In addition to late patient presentation, the high mortality rate in lung cancer can be largely attributed to the complex nature of the disease and a very high rate of heterogeneity in the causative molecular abnormalities.
These cancers are classified into subtypes based on underlying genetic mutations, such as epidermal growth factor receptor (EGFR),KRAS,EML4-ALK,c-MET,AKT/p13K, vascular endothelial growth factor (VEGF),ROS-1, insulin-like growth factor (IGF), or epigenetic alterations.1Among these, approximately 10% of patients with nonsmall cell lung cancer (NSCLC) in the United States and 35% in East Asia have tumor-associated mutations in exons 18-21 of theEGFRgene.2-4
In 2013, molecular testing for lung tumors became part of a national protocol, and patients with NSCLC now routinely undergo molecular testing forEGFRmutations. Treatment of select patients with tyrosine kinase inhibitors (TKIs) to block EGFR overactivation has shown an increase in progression-free survival (PFS) by several years. However, only some patients with NSCLC are sensitive to this treatment and, in many instances, acquired secondary mutations are observed in response to TKI therapy.
To understand the basis for nonresponse, as well as the genesis of secondary mutations, researchers want to better understand the molecular interactions leading to tumorigenesis and then design combination therapies that target multiple genetic abnormalities. Resistance to TKI treatment can be caused by primary nonresponse, acquired secondary mutations, interactions between various genetic alterations, or other functional aspects. Numerous clinical trials are under way to evaluate increased effectiveness of gene analysis-based combination treatment for patients with lung cancer (Table). The approach is to combine EGFR inhibitors with other downstream gene modifiers based on the individual patient’s molecular profile. Below is a brief summary of some of these studies.
CTLA-4 indicates cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death ligand 1; TKI, tyrosine kinase inhibitor
On the frontline is the phase II, nonrandomized, pilot trial being conducted by the National Cancer Institute (NCI) to evaluate the effectiveness of genetic analysis in determining targeted therapy for individuals with advanced NSCLC, small cell lung cancer, and thymic cancer.5The study aims to recruit 600 patients by January 2017 and will test the efficacy of erlotinib on patients withEGFRmutations; of AZD6244 on patients withKRAS,BRAF,HRAS, orNRAFmutations; of MK-2206 on patients withPIK3CA,AKT, orPTENmutations; of sunitinib on patients withKITorPDGFRAmutations; and of lapatinib on patients withERBB2mutations. Keeping in mind the likelihood of resistance to these inhibitors, the study has been designed to offer resistant patients a second evaluation and a different treatment option. The results of the study will provide data on a huge patient population in favor of or against a personalized medicine approach for treating lung cancer.
A clinical trial being conducted at the MD Anderson Cancer Center in Houston, in collaboration with AstraZeneca, Bayer, Merck, OSI Pharmaceuticals, Yale University, and the NCI, aims to identify effective regimens (monotherapy or combinations) based on matched biomarker-targeted drug pairs in patients with metastatic NSCLC who were previously treated with either chemotherapy or an EGFR TKI.6This phase II safety/efficacy study is designed to enroll 450 patients by June 2017, and will test drug combinations of erlotinib with MK-2206, with AZD6244 + MK-2206, and with sorafenib. The study results will establish a National Clinical Trials Network (NCTN)mechanism for genetically screeninglarge but homogeneous cancer populations, leading to a master protocol for comparing new targeted therapy to standard of care based on designated therapeutic biomarker-drug combinations.
A phase II GlaxoSmithKline clinical trial is testing the efficacy of the MEK1/MEK2 inhibitor trametinib (GSK1120212) alone and in combination with erlotinib (TKI for EGFR mutation), everolimus (mTOR inhibitor), and chemotherapy drugs docetaxel, pemetrexed, carboplatin, nab-paclitaxel, and gemcitabine.7.
A phase II study sponsored by Pfizer is a nonrandomized trial assessing the impact of daily dacomitinib (EGFR inhibitor) as prophylactic treatment on the incidence of adverse events (AEs, dermatologic and GI) in patients with first-line advanced NSCLC and with anEGFRmutation, postchemotherapy.8The trial will also evaluate the effect of clinical interventions on dacomitinib-induced dermatologic or GI AEs by treatment with either dacomitinib plus blinded doxycycline or placebo, or dacomitinib plus probiotic and topical alclometasone cream. Dacomitinib has previously demonstrated superior antitumor activity versus reversible EGFR TKIs in gefitinib- and erlotinib-sensitive and resistant preclinical models.9
Pfizer is also sponsoring a phase I study to evaluate the effect of PF-05212384 (a PI3K/mTOR inhibitor) in combination with chemotherapy drugs docetaxel or cisplatin or with the EGFR inhibitor dacomitinib in patients with advanced solid tumors to assess the safety, pharmacokinetics, and pharmacodynamics, and the maximum tolerated dose (MTD) in each combination.10
A multiarm, multicohort, phase IIa, open-label study by AstraZeneca is designed to assess the effectiveness of the immunotherapy drug MEDI4736 (an anti-programmed cell death ligand 1 [PD-L1] antibody) in patients with locally advanced or metastatic NSCLC given in sequence with small molecule drugs.11In this study, patients will be given an initial treatment with gefitinib (EGFR inhibitor), AZD9291 (a selective, irreversible EGFR TKI designed to target both the activating sensitizing mutation,EGFRm, andT790M), selumetinib (MEK1/2 inhibitor) + docetaxel (chemotherapy) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated protein-4 [CTLA-4] antibody). Then patients will begin therapy with MEDI4736. The trial will assess the efficacy, safety, and tolerability of these drug combinations.
In another trial, MedImmune and AstraZeneca are testing the combination of an immunotherapy antibody with an EGFR inhibitor. This phase I, open-label, multicenter study will assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of gefitinib (EGFR inhibitor) in combination with MEDI4736 (anti PD-L1) in patients with NSCLC. The study consists of two phases: an escalation phase and an expansion phase to be conducted in patients with locally advanced or metastatic NSCLC.12
Amgen is collaborating in a phase I/II study of erlotinib (EGFR TKI) and AMG 102 (antihepatocyte growth factor antibody) in previously treated patients with advanced NSCLC.13Patients will be enrolled with recurrent or progressive, advanced-stage NSCLC who have been treated with at least one, but no more than two, prior chemotherapy regimens. The phase I part of the study will determine the safety of the AMG 102 and erlotinib combination and the recommended dose for phase II. Phase II will determine whether or not the combination works enough to warrant further interest.
An Astellas Pharma study being conducted at Memorial Sloan Kettering Cancer Center in New York City is a phase I study testing the safety of different ways of taking rilotinib (TKI). The investigators want to find out the effects of the combination of daily low-dose and twice-weekly, high-dose erlotinib on patients with lung cancer. The study will determine the MTD for erlotinib in patients withEGFR-mutant lung cancer14.
A phase I/1b, open-label study, sponsored by Abbvie, is evaluating the safety, pharmacokinetics, and preliminary efficacy of ABBV-399 in patients with advanced solid tumors. The trial is designed to test the effective dose of ABBV-399, as well as this drug in combination with erlotinib, with cetuximab, with bevacizumab, and with carboplatin.15
Finally, Regeneron has sponsored an interventional, nonrandomized, phase I, multicenter dose study of REGN1400 alone and in combination with erlotinib (TKI) or cetuximab administered to patients with certain types of cancer, including NSCLC. Preliminary data show that combination therapy did not appear to potentiate any anti-EGFR-related AEs. Enrollment into combination expansion cohorts is ongoing and will include patients naïve to EGFR inhibitors.16
These studies may collectively indicate how the launch of the national precision medicine initiative by the White House in 2015 has accelerated the trend to make precision medicine a norm rather than an exception. Precision medicine is an approach to treat patients in a way that is mindful of their individual differences in their genes, environment, and lifestyles.
1. West L, Vidwans SJ, Nicholas P, et al. A novel classification of lung cancer into molecular subtypes.PLoS One. 2012;7(2):e31906.
2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med. 2004;350(21):2129-2139.
3. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science. 2004;304(5676):1497-1500.
4. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc Natl Acad Sci U S A. 2004;101(36):13306-133011.
5. Clinicaltrials.gov. Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies.https://www.clinicaltrials.gov/show/NCT01306045.
6. Clinicaltrials.gov. BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study.https://www.clinicaltrials.gov/show/NCT01248247
7. Clinicaltrials.gov. GSK1120212 Rollover Study. https://www.clinicaltrials.gov/show/NCT01376310
8. Clinicaltrials.gov. Study of Dacomitinib (PF-00299804) in Advanced NSCLC Patients (Post Chemo or Select First Line) to Evaluate Prophylactic Intervention on Derm and GI AEs and PRO (ARCHER 1042).https://www.clinicaltrials.gov/show/NCT01465802
9. Gonzales AJ, Hook KE, Althaus IW, et al.Mol Cancer Ther. 2008;7:1880-1889.
10. Clinicaltrials.gov. A study of PF-05212384 in Combination With Other Anti-Tumor Agents. https://www.clinicaltrials.gov/show/NCT01920061
11. Clinicaltrials.gov. Immune-Modulated Study of Selected Small Molecules (Gefitinib, AZD9291, or Selumetinib + Docetaxel) or a 1st Immune-Mediated Therapy (IMT; Tremelimumab) With a Sequential Switch to a 2nd IMT (MEDI4736) in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. https://www.clinicaltrials.gov/show/NCT02179671
12. Clinicaltrials.gov. MED14736 (Anti PD-L1) Combined With Gefitinib in Subjects With Non-Small Cell Lung Cancer (NSCLC).https://www.clinicaltrials.gov/show/NCT02088112
13. Clinicaltrials.gov. AMG 102 and Erlotinib for Advanced Non-Small Cell Lung Cancer.https://www.clinicaltrials.gov/show/NCT01233687
14. Clinicaltrials.gov. Low Dose Daily Erlotinib in Combination With High Dose Twice Weekly Erlotinib in Patients With EGFR-Mutant Lung cancer.https://www.clinicaltrials.gov/show/NCT01967095
15. Clinicaltrials.gov. A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors.https://www.clinicaltrials.gov/show/NCT02099058
16. Clinicaltrials.gov. Study of REGN1400 Alone and in Combination with Erlotinib or Cetuximab in Patients With Certain Types of Cancer. https://www.clinicaltrials.gov/show/NCT01727869