New-generation targeted therapies for NSCLC overcome therapy resistance and improve survival
New-generation therapies targeted toward specific genetic alterations such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in non-small cell lung cancer (NSCLC) can overcome resistance to first-generation therapies and improve survival of patients, according to a presentation at the 21st Congress of the Asian Pacific Society of Respirology (APSR 2016) held in Bangkok, Thailand.
Molecular testing for actionable mutations in advanced NSCLC has now become a routine clinical practice, said Professor Liam Chong-Kim, a professor of the Faculty of Medicine and senior consultant of Respiratory Medicine at the University Malaya Medical Centre in Kuala Lumpur, Malaysia, during the presentation. [APSR 2016, abstract APSR6-0833]
“First-line treatment with an EGFR TKI [(tyrosine kinase inhibitor) such as] gefitinib, erlotinib, or afatinib is [the] standard of care for EGFR mutant NSCLC,” said Liam. “However, despite dramatic initial responses, acquired resistance invariably develops with clinical disease progression after a median of 9 to 12 months.”
Upon disease progression, rebiopsy is important to establish the mechanism of resistance, according to Liam, who suggested that liquid biopsy can be an alternative to tissue rebiopsy.
One of the main mechanisms of acquired resistance to first-generation EGFR TKIs is due to a secondary mutation in the EGFR intracellular kinase domain T790M, which constitutes 50–60 percent of the resistance cases in EGFR-mutant NSCLC, explained Liam. [Sci Transl Med 2011;3:75ra26; Clin Cancer Res 2011;17:1169-1180; Clin Cancer Res 2013;19:2240-2247]
“New and improved targeted therapies that can overcome resistance to first-generation drugs are in clinical trials with some having received regulatory approvals for use in the clinic,” he said.
Currently, osimertinib is the only third-generation EGFR TKI that has been approved by the US FDA for patients with advanced T790M-positive NSCLC who had progressed following previous therapy with other EGFR TKIs, based on results of the phase I and II AURA* studies, informed Liam. [WCLC 2015, abstract 943; WCLC 2015, abstract 1406]
Among 210 patients treated with osimertinib 80 mg orally once daily in the phase II, open-label, single-arm AURA2 study, objective response rate (ORR) was 70 percent and median progression-free survival (PFS) was 8.6 months. [Lancet Oncol 2016;doi:10.1016/S1470-2045(16)30508-3]
“The beauty of this mutant specific EGFR TKI is that it also inhibits TKI-sensitive EGFR mutants,” said Liam. “Because [of] the selectivity of this third-generation EGFR TKI on T790M over wild-type [EGFR], the toxicity that is commonly seen with the use of first- and second-generation TKI which is related to the inhibition of wild-type EGFR is less common.”
Another genetic aberration commonly found in NSCLC patients is rearrangement of the ALK gene, which occurs at a higher frequency in patients with adenocarcinoma without EGFR mutation who never smoked, said Liam. [J Clin Oncol 2009;27:4247-4253]
The first-line ALK inhibitor crizotinib has been shown to improve PFS (10.9 vs 7.0 months; p<0.001) and ORR (74 percent vs 45 percent; p<0.001) more than the standard first-line chemotherapy of pemetrexed plus platinum in the phase III PROFILE 1014** trial which enrolled 343 patients with ALK-positive, nonsquamous advanced NSCLC. [N Engl J Med 2014;371:2167-2177]
Next-generation ALK inhibitors such as ceritinib and alectinib have been shown to be more potent, with lower IC50 than crizotinib and also suppress the kinase activity of several mutations associated with crizotinib-resistance including L1196M and G1296A, according to Liam.
Both ceritinib and alectinib have been approved for treating patients with ALK-positive, metastatic NSCLC with disease progression or who are intolerant to crizotinib, based on findings from early phase trials. [Lancet Oncol 2016;17:452-463; Lancet Oncol 2016;17:234-242; J Clin Oncol 2016;34:661-668]
“The peculiar feature of the second-generation ALK inhibitors... is that they have better penetration across the blood-brain barrier,” observed Liam, indicating that they could have activity on brain metastases, which is common among NSCLC patients.
In fact, alectinib has been demonstrated to significantly extend PFS compared with crizotinib (median PFS, not reached vs 10.2 months, hazard ratio for death or disease progression, 0.34; p<0.0001) in the open-label phase III J-ALEX*** study which randomized 207 ALK-positive NSCLC patients to alectinib at a lower than recommended dose of 300 mg twice daily or crizotinib 250 mg twice daily. [ASCO 2016, abstract 9008]