TKIs Combined With Other Drugs May Prove More Effective in NSCLC

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.

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 = .005).

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

In that Japanese study, patients with the EGFR mutation were randomized to erlotinib with or without bevacizumab, and there was “a huge difference in PFS time that we have not seen before,” Yang said. PFS was 16 months for the combination versus 9.7 months with erlotinib alone. “Probably there is something in bevacizumab that we should reconsider, and repeat the study that the Japanese did in EGFR-positive patients to prove that adding bevacizumab to an EGFR TKI did increase PFS time.”

An additional question for that trial, he said, is whether OS can also be improved.

TKIs With Other Targeted Agents

Randomized trials of EGFR TKIs with or without another targeted drug have included treatment with c-MET inhibitor tivantinib, HER3-targeting agent MM-121, IGFR-targeting agent figitumumab, HGF inhibitor ficlatuzumab, MET inhibitor onartuzumab, and VEGFR-targeting agent vandetanib. The results with all of those trials, which were both small and large and in groups of selected and unselected patients, were negative, according to Yang.

“It’s difficult to get a positive result if you do not select the right population,” Yang said. “By that, we mean not only the right driver mutations, but also associated molecules.”

Yang noted that investigators need to know what mechanisms of resistance their trial enrollees have, something that can be achieved via biopsies both before and after TKI failure.

For example, he said, “Nowadays, in a trial, if we test for T790M only, we will miss those who have cMET simultaneously, so 21% probably will not respond. If we only check for cMET, those 60% with T790M probably will not respond if we do not add the right agent, for example gefitinib.”

However, Yang did cite a study in which cMET was not a major obstacle. The study of monotherapy with the experimental AZD9291 in patients who had failed EGFR TKIs was “very, very effective,” he said, and testing for cMET was unnecessary, because patients with that mutation had a good response to the drug.

Yang emphasized the importance of having good methods for quantitating resistant biomarkers and conquering disease heterogeneity.

“If we want to add these targeted agents, we probably don’t know the answer about what will be the proportion of cells that need to be positive to predict that a drug will be effective, so we must be smarter in the future to test for these mutations,” he said.


  1. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. JCO. 2007;25(12):1545-1552.
  2. Janne PA, Wang X, Socinski MA, et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. JCO. 2012;30(17):2063-2069.
  3. Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small cell lung cancer (FASTACT-2): a randomized, double-blind trial. Lancet Oncol. 2013;14(8):777-786.
  4. Schuler MH, Yang C-H, Park K, et al. Continuation of afatinib beyond progression: results of a randomized, open-label, phase III trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy in patients with metastatic non-small cell lung cancer progressed on erlotinib/gefitinib and afatinib—LUX-Lung 5. JCO. 2014;32:5s (suppl; abstract 8109).
  5. Lee CK, Brown C, Gralla RJ, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. JNCI. 2013;105(9):595-605.
  6. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation—positive nonsquamous non-small cell lung cancer (NSCLC): An open-label randomized trial. JCO. 2014;32:5s (suppl; abstract 8005).


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