In Advanced Lung Cancer, Targeted Combinations Are Still Works in Progress

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James CH Yang, MD, PhD

In EGFR mutation–positive patients resistant to [tyrosine kinase inhibitors], we need good methods to quantitate resistant biomarkers and conquer heterogeneity.… We must be smarter in designing biomarker-driven trials.

—James CH Yang, MD, PhD

For the treatment of advanced non–small cell lung cancer (NSCLC), combinations of targeted agents are of great research interest but have not yet been shown to improve outcomes. Single-agent treatment with tyrosine kinase inhibitors, therefore, remains the standard of care for patients with specific mutations, according to James CH Yang, MD, PhD, Professor of the Graduate Institute of Oncology and Director of the Cancer Research Center at National Taiwan University College of Medicine in Taipei.

High Benchmark

“Though tyrosine kinase inhibitor combinations are under active investigation as front-line therapy, tyrosine kinase inhibitor monotherapy is still the standard treatment for patients with specific driver mutations such as EGFR or ALK fusion,” Dr. Yang noted at the 15th Annual International Lung Cancer Congress in Huntington Beach, California.

Single-agent tyrosine kinase inhibitors—gefitinib (Iressa), erlotinib, and afatinib (Gilotrif) for patients with EGFR-mutated disease, and crizotinib (Xalkori) and ceritinib (Zykadia) in patients with ALK fusions—produce high response rates (60%–70%) and very high disease control rates (85%–95%). Compared to the standard median 5 to 7 months of progression-free survival for platinum-based chemotherapy, these tyrosine kinase inhibitors provided a progression-free survival of  9 to 14 months, he noted.

“If we want to combine any drugs with these agents and beat these outcomes, it will be difficult. The long progression-free survival associated with currently available [tyrosine kinase inhibitor] treatment in patients with specific mutations is a very high benchmark,” according to Dr. Yang.

“On the other hand, targeted therapy combinations are also intensively evaluated in patients who have progression of their tumor after [tyrosine kinase inhibitor] treatment. Acquired resistance to EGFR tyrosine kinase inhibitors is an important issue for patients with EGFR mutations, and novel salvage treatments are much needed in this population. Since different resistant mechanisms may emerge after acquiring resistance to [tyrosine kinase inhibitors], combination therapy would be better tested using molecularly characterized rebiopsy samples,” he said.

Combinations With Chemotherapy

Summarizing the data on the combination of chemotherapy plus an EGFR tyrosine kinase inhibitor, Dr. Yang noted that no benefit was shown for adding gefitinib or erlotinib to chemotherapy in the INTACT-1,1 INTACT-2,2 ­TRIBUTE,3 and TALENT4 trials, nor was there benefit in adding paclitaxel and carboplatin to erlotinib in never-smokers in the CALGB 30406 study.

However, benefit was shown in progression-free and overall survival for adding intercalated erlotinib to gemcitabine plus cisplatin or carboplatin in FASTACT 15 and FASTACT 2,6 in an EGFR mutation–positive subgroup. Progression-free survival advantage was shown when afatinib was added to paclitaxel in the fourth- or fifth-line setting in LUX-Lung-5 study, but there was no difference in overall survival outcome.7

He commented, “We saw differences in important outcomes using a strategy of intercalating erlotinib to chemotherapy in  the FASTACT 2 study in patients with EGFR mutations.” In that subset, progression was reduced by 75% (P < .0001) with the combination, and deaths were reduced by 52% (P = .0092). “However, we have to compare intercalating therapy to EGFR [tyrosine kinase inhibitor] monotherapy in EGFR muation–positive patients in order to show that this strategy is successful,” he said.

Regarding the Lux-LUNG-5 trial, Dr. Yang suggested that a population of patients who had benefit from prior gefitinib or erlotinib and again received benefit of afatinib and managed to receive at least four lines of treatment may be quite different from the average NSCLC patient.

These mixed results led Dr. Yang and his colleagues to revisit the results of the INTACT, TRIBUTE, and ­TALENT studies, according to EGFR mutation status, in a meta-analysis of 23 trials that evaluated EGFR inhibitors as monotherapy or in combination with chemotherapy.8 In the four above-mentioned trials, which initially were negative, EGFR mutation–positive patients did derive a progression-free survival benefit (hazard ratio [HR] = 0.54). In the mutation-negative group, the effect was less pronounced, though still present (HR = 0.82).

“It seems that if we separate patients according to EGFR mutation status, there could be added benefit for combining an EGFR inhibitor with chemotherapy. This was not seen originally because we lumped these groups together,” he said.

“Adding chemotherapy to an EGFR [tyrosine kinase inhibitor] was shown at least in some studies to be effective in terms of progression-free survival.”

Findings from the IMPRESS trial, expected soon, will indicate whether patients for whom gefitinib fails will benefit from gefitinib plus pemetrexed/platinum, vs chemotherapy alone.

Combinations With Antiangiogenesis Agents

Activity has recently been shown for a tyrosine kinase inhibitor plus an antiangiogensis agent, but requires confirmation, Dr. Yang said.

The Japanese JO25567 trial randomly assigned 150 chemotherapy-naive EGFR-mutation-positive patients to erlotinib alone or with bevacizumab, demonstrating a 6.3-month difference in progression-free survival with the combination (P = .0015; HR = 0.54).9 The phase III BeTa trial of erlotinib vs erlotinib plus bevacizumab in 636 unselected chemotherapy-treated patients showed no difference in progression-free survival, although the hazard ratios were impressive in Asians (HR = 0.26) and nonsmokers (HR = 0.39).10

“I think we need to examine these trial data seriously and confirm them in a large randomized study,” Dr. Yang suggested. “The important question, however, still remains: is overall survival also improved?”

Combinations With Novel Targeted Agents

Many randomized trials of an EGFR tyrosine kinase inhibitor with or without a drug targeting another pathway have been negative (Table 1). “Unselected populations may be the key failure factor. And even in the right population, it’s not only about the right mutations—the associated targeted molecules will be important as well,” Dr. Yang suggested.

For example, targeting cMET is thought to be of importance. However, the global phase III MetLung trial of onartuzumab plus erlotinib was disappointing.11 Dr. Yang suggested that the negative results might be a reflection of the method for measuring cMET for patient selection.

“There are many tests for cMET—fluorescence in situ hybridization (FISH) for cMET DNA amplification, quantitative reverse transcription polymerase chain reaction (PCR) for mRNA amount, or immunohistochemistry for protein expression—and we don’t know which is best and what is the cutoff point for cMET to be important in driving tumor cells to grow,” he indicated.

In addition, the level of extracellular hepatocyte growth factor (the ligand of cMET) could be a confounder, as production of this growth factor is a resistance mechanism in EGFR-mutant NSCLC. 

It is also difficult to draw conclusions, he added, from recent studies showing activity for the cMET inhibitor INC280 in combination with gefitinib, since it is unclear whether the responses are to both agents or to either agent alone. He added that much work needs to be done to understand acquired resistance, and how to test for and target the relevant and sometimes overlapping mutations.

For example, by testing only for the EGFR mutation T790M or the cMET mutation, patients harboring both abnormalities could be undertreated. Some, though clearly not all, would require a T790M mutation–specific drug such as AZD9291 and also a cMET inhibitor such as crizotinib or any new cMET inhibitors that are in development.

That aside, he added that AZD9291 monotherapy is an effective treatment for patients who fail to benefit from EGFR tyrosine kinase inhibitor therapy and who harbor the T790M mutation. At this year’s ASCO Annual Meeting, Jänne et al reported a response rate of 64% and disease control rate of 94% with this approach.12 “Though we know there will be some cMET mutation–positive patients in there, we still see very good responses,” he said.

“In EGFR mutation–positive patients resistant to tyrosine kinase inhibitors, we need good methods to quantitate resistant biomarkers and conquer heterogeneity. If we want to add targeted agents, we need to know how to measure resistant pathways in tumor cells to predict that a corresponding agent will be effective. We must be smarter in designing biomarker-driven trials,” Dr. Yang said. ■

Disclosure: Dr. Yang has received honoraria from AstraZeneca, Roche/Genentech, Pfizer, Novartis, Merck Serono, MSD, Bayer, Clovis Oncology, and Boehringer Ingelheim for an advisory role or as a speaker.


1. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine plus cisplatin in advanced non-small –cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004.

2. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel plus carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004.

3. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005.

4. 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. J Clin Oncol 25:1545-1552, 2007.

5. Mok TS, Wu YL, Yu CJ, et al: Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 27:5080-5087, 2009.

6. Wu Y-L, 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 14:777-786, 2013.

7. Schuler MH, Yang J 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. ASCO Annual Meeting. Abstract 8019. Presented June 3, 2014.

8. 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. J Natl Cancer Inst 105:585-605, 2013.

9. Kato T, Seto T, Nishio M, et al: Erlotinib plus bevacizumab versus erlotinib alone as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer: An open-label randomized trial. ASCO Annual Meeting. Abstract 8005. Presented June 2, 2014.

10. Herbst RS, Ansari R, Bustin F, et al: Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): A double-blind, placebo-controlled, phase 3 trial. Lancet 377:1846-1854, 2011.

11. Spigel DR, Edelman MJ, O’Byrne K, et al: Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial. ASCO Annual Meeting. Abstract 8000. Presented June 2, 2014.

12. Jänne PA, Ramalingam SS, Yang JC, et al: Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor-resistant non-small cell lung cancer. ASCO Annual Meeting. Abstract 8009. Presented May 31, 2014.