Treatment Paradigm for NSCLC May Be Shifting

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Driver mutations, most commonly KRAS and EGFR, account for about half 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. 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 about 1 year in NSCLC, said Horn, associate professor of medicine, Department of Hematology/Oncology, Vanderbilt University, Nashville, TN.

Erlotinib, docetaxel, pemetrexed, and gemcitabine have each been shown to be effective as switch maintenance regimens. “There is still the option of delaying and careful observation of patients’ use of erlotinib, docetaxel, pemetrexed, or gemcitabine at the time of progression,” she said.

Targeted Therapy Evolving
“What’s driving lung cancer these days and what’s happening, which is really exciting, is defining these multiple molecular subsets of NSCLC patients,” she 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 with an EGFR tyrosine kinase inhibitor (TKI) such as gefitinib, erlotinib, and afatinib outperformed chemotherapy in NSCLC patients with EGFR mutation on the end point of median progression-free survival (PFS), she 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,” said Horn.

A common mechanism of acquired resistance to an EGFR TKI is a second site mutation, most often T790M, which is observed in about 50% of patients.

Disease flare, or rapid acceleration of disease resulting in hospitalization or death, occurs in about 20% of patients who go off EGFR TKIs. Patients with disease flares who resume their TKI treatment “can once again get control of these tumors because we know that they are oncogene addicted,” she said. Another treatment regimen that can control disease in patients who develop acquired resistance to a TKI is the combination of afatinib and cetuximab, she said.

Encouraging data in acquired resistance have been obtained with the third-generation TKI, AZD9291. Fifteen of the first 35 evaluable patients treated in a clinical study had a partial response, including 9 of 18 with T790M-positive tumors. CO-1686 is another agent being explored in clinical trials in patients with T790M-positive tumors and acquired resistance to EGFR TKIs.

In patients with ALK-positive NSCLC, single-agent crizotinib more than doubled median PFS compared with chemotherapy. In patients with ALK-positive NSCLC with acquired resistance to crizotinib as well as those who are crizotinib-naive, the second-generation ALK inhibitor LDK378 has produced impressive response rates, said Horn, including in patients with central nervous system disease.

Immune Therapy Being Explored
PD-1 and PD-L1 antibodies are being looked at in lung cancer. “There appears to be a reaction between PD-1 and its ligands that promotes an immunosuppressive tumor microenvironment,” said Horn. PD-L1 is broadly expressed in NSCLC patients with adenocarcinoma and squamous cell carcinoma.

Nivolumab, a PD-1 inhibitor, is an IgG4 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 also 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 Horn. A majority of patients respond by 12 to 21 weeks of therapy, at the time of their first CT scan. When responses were examined by PD-L1 immunohistochemistry (IHC) status, a higher response rate was observed in tumors that had an IHC score of 3 (83%) compared with IHC 2 and IHC 1. Some patients with tumors that were PD-L1 negative also exhibited a response.

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