Here you can read summaries of some of the key clinical trials that have influenced the way in which ALK+ non-small cell lung cancer (NSCLC)  is currently treated.

Advanced or metastatic ALK+ NSCLC

Crizotinib vs chemotherapy in the first-line setting: PROFILE-1014

Crizotinib was compared to platinum-pemetrexed chemotherapy in the phase III PROFILE-1014 trial. The trial demonstrated that crizotinib had a significantly higher objective response rate (ORR) and longer progression-free survival (PFS), extending to almost one year. However, there were no significant differences in overall survival (OS), partly due to the fact that 70% of patients who initially received chemotherapy subsequently received crizotinib after disease progression. These results led to the approval of crizotinib as a first-line treatment.

Where to read more:

Solomon, B.J. et al. (2014) ‘First-Line Crizotinib versus Chemotherapy in ALK -Positive Lung Cancer’, New England Journal of Medicine, 371(23), pp. 2167–2177. Available at: https://doi.org/10.1056/NEJMoa1408440.

Ceritinib vs chemotherapy in the first-line setting: ASCEND-4

Ceritinib, a second-generation ALK inhibitor, was compared to chemotherapy in the phase III ASCEND-4 trial. It demonstrated a longer progression-free survival (PFS) and a higher response rate. Notably, the rate of grade 3-4 adverse events was 78%. Additionally, the fact that ceritinib was not tested against crizotinib made it less preferable compared to other second-generation inhibitors in this setting.

Where to read more:

Soria, J.-C. et al. (2017) ‘First-line ceritinib versus platinum-based chemotherapy in advanced ALK -rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study’, The Lancet, 389(10072), pp. 917–929. Available at: https://doi.org/10.1016/S0140-6736(17)30123-X.

Brigatinib vs crizotinib in the first-line setting: ALTA-1L

Brigatinib was compared to crizotinib in a phase III trial. It demonstrated a significantly longer progression-free survival (PFS) and, notably, a higher intracranial response rate (78% vs. 29%), underscoring the superior blood-brain barrier penetration of this second-generation inhibitor.

Where to read more:

Camidge, D.R. et al. (2018) ‘Brigatinib versus Crizotinib in ALK -Positive Non–Small-Cell Lung Cancer’, New England Journal of Medicine, 379(21), pp. 2027–2039. Available at: https://doi.org/10.1056/NEJMoa1810171.

Alectinib vs crizotinib in the first-line setting: ALEX

The phase III ALEX trial compared alectinib to crizotinib in the first-line setting. The trial demonstrated that alectinib provided a significantly longer progression-free survival (PFS) and better clinical outcomes for patients with brain metastases. Notably, the median PFS for patients treated with alectinib was 34.8 months, compared to just 10.9 months for those treated with crizotinib.

Where to read more:

Mok, T. et al. (2020) ‘Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study’, Annals of Oncology, 31(8), pp. 1056–1064. Available at: https://doi.org/10.1016/j.annonc.2020.04.478.

Lorlatinib after first- or second-generation ALK TKIs

A global phase II trial tested lorlatinib in various settings, including patients who had progressed on Crizotinib and/or second-generation ALK inhibitors. It demonstrated efficacy in terms of overall response rate in both settings. This trial indicated that lorlatinib could overcome some resistance mechanisms associated with previous-generation inhibitors.

Where to read more:

Solomon, B.J. et al. (2018) ‘Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study’, The Lancet Oncology, 19(12), pp. 1654–1667. Available at: https://doi.org/10.1016/S1470-2045(18)30649-1.

Lorlatinib vs crizotinib in the first-line setting: CROWN

Lorlatinib was compared to crizotinib in a phase III trial, which demonstrated significant improvements in progression-free survival (PFS) and intracranial outcomes. The 5-year update published in 2024 revealed that more than half of the patients remaining progression-free after 60 months of treatment.

Where to read more:

Solomon, B.J. et al. (2024) ‘Lorlatinib Versus Crizotinib in Patients With Advanced ALK -Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study’, Journal of Clinical Oncology, 42(29), pp. 3400–3409. Available at: https://doi.org/10.1200/JCO.24.00581

Earlier stage ALK+ NSCLC

Alectinib vs. chemotherapy in resected ALK-positive NSCLC: ALINA

Patients diagnosed with resected non-small cell lung cancer (NSCLC) that is larger than 4 cm or has spread to the lymph nodes are offered adjuvant chemotherapy to reduce the risk of the tumour returning. A phase III trial compared platinum-based chemotherapy to alectinib in patients whose tumour had been resected and who were ALK-positive. The trial demonstrated improved disease-free survival with alectinib, meaning that patients treated with alectinib lived longer without disease recurrence.

Where to read more:

Wu, Y.-L. et al. (2024) ‘Alectinib in Resected ALK -Positive Non–Small-Cell Lung Cancer’, New England Journal of Medicine, 390(14), pp. 1265–1276. Available at: https://doi.org/10.1056/NEJMoa2310532.

 

Please be aware that the above links are current (as of March 2025), some may reside behind a paywall.