First-line therapy with TKIs in NSCLC

Advances in treatment options for anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC) have improved patient outcomes considerably in the last few years.

This article highlights some of the most recent developments, including the latest results from a Phase III clinical trial involving lorlatinib, as well as the FDA approval of brigatinib.

Phase III CROWN clinical trial

Recently presented at the European Society of Medical Oncology (ESMO) Virtual Congress 2020, CROWN (NCT03052608), a Phase III clinical trial, investigated the use of lorlatinib, a third-generation ALK TKI, as a potential 1L standard treatment in ALK+ NSCLC settings.1

The study compared the use of lorlatinib and crizotinib, with the primary endpoint noted as progression-free survival (PFS) by blinded independent central review (BICR). Results demonstrated that lorlatinib led to a 72% improvement in PFS by BICR compared with crizotinib. Furthermore, the median 12-month PFS rate by BICR with lorlatinib was 78.1%, compared to 38.7% with crizotinib. With respect to achieving best overall response (BOR), through measuring a complete response (CR) or partial response (PR), lorlatinib achieved 76% (CR, n = 4 and PR, n = 109) compared to 58% in crizotinib (CR, n = 0 and PR, n = 85). A number of grade 3–4 adverse events leading to treatment discontinuation were reported: 72.5%/6.7% for lorlatinib; 55.6%/9.2% for crizotinib.2

To conclude, the CROWN study demonstrated that lorlatinib resulted in a statistically significant and clinically meaningful improvement in PFS when compared with crizotinib, although the number of adverse events leading to treatment discontinuation were reported and should be noted for this treatment. Data reported from the CROWN study supports the use of lorlatinib as a future 1L standard treatment in ALK+ NSCLC.

Brigatinib approval in frontline

Also in 2020, it was announced that the U.S. Food and Drug Administration (FDA) have approved brigatinib for the treatment of adult patients with ALK+ metastatic NSCLC. Brigatinib is a small-molecule, next-generation TKI used for targeting ALK molecular alterations and this recent FDA approval means its use can now be expanded to include 1L setting.

The approval comes after results from the Phase III ALTA-1L (NCT02737501) clinical trial which demonstrated the safety and efficacy of brigatinib compared to crizotinib in ALK+ advanced or metastatic NSCLC adult patients, who had not been previously exposed to an ALK inhibitor.

Brigatinib can now be added to the list of 1L treatment options for ALK+ NSCLC patients, a list which contains therapies that have outperformed crizotinib – a conventional targeted therapy used to treat advanced NSCLC. Brigatinib was proven superior to crizotinib through improved efficacy, low frequency of administration (at only one pill a day) and significant anti-tumor activity.

ALK+ NSCLC is a rare, complex and aggressive cancer with various treatment challenges, such as brain metastases. This approval is promising news for the ALK+ NSCLC community and will open up a new window of possibilities for physicians and their patients.3

How does all of this improve patient outcomes?

The results from the CROWN clinical trial, supporting the use of lorlatinib for ALK+ NSCLC patients, as well as the FDA approval of brigatinib, adds to the progress that has been made in the treatment of ALK+ NSCLC.

Adding to the existing first-line treatments for ALK+ NSCLC, including alectinib and crizotinib, provides clinicians with more options for their patients, aiding clinical decisions and improving outcomes for patients.

Written by Frankie Lewns


  1. Solomon B, Bauer T, De Marinis F, et al. Lorlatinib vs crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): Results of the phase III CROWN study. Annals of Oncology. 2020;31(supple 4):S1142-S1215.
  2. ESMO. Crown Trial Supports Lorlatinib as a Future First-Line Standard Treatment in ALK-Positive Non-Small Cell Lung Cancer. Available from: (Last accessed 22/09/20).
  3. Takeda. U.S. FDA Approves Takeda’s ALUNBRIG® (brigatinib) as a First-Line Treatment Option for Patients Diagnosed with Rare and Serious Form of Lung Cancer. Available from: (Last accessed 22/09/20).