Personalized targeted therapy in advanced non–small cell lung cancer

Sensitizing mutations lead to better response

With the approval and clinical use of EGFR-TKIs came knowledge of EGFR kinase mutations that sensitize the mutated RTK to EGFR-TKI; this mechanism translates into dramatic tumor responses.^9,10 Certain EGFR mutations contribute to sensitivity to EGFR-TKI treatment. The most common sensitizing mutations are the Exon 21 L858R mutation and the Exon 19 short in-frame deletions. The Exon 20 tends to yield resistant alterations (eg, prototypical T790M mutation and some Exon 20 Dup/Ins) in patients who initially derived benefit from targeted therapeutics. Although advances have been made in targeted therapeutics in lung cancer and other cancers, clinical resistance, particularly acquired or secondary resistance, remains the rule rather than the exception, which inherently limits the long-term clinical success of targeted therapeutics. A higher level of understanding of the mechanisms of resistance could have a substantial impact in maintaining the clinical efficacy of these targeted therapies.

The Iressa Pan-Asia Survival Study (IPASS) was a phase 3 study in which patient selection was based on clinical factors that predict a higher probability of harboring sensitizing EGFR mutations, thus enriching the mutant population, rather than screening for mutation status.¹¹ Patients selected for participation were East Asians with advanced lung adenocarcinoma who were never smokers or former light smokers. They were randomized to treatment with platinum-based doublet chemotherapy (carboplatin-paclitaxel) or the EGFR-TKI gefitinib.

The primary end point—PFS—favored gefitinib over the chemotherapy doublet in the overall patient population. Of the 1,217 patients enrolled, EGFR mutation data for 35.9% could be evaluated. Sixty percent of the patients’ tumors harbored sensitizing EGFR mutations and, in this subset, the benefit of gefitinib was greater than it was in the overall population. In patients without an EGFR mutation, particularly those without Exon 19 deletions or Exon 21:L858R mutations (sensitizing mutations), platinum-based doublet chemotherapy performed better than gefitinib on the PFS end point. Of the mutation-positive patients, 4.2% had T790M mutations, which confers resistance to TKIs; this finding underscored the observation that all mutations cannot be treated the same.

The important message from the IPASS results is that even in a population preselected for EGFR mutation occurrence, the actual presence of the alteration of the target (EGFR mutations) leads to better survival with gefitinib. Molecular profiling of the tumor, therefore, is ultimately superior to profiling by patient phenotype or ethnicity. Thus, molecular selection trumps clinical selection.¹²

On the basis of IPASS and four similar phase 3 randomized controlled trials, the American Society of Clinical Oncology issued a clinical opinion that “patients with NSCLC who are being considered for first-line therapy with an EGFR-TKI (patients who have not previously received chemotherapy or an EGFR-TKI) should have their tumor tested for EGFR mutations to determine whether an EGFRTKI or chemotherapy is the appropriate first-line therapy.”¹³

Monoclonal antibody against EGFR

The First-Line Erbitux in Lung Cancer (FLEX) phase 3 worldwide study demonstrated that cetuximab, a monoclonal antibody directed against EGFR, as add-on therapy to a platinum-based doublet (cisplatin and vinorelbine) can extend median OS in patients with advanced EGFR-expressing NSCLC (stage wet IIIB or stage IV).¹⁴ As a result, the use of cetuximab combined with cisplatin-vinorelbine has been endorsed by a National Comprehensive Cancer Network (NCCN) guideline as a first-line option for the treatment of advanced NSCLC.

EML4-ALK fusion gene as target for crizotinib

The EML4-ALK fusion translocation oncogene was first identified in 2007 in a small proportion of patients with NSCLC,^15,16 and a targeted therapy (crizotinib, an inhibitor of the ALK tyrosine kinase) has been developed. A single-arm phase 1 trial of crizotinib in patients selected for the EML4-ALK fusion gene has been completed.¹⁷ Of the approximately 1,500 NSCLC patients screened for the trial, 82 were identified as having advanced ALK-positive disease and were entered. These patients tended to be younger than those with ALK-negative disease, most had little or no exposure to tobacco, and all had adenocarcinoma.

The mean treatment duration was 6.4 months. Most treatment-related side effects were grade 1 or grade 2 gastrointestinal adverse events. The overall response rate was 57%. The disease control rates were 87% at 8 weeks and 66% at 16 weeks. Crizotinib has since moved to phase 2 and phase 3 trials and received FDA approval on August 26, 2011, for treatment of EML4-ALK–positive patients as assayed by a simultaneously approved companion molecular diagnostic test.

Crizotinib-resistant mutations of the ALK-kinase domain have recently been identified; L1196M and C1156Y mutations have been found to confer resistance to crizotinib in initially responsive patients.¹⁸

MET: An emerging molecular target

An emerging molecular target being tested in clinical trials is MET, a multifaceted receptor kinase that, when activated, induces tumor cell activities such as cell proliferation and angiogenesis, epithelial-mesenchymal transition, and cell scattering, leading to tumor cell invasion and metastasis.¹⁹

MET receptors and EGFR in lung cancer often are coexpressed and coactivated. Dual targeting of MET and EGFR pathways simultaneously is an attractive combined targeted strategy and is being studied in the hope of overcoming secondary resistance to EGFRTKI as well as enhance the primary response to targeted therapy. A number of MET targeting agents, including both small molecular inhibitors and monoclonal antibodies, are currently undergoing various stages of clinical development.^20,21

In a phase 2 study, erlotinib plus the MET inhibitor ARQ197 was compared with erlotinib plus placebo in 117 previously treated EGFR-inhibitor–naïve patients with advanced NSCLC.²² In the population of patients with nonsquamous NSCLC, both PFS and OS were extended incrementally by the use of combined inhibition that targeted both the EGFR and MET pathways. Interestingly, the benefit on PFS appears to be more significant in EGFR wild type and KRAS-mutant molecular subgroups. A phase 3 global trial using a similar design, with a goal of enrolling 1,000 patients, has been activated in an attempt to validate the findings from the phase 2 study.

UNDERSTANDING RESISTANCE MECHANISMS WILL OPEN DOORS

Other than novel and more rational combined TKI in lung cancer, a deeper understanding of the resistance mechanisms in the context of oncogene addiction targeting would ultimately have a large impact on the long-term clinical success in lung cancer targeted therapy.

Resistance arises because of cellular heterogeneity within an oncogene-addicted tumor. Tumor shrinkage indicates a response to a molecularly targeted therapy, but residual tumor may be a source of slow-growing drug-tolerant “persistor” cells that promote tumor regrowth, regeneration, and heterogeneity.^23,24 Coaddiction, reversible resistance, and addiction-switching models have been proposed to explain resistance, but it is unlikely that a single mechanism can fully explain tumor cell maintenance.

FUTURE OF TARGETED THERAPY IN LUNG CANCER

Technologic advances provide hope for the future of targeted therapy in lung cancer. Some of these advances are cancer genome deep sequencing and tumor molecular profiling. A greater understanding of tumor heterogeneity at the molecular level and tumor-resistant mechanisms, both intrinsic and acquired, should provide further therapeutic opportunity. In the modern era of targeted cancer therapy, identification of novel “druggable” driver oncogene targets can lead to swift development of inhibitors of those targets and adoption of improved and rational combinations of drugs. It is hoped that a better tumor response and more durable responses can be achieved with targeted therapy.