The Lynx Group

Mixed Results with Postprogression EGFR Inhibition in Advanced Non–Small-Cell Lung Cancer

October 2014, Vol 5 , No 8

Madrid, Spain—Continuing an EGFR inhibitor after acquired resistance does not slow the progression of advanced non–small-cell lung cancer (NSCLC) in patients receiving chemotherapy, according to a report presented at the 2014 European Society for Medical Oncology (ESMO) Congress. However, extending anti-EGFR therapy with erlotinib beyond disease progression may be beneficial, according to a second report presented at the meeting.

Adding Gefitinib to Chemotherapy

Patients who continued gefitinib during initial chemotherapy had a median progression-free survival (PFS) of 5.4 months, which was identical to patients who received placebo at the start of cisplatin-pemetrexed chemotherapy.

“This is the first and only randomized, phase 3 study to confirm that continuation of gefitinib in addition to cisplatin-pemetrexed chemotherapy would be of no clinical benefit for patients with acquired resistance to gefitinib,” said Tony Mok, MD, Professor of Clinical Oncology, Chinese University of Hong Kong. “Thus, the standard of care should remain doublet chemotherapy alone.”

During a late-breaking presentation at the Presidential Symposium, Dr Mok noted that most patients with advanced NSCLC respond to an EGFR inhibitor, but inevitably, virtually all develop acquired resistance and the disease progresses, at which point most begin chemotherapy.

Some evidence has suggested that continuing an EGFR inhibitor with chemotherapy at least partly overcomes acquired resistance, resulting in an additional progression-free interval that extends beyond what is expected with chemotherapy alone. To test this hypothesis, investigators at 71 centers in Europe and Asia Pacific enrolled and treated 265 Asian patients with advanced/metastatic NSCLC with documented activating EGFR mutations. All patients had initially received gefitinib, and the disease had met the Response Evaluation Criteria in Solid Tumors (RECIST) for progression. Patients were randomized to either continue gefitinib with chemotherapy or to receive a placebo plus chemotherapy.

The primary end point was PFS, and the secondary end points included OS, objective response rate, disease control rate, and safety/tolerability.

The results showed an identical duration of PFS in the 2 treatment groups; OS remained immature at the analysis. Nonetheless, the available data showed a significant increase in the survival hazard in the gefitinib group versus the placebo group (hazard ratio, 1.62; P = .029).

Extending Erlotinib Therapy beyond Disease Progression
In a related presentation at ESMO, investigators reported that extending the EGFR inhibitor erlotinib beyond progression resulted in a second PFS (PFS2; time from progression to discontinuation of treatment or death) with a longer duration than the first PFS (PFS1; start of treatment to progression).

This study of extending anti-EGFR therapy beyond disease progression involved 207 Asian patients with stage IV EGFR-positive NSCLC. All patients had disease progression by RECIST criteria, reported Keunchil Park, MD, PhD, Professor of Medical Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The phase 2, open-label trial had a primary end point of first PFS. Secondary end points included PFS2, objective response rate, best objective response, OS, and PFS1 in the subgroup of patients with the exon 19 deletion.

Subsequently, disease progression occurred in 150 patients, of which 81 continued erlotinib and 69 did not. Patients continuing erlotinib had a median PFS1 of 9.3 months versus 7.2 months among patients who did not. In the patients who continued erlotinib, the median PFS2 exceeded the PFS1 by 3.7 months. The objective response rate was 65.2%, and the disease control rate was 82.5%. Among patients who had centrally confirmed exon 19/L858R mutations, the median PFS1 was 11 months (N = 144), and the median PFS2 was 13.1 months (N = 54).

“The data show that continuing erlotinib beyond RECIST progression is feasible, with a difference between PFS1 and PFS2 of 3.7 months in postprogression erlotinib-treated patients,” said Dr Park. “However, validation of the optimal patient subset to benefit from postprogression erlotinib needs further research.”

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