In NSCLC After Progression on First-line TKI, What Next?

Zosia Chustecka

September 29, 2014

MADRID — New clinical trial data in non-small cell lung cancer (NSCLC) address an important clinical question: Once a patient who has tested positive for EGFR and been treated first-line with a tyrosine kinase inhibitor (TKI) starts to progress, as they almost inevitably do after about 10 months, what is the next step?

There are several options, including continuing therapy with the TKI and adding on chemotherapy or stopping the TKI and using chemotherapy alone.

Dr. Tony Mok

There are a few arguments for continuing with the TKI, commented Tony Mok, MD, PhD, professor in the Department of Clinical Oncology at the Chinese University of Hong Kong. Sometimes stopping the TKI results in a disease flare, and there are also considerations of tumor heterogeneity; some cancer clones may have become resistant to the TKI, but others may still respond.

Dr. Mok said that he suspected that the combination of inhibiting TKI-sensitive cancer cells with the targeted drug plus inhibiting the resistant cells with chemotherapy would optimize the treatment outcome. However, the clinical data "show otherwise," he said.

Dr. Mok presented results from the IMPRESS study here at a presidential session at the European Society for Medical Oncology (ESMO) Congress 2014. They show that there is no extra benefit from the combination of TKI and chemotherapy, and so the standard treatment at this point should be chemotherapy alone, he said.

The main message from the IMPRESS study is that after progression on first-line TKI therapy, the combination of chemotherapy plus TKI should not be used, especially as there was a suggestion of a deterimental effect, said Solange Peters, MD, PhD, from the University of Lausanne in Switzerland, who acted as a discussant for the study.

Commenting on the study, Marina Garassino, MD, from medical oncology division of the National Cancer Institute of Milan, said in a statement that the results from the IMPRESS study were "very robust and reliable, and they will help clinicians in their daily clinical practice."

Randomization After Progression

The IMPRESS trial was conducted in Europe and Asia and involved 265 patients with locally advanced or metastatic NSCLC with an activating EGFR mutation who received gefitinib (Iressa, AstraZeneca) as first-line therapy.

At the press briefing, Dr. Mok said that he would expect that the results would apply also to erlotinib (Tarceva), which is the TKI used most widely in the United States.

When patients had disease progression (on RECIST criteria), they were randomized to continue on gefitinib (250 mg/day) or placebo, and all patients also received chemotherapy (cisplatin 75 mg/m² and pemetrexed 500 mg/m²).

So one group received gefitinib plus chemotherapy and the other group chemotherapy alone.

The primary end point was progression-free survival, and there was no difference between the 2 groups — median progression-free survival was 5.4 months in both groups.

The data for overall survival (a secondary end point) are "very immature," Dr. Moke commented, but at present they favour the placebo group. The median overall survival was 14.8 months with gefitinib plus chemotherapy compared with 17. 2 months with chemotherapy alone (a difference of 3.6 months, which was statistically significant; P = .029).

"I certainly believe that these data are immature (only 33% of events) and that they will change with time," Dr. Mok commented, but as they show a potential detrimental effect "we felt obliged to share these data."

Further analysis showed that there were fewer patients under 65 years old who had brain metastases in the placebo group (23% vs 33% on gefitinib), and also that more patients in the placebo group had a better response to first-line gefitinib (76% in the placebo group had had a complete response vs 68% in the gefitinib group). In addition, the poststudy treatment was different in the 2 groups, with more patients in the placebo group going on to receive chemotherapy (12.9% vs 3.8% on gefitinib) and/or a TKI (33.3% on placebo vs 22.6% on gefitinib).

Although these are post hoc analyses, these differences between the groups may have contributed toward the differences in overall survival, Dr. Mok said.

IMPRESS is the first and only randomized phase 3 study to confirm that continuation of gefitinib in addition to chemotherapy would be of no clinical benefit for patients with acquired resistance to gefitinib, he concluded.

"This study was designed to resolve a greatly debated issue: whether tyrosine kinase inhibitors should be continued beyond progression," Dr. Mok said in a statement. "As the result demonstrated no difference in progression-free survival, the standard treatment is chemotherapy alone," he added.

Some Benefit From Continuing on TKI?

However, at the ESMO meeting, there was also another trial presented that suggested there may be some benefit from continuing with a TKI on first progression. These data come from ASPIRATION, a smaller, phase 2 study that was not randomized, which followed patients with EGFR-positive NSCLC who received erlotinib as first-line treatment. The median progression-free survival on first-line treatment was 10.8 months, and after progression (as measured by RECIST criteria), the researchers continued these patients on erlotinib and gained another 3.4 months free from the next progression.

Asked to comment on the findings and their implications for clinical practice, Floriana Morgillo, MD, from the Second University of Naples in Italy, explained that the RECIST criteria are "very strict." They define progression as a 20% increase in the diameter of the tumor, but this may not yet signify clinical progression, she told Medscape Medical News. It may be that the tumor is becoming resistant to the TKI, but some cancer clones are still responsive, and there is still some benefit to be derived from continuing with the TKI, as suggested by the data from the ASPIRATION study.

However, when there are further signs of progression, such as a further increase in size of the index lesion, or development of other metastases, or clinical symptoms, then it becomes apparent that the disease really is progressing, she said. Then it is time to stop the TKI and use chemotherapy, as suggested by the results of the IMPRESS study, she commented.

At the press briefing, Dr. Mok mentioned the results from the ASPIRATION study, and said that there is some debate about what is meant by "progression of disease." The RECIST criteria were developed for gauging the effects of chemotherapy, and they may not apply quite as well to the effects seen with targeted drugs, he said.

Dr. Peters also highlighted the ASPIRATION results in her discussion, in addition to other clinical trials that have been conducted in this field, and commented: "I think that first-line TKI should be continued for as long as possible."

She also discussed other possibilities for treatment after progression on first-line TKI, including the potential use of immunotherapies (none of which are approved yet in lung cancer) and trying other TKI inhibitors, noting there has been some success in the small percentage of patients who develop the T790M mutation with the investigational compounds AZD-9291 and CO-1686, as previously reported by Medscape Medical News.

But Dr. Peters emphasized that the treatment strategy that should not be used after progression on first-line TKI is the combination of TKI with chemotherapy; if chemotherapy is to be used, it should be used alone.

The study was funded by AstraZeneca,the manufacturer of gefitinib. Dr. Mok reports serving as an adviser for AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, and BioMarin. Dr. Peters has disclosed no relevant financial relationships.

European Society for Medical Oncology (ESMO) Congress 2014: Abstract LBA2_PR. Presented September 28, 2014.

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