Treatment Paradigm for Lung Cancer Shifting Toward Targeted Therapies, Immunotherapy

Wayne Kuznar

May 2014, Vol 5, No 4 - Lung Cancer


Hollywood, FL—Driver mutations, most frequently KRAS and EGFR, account for approximately 50% of non–small-cell lung cancer (NSCLC), and this recognition is shifting the NSCLC treatment paradigm toward targeted therapy when possible, said Leora Horn, MD, MSc, Assistant Professor of Medicine, Division of Hematology/Oncology, Vanderbilt University, Nashville, TN, at the 2014 National Comprehensive Cancer Network Conference.

In the future, immunotherapy may play a significant role in the NSCLC treatment armamentarium.

Chemotherapy hit a plateau in the treatment of metastatic NSCLC, with little difference in survival between the most frequently used regimens. Platinum-based doublet therapy as first-line therapy is associated with overall survival (OS) of approximately 1 year in NSCLC, said Dr Horn. “There is still the option of delaying and careful observation of patients’ use of erlotinib, docetaxel, pemetrexed, or gemcitabine at the time of progression,” Dr Horn said.

Targeted Therapy Leading the Way
“What’s driving lung cancer these days and what’s happening, which is really exciting, is defining these multiple molecular subsets of NSCLC patients,” Dr Horn said. “About 55% of patients with lung cancer will have a driver mutation that we’re able to identify. That’s not necessarily a driver mutation for which we have a targeted therapy at this time.”

The most common molecular subtype is a KRAS mutation, observed in 15% to 25% of patients with NSCLC, followed by an EGFR mutation in 10% to 35%.

First-line treatment of patients with NSCLC and EGFR mutations with a tyrosine kinase inhibitor (TKI), such as gefitinib, erlotinib, or afatinib, outperformed chemotherapy on median progression-free survival, Dr Horn said. “What they’ve also shown us is that there is no significant difference in overall survival, and that’s because in the majority of these trials, 80% of patients or more were crossing over to a TKI at the time of progression on chemotherapy,” she said.

A common mechanism of acquired resistance to an EGFR-related TKI therapy is a second-site mutation, most often the T790M mutation, which is seen in approximately 50% of patients.

Disease progression, or rapid acceleration of disease resulting in hospitalization or death, occurs in approximately 20% of patients who discontinue TKI therapy. Patients with disease progression who resume their TKI therapy “can once again get control of these tumors, because we know that they are oncogene addicted,” Dr Horn said. Another treatment regimen that can control disease progression in patients with acquired resistance to a TKI is the combination of afatinib and cetuximab, she said.

Encouraging data in acquired drug resistance have been obtained with the third-generation TKI, AZD9291. Of the first 35 evaluable patients in a clinical trial, 15 patients have had a partial response, including 9 of 18 with the T790M mutation.

CO-1686 is another agent being explored for the treatment of patients with the T790M mutation and acquired resistance to TKIs in clinical trials in the United States; the response rate was 67% in 9 evaluable patients.

In patients with anaplastic lymphoma kinase (ALK)-positive NSCLC, single-agent crizotinib more than doubled the median PFS compared with chemotherapy.

In patients with ALK-positive NSCLC with acquired resistance to crizotinib, as well as in crizotinib-naïve patients, the second-generation ALK inhibitor LDK378 has produced impressive response rates, said Dr Horn, including in patients with central nervous system disease.

Immunotherapy in Development
Programmed death (PD)-1 and PD-L1 antibodies are being looked at as targets in lung cancer. “There appears to be a reaction between PD-1 and its ligands that promote an immunosuppressive tumor microenvironment,” said Dr Horn. PD-L1 is broadly expressed in patients with NSCLC with adenocarcinoma and squamous-cell carcinoma.

Nivolumab, a PD-1 inhibitor, is an immunoglobulin G4 monoclonal antibody that was associated with an overall response rate as high as 24%, and a median OS of 14.9 months in heavily pretreated patients with NSCLC.

The anti–PD-L1 monoclonal antibody MPDL3280A is being explored in NSCLC. In a phase 1 study, “what we saw was rapid and durable responses in both squamous and nonsquamous NSCLC patients,” said Dr Horn. A majority of patients respond by 12 to 21 weeks of therapy at the time of their first computed tomography scan. When responses were examined by PD-L1 immunohistochemistry (IHC) status, a higher response rate (83%) was observed in tumors with an IHC score of 3 compared with an IHC score of 2 or 1. Some patients with PD-L1–negative tumors also exhibited a response.