progressed on erlotinib/gefitinib and afatinib.4
Patients demonstrated a median PFS of 5.6 months in the combination arm versus 2.8 months in the chemotherapy-alone arm (hazard ratio [HR] 0.60; CI: 0.43-0.85; P
= .003). The overall response rate was also significantly higher in the combination arm versus the control arm (32.1% vs 13.2%; P
Further, a benefit was seen when Yang and colleagues conducted a meta-analysis of the INTACT 1 and 2, TRIBUTE and TALENT studies.5
The investigators determined which patients were EGFR-positive and considered how they had responded to treatment with an EGFR TKI plus chemotherapy, in contrast to chemotherapy alone.
“We did find a difference, if we combined all 4 studies, in terms of PFS time in EGFR mutation-positive patients (HR 0.54),” he said. “So it seems that, if we separate these patients with an EGFR mutation, there could be some added benefit of combining these two [treatments]. The reason we did not see it before is that we lumped them together.”
More information on combining TKIs with chemotherapy will be generated in the IMPRESS trial, which “will tell us whether combining pemetrexed/cisplatin plus gefitinib will have benefit over chemotherapy alone after gefitinib failure,” Yang said.TKI With an Anti-Angiogenic Agent
Although the BETA study of 600 unselected patients with lung cancer who had failed chemotherapy found no difference in PFS using erlotinib either with or without bevacizumab, a more recent study, J025567, demonstrated positive results.6