Advances in the management of ALK-rearranged NSCLC


The introduction of anaplastic lymphoma kinase (ALK) inhibitors has dramatically improved patient survival and quality of life in patients with ALK-rearranged (or ALK+) non-small cell lung cancers (NSCLC).1 There are now a number of ALK inhibitors available in Australia for first-line treatment of ALK+ NSCLC, including the second-generation ALK inhibitor brigatinib.2

The limbic spoke to medical oncologist Doctor Malinda Itchins from the Royal North Shore Hospital in Sydney about the current treatment landscape for ALK+ NSCLC and the role of brigatinib, which is now approved in Australia for adult patients with locally advanced or metastatic ALK+ NSCLC.

Around 3 – 7% of NSCLCs harbour an ALK rearrangement. These ALK+ NSCLCs are typically found in adenocarcinomas, and often occur in young, fit patients who have never smoked, although not exclusively.1 “Particularly in younger non-smokers presenting with NSCLC, the potential for an ALK rearrangement should be routinely considered and adequately explored through an appropriate diagnostic pathway, with reflex testing recommended in all advanced adenocarcinomas,” said Dr Itchins.

In patients diagnosed with advanced ALK+ NSCLC, ALK inhibitors considerably extend survival and improve quality of life.2 Despite this, the cancer eventually becomes resistant to treatment, which has prompted the development of increasingly potent ‘next generation’ ALK inhibitors with an evolving understanding of how to best sequencing treatments. Resistance mutations are more frequent with each line of therapy, and with later generation inhibitors. These mutations can help inform how to sequence ALK inhibitors but are not tested for in routine clinical practice.3

“It’s important to understand how we best sequence and choose ALK inhibitors,” said Dr Itchins. Clinical trial efficacy data, often however restricted to first and second line investigation, side effect profiles and activity against the commonly emerging resistance mutations are all key considerations, she explained.

ALK inhibitors – an overview

Crizotinib, a first-generation ALK inhibitor, was found to improve progression-free survival (PFS), symptom burden and quality of life compared to conventional chemotherapy and was the first ALK inhibitor available in Australia.3 However, central nervous system (CNS) penetration is insufficient to effectively manage CNS metastases, which occur in up to a third of patients at initial diagnosis of metastatic disease.4 Progression with CNS relapse has been found to occur in up to 50% of patients with CNS disease treated with crizotinib.3

Second-generation (ceritinib, alectinib,brigatinib and ensartinib) and third generation (lorlatinib) ALK inhibitors have higher systemic and intracranial efficacy compared to crizotinib.3,5

The second generation agents differ in their side effect profiles, with ceritinib associated with diarrhoea, alectinib associated with myalgias, and brigatinib associated with idiopathic elevation of creatinine kinase and lipase and reports of steroid-responsive early onset pneumonitis.3 They also differ in their activity against different ALK resistance mutations.3

Brigatinib for ALK+ NSCLC

Second-generation ALK inhibitor brigatinib (Alunbrig®) was introduced in Australia in 2020 and is available for first-line treatment of locally advanced or metastatic ALK+ NSCLC.2 It is a one tablet once-daily oral therapy which can be taken with or without food.2

Data from the ALTA clinical trial program provide an insight into the potential place of brigatinib in the treatment of ALK+ NSCLC.

For first-line treatment of ALK+ NSCLC (ALTA-1L6): The open-label Phase III ALTA 1L trial compared brigatinib (180 mg daily; 7 day lead-in at 90 mg daily) to crizotinib (250 mg twice daily) in patients with advanced ALK+ NSCLC who had not previously received an ALK inhibitor. At median follow-up of 24.9 months, brigatinib showed superior PFS compared to crizotinib; 24.0 versus 11.0 months (HR 0.49 [95% CI, 0.35 to 0.68]; P<0.0001) by blinded independent review committee (Figure 1). Brigatinib also delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; P = 0.049.)

Figure 1. Efficacy of brigatinib and crizotinib in tyrosine kinase inhibitor (TKI)- naive ALK+ NSCLC. Kaplan-Meier-estimated blinded independent review committee (BIRC)-assessed PFS.6

 

The most common treatment-emergent adverse events (TEAEs) were GI events, increased blood creatinine phosphokinase, cough and increased aminotransferases. Grade 3 – 5 TEAEs occurred in 73% versus 61% of patients on brigatinib and crizotinib, respectively. Interstitial lung disease or pneumonitis at any time occurred in 5% (7 of 136) and 2% (3 of 137) patients in the brigatinib and crizotinib groups, respectively.

In crizotinib-refractory ALK+ NSCLC  (ALTA7): A phase 2 study investigated the efficacy of brigatinib in crizotinib-refractory ALK+ NSCLC. Patients were randomised to either 90 mg or 180 mg brigatinib once daily (with a lead-in of 90 mg once daily in the 180 mg arm). A total of 59 of 222 (27%) of randomised patients remained on brigatinib at analysis (median follow up 19.6 months for 90mg arm and 24.3 months for 180 mg arm). For the 90 mg and 180 mg arms, objective response rate was 46% versus 56%, median independent review committee PFS was 9.2 months (95% CI: 7.4–12.8) versus 16.7 months (95% CI: 11.6–21.4), and median overall survival was 29.5 months (18.2 – not reached) and 34.1 months (27.7 – not reached), respectively.  Intracranial objective response rates and progression free survival (PFS) were also measured in patients with baseline brain metastases, showing the benefits of therapy, with greater benefits seen with the higher brigatinib dose.

The most common treatment-related adverse events (AEs) were diarrhea (16% and 35% in the 90 mg and 180 mg arms, respectively), nausea (26% and 33%) and increased blood creatine phosphokinase (14% and 32%). Dose reduction due to any AE occurred in 7% and 29% of treated patients, with dose interruption in 41% and 62%, and discontinuation in 4% and 11% of treated patients (90 mg and 180 mg arms, respectively). Clinically apparent pulmonary AEs occurring on initiation of brigatinib occurred in 6% of treated patients.

The authors concluded, “Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. No new safety concerns were noted.”

Efficacy of brigatinib in patients refractory to alectinib (J_ALTA8): A phase II trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK+ NSCLC refractory to alectinib or other ALK inhibitors. Alectinib was the most recent ALK inhibitor in 47 of the 72 enrolled patients (with or without crizotinib). At a median follow-up of 12.4 months, 14 of 47 alectinib-refractory patients remained on brigatinib. In these patients, the objective response rate was 34% (95% CI: 21% – 49%), with a median duration of response of 11.8 months (95% CI: 5.5 – 16.4). Progression-free survival was 7.3 months (95% CI: 3.7 – 9.3). Two of eight patients with brain lesions at baseline had intracranial partial response. The safety profile in this study population of Japanese patients was consistent with other studies.

The authors concluded, “Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib). “

Dr Itchins commented that the clinical trial data definitely supports the role for brigatinib in first-line treatment of ALK+ NSCLC. “Brigatinib is also an excellent choice in patients who progress on crizotinib where we first saw how active this drug really is,” she added. The J-ALTA8 data may also suggest some role in alectinib refractory disease, she said. “These recent results are interesting and unexpected based on resistance mechanisms often co-occurring between alectinib and brigatinib,” she explained.

Dr Itchins considered brigatinib to be a well-tolerated drug. She noted the lead-in dosing mitigates the pneumonitis risk. However, if pneumonitis does occur, she explained that it is reversible and steroid-responsive, and treatment can be continued. “It’s important to educate the patients from the outset about the possibility of particular adverse events so they can be proactive with intervention at lower grades if required,” noted Dr Itchins.

Improving outcomes by earlier identification of ALK+ NSCLC

“The number-one treatment challenge at the moment is that up to three quarters of people with ALK+ NSCLC are diagnosed with advanced incurable disease,” noted Dr Itchins. “As a result, targeted agents are most often used in a palliative setting, even though they are highly efficacious drugs,” she said. She explained that it’s important to aim for diagnosing more patients with oncogene-driven lung cancers in general (including ALK-rearrangements) at a curable stage of disease which is difficult, given most do not develop symptoms until disease is more advanced.

“If you don’t look you don’t find and treatment options become academic,” Dr Itchins pointed out. “We need to be  reflex testing 100% of advanced lung adenocarcinomas for an ALK rearrangement using the highly sensitive and specific immunohistochemical panel IHC,” she said.

 

References

  1. Itchins M et al. ALK-rearranged non-small cell lung cancer in 2020: real-world triumphs in an era of multigeneration ALK-inhibitor sequencing informed by drug resistance. The Oncologist 2020; 25:641–649. https://pubmed.ncbi.nlm.nih.gov/32558067/
  2. Alunbrig Australian Approved Product Information V2.0, Revised 10th February 2021. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2019-PI-01282-1 
  3. Itchins M et al. Treatment of ALK-rearranged non-small cell lung cancer: a review of the landscape and approach to emerging patterns of treatment resistance in the Australian context. Asia-Pac J Clin Oncol 2017;13:3–13. https://pubmed.ncbi.nlm.nih.gov/28795492/
  4. Aldea M et al. ALK inhibitors in ALK-positive NSCLC with central nervous system metastases. European Oncology & Haematology 2020;16(1):18–21. https://touchoncology.com/lung-cancer/journal-articles/alk-inhibitors-in-alk-positive-nsclc-with-central-nervous-system-metastases/
  5. Elsayed M and Christopoulos P. Therapeutic sequencing in ALK+ NSCLC. Pharmaceuticals 2021;14:80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912146/
  6. Camidge DR et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naïve ALK-positive non-small cell lung cancer: second interim analysis of the Phase III ALTA-1L trial. J Clin Oncol 2020; 38. https://pubmed.ncbi.nlm.nih.gov/32780660/
  7. Huber RM et al. Brigatinib in crizotinib-refractory ALK+ NSCLC: 2-year follow-up on systemic and intracranial outcomes in the phase 2 ALTA trial. JTO 2019;15(3):404–415. https://pubmed.ncbi.nlm.nih.gov/31756496/
  8. Nishio M et al. Brigatinib in Japanese patients with ALK-positive NSCLC previously treated with alectinib and other tyrosine kinase inhibitors: outcomes of the phase 2 J-ALTA trial. JTO.  16(3):452–463. https://www.jto.org/article/S1556-0864(20)31026-1/fulltext

 

Minimum Product Information ALUNBRIG (brigatinib)

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