Next-Generation Targeted Therapies in NSCLC

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Multiple next-generation ALK inhibitors are under investigation for patients with ALK-positive non-small cell lung cancer (NSCLC). As these therapies rush toward approval, it remains unclear how they will fit into the current treatment landscape for patients with NSCLC.

The three front-runners in the next-generation ALK inhibitor race include ceritinib (LDK378), alectinib, and AP26113. Each treatment interacts differently allowing some to be sequenced while others cannot. For instance, Heather A. Wakelee, MD, notes that crizotinib followed by ceritinib appears to be an effective sequence. However, prior treatment with crizotinib or ceritinib was shown to increase toxicity in patients treated with AP26113, notes Corey J. Langer, MD. More research is needed in this area, but these early findings set the groundwork for an optimal sequence.

Outside of clinical studies, patients with driver mutations respond well to treatment with chemotherapy, states Benjamin P. Levy, MD. Upon progression on a targeted therapy, chemotherapy remains a viable and effective option, specifically if EGFR or ALK tests are unclear, adds Mark G. Kris, MD. Moreover, in the absence of a positive test result, chemotherapy remains the standard option.

In addition to ALK, a number of next-generation EGFR inhibitors are in early phase clinical studies for patients with NSCLC, notes Langer. These therapies are being examined primarily in patients with T790M resistance mutations. The two leading therapies in this space are AZD9291 and CO-1686, which have demonstrated impressive overall response rates for patients with T790M mutations.

These next-generation therapies are highly selective for T790M and EGFR mutations, notes Kris. As a result, the usual side effects seen with EGFR inhibitors, such as rash and diarrhea, are rare. As a result, these therapies are poised to be game-changers, since T790M mutations occur in approximately 60% of patients with EGFR mutations.