Most Read Articles
14 Feb 2020
The phase III CASTOR and POLLUX studies previously demonstrated benefit of daratumumab plus bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) vs standard-of-care (SoC) Vd or Rd regimen in relapsed or refractory multiple myeloma (R/R MM). The latest efficacy and safety results after 4 years of follow-up from CASTOR and POLLUX were presented at the American Society of Hematology (ASH) 61st Meeting & Exposition 2019 held in Orlando, Florida, US.  
Natalia Reoutova, 20 May 2020

Cancer patients infected with coronavirus disease 2019 (COVID-19) appear to be at higher risk of severe outcomes, including death, but cancer type and treatment serve as better predictors, according to recent research presented at the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting I.

At the time of writing, COVID-19 has spread to more than 200 countries and territories, affecting an estimated 4.5 million people and killing over 300,000. Cancer, on the other hand, is newly diagnosed in 18 million people and takes the lives of 10 million every year.

“We have invited physician scientists who are at the epicentre of the COVID-19 pandemic, taking care of patients with cancer. They gathered prospective information to understand the effects of COVID-19 on patients with cancer, are testing new treatments, and are making this knowledge available to the global research community, so we can all benefit from their experience,” said Professor Antoni Ribas from UCLA Medical Center, Los Angeles, California, US, chairperson of the COVID-19 and cancer plenary session of the meeting.

Natalia Reoutova, 28 May 2020

Fasting-mimicking diet (FMD) cycles in combination with endocrine therapy (ET) cause metabolic changes in hormone receptor (HR)-positive breast cancer patients analogous to those observed in animal models, where they are associated with anticancer activity.

Dr. Jason Butler, 01 Apr 2020
Proteasome inhibitors have become a cornerstone of therapy for multiple myeloma (MM). At the Hong Kong Society of Myeloma Annual Scientific Meeting 2019, Dr Jason Butler of the Icon Cancer Care & Royal Brisbane and Women’s Hospital, Brisbane, Australia, reviewed current evidence for the use of proteasome inhibitors in the management of relapsed/refractory MM (R/R MM), with a focus on the efficacy and safety profile of carfilzomib.

Role of brigatinib in crizotinib-resistant ALK-positive NSCLC

Prof. Myung-Ju Ahn
School of Medicine
Sungkyunkwan University
South Korea
02 Apr 2020
Inhibition of the anaplastic lymphoma kinase (ALK) oncogenic driver can improve survival in patients with advanced non-small-cell lung cancer (NSCLC). However, optimal sequencing of ALK-targeted therapies that would overcome acquired resistance to these agents remains a challenge in treating ALK mutation–driven tumours. At a satellite symposium held during the European Society for Medical Oncology (ESMO) Asia 2019 Congress in Singapore, Professor Myung-Ju Ahn of the Sungkyunkwan University School of Medicine, Seoul, South Korea, discussed the clinical benefits of the second-generation ALK tyrosine kinase inhibitor (TKI), brigatinib, in ALK-positive NSCLC patients who have progressed on crizotinib.

Crizotinib in the first-line setting

Crizotinib was the first ALK TKI approved as first-line therapy for patients with NSCLC based on the improved response rate and progression-free survival (PFS) vs chemotherapy in the PROFILE 1014 phase III randomized trial. [N Engl J Med 2014;371:2167-2177]

“Despite these clinical benefits, patients inevitably become resistant to crizotinib treatment and experience disease progression, with the brain being the most frequent site of relapse,” noted Ahn. [J Clin Oncol 2015;33:1881-1888] “A cerebrospinal fluid-to-plasma ratio of 0.0026 has been reported for crizotinib, implying poor central nervous system [CNS] drug penetration.” [J Clin Oncol 2011;29:e443-e445]

“About 20 percent of ALK-positive patients develop a spectrum of crizotinib-resistant ALK mutations after disease progression on crizotinib. Among these, ALKL1196M gatekeeper mutation is most frequently observed,” she said. [Cancer Discov 2016;6:1118-1133]

Several more potent second-generation (eg, ceritinib, alectinib, and brigatinib) and third-generation (lorlatinib) ALK TKIs have been developed, each effective against tumour cell lines with particular ALK mutations. [Cancer Discov 2016;6:1118-1133]

Brigatinib: Significant clinical efficacy after crizotinib failure

Brigatinib is indicated for the treatment of patients with ALK-positive metastatic NSCLC who have disease progression on or are intolerant of crizotinib. [Alunbrig Hong Kong Prescribing Information, Nov 2018]

The phase II, open-label, randomized ALTA trial evaluated two brigatinib doses (90 mg and 180 mg once daily) in 222 patients with crizotinib-refractory ALK-positive NSCLC. [J Clin Oncol 2017;35:2490-2498] After a median follow-up of >24 months, median PFS as assessed by the independent review committee (IRC) was 16.7 months in the 180 mg arm vs 9.2 months in the 90 mg arm. (Figure 1A) [Huber RM, et al, ASCO 2018, abstract 9061]

A subgroup analysis of Asian vs non-Asian patients in the ALTA study also revealed consistent improvements in median PFS with the 180 mg dose in both groups (90 mg dose: 9.1 months vs 9.9 months; 180 mg: 15.6 months vs 17.9 months, respectively). [Ann Oncol 2019;5:1543P]

094mo
 
Given the lack of head-to-head studies comparing second-line ALK TKIs, a matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting. The analysis showed that brigatinib may prolong median PFS vs ceritinib (ASCEND-1: 15.7 months vs 6.9 months; hazard ratio [HR], 0.38; 95 percent confidence interval [CI], 0.26 to 0.57) (ASCEND-2: 18.3 months vs 7.2 months; HR, 0.33; 95 percent CI, 0.20 to 0.56) and alectinib (NP28761: 17.6 months vs 8.2 months; HR, 0.56; 95 percent CI, 0.36 to 0.86) (NP28673: 17.6 months vs 8.9 months; HR, 0.61; 95 percent CI, 0.40 to 0.93). However, limitations of indirect comparison studies call for caution in interpreting these results. (Figure 1B) [
Curr Med Res Opin 2019;35:569-576]
 

Brigatinib overcomes resistance to ALK inhibitors

“Similar to crizotinib, most patients who receive second-generation ALK TKIs also develop ALK mutations, at rates as high as 50–70 percent. The proportion of patients with ALKG1202R mutations is higher with second-generation ALK TKIs than with crizotinib [35–60 percent vs 10 percent],” said Ahn. [Cancer Discov 2017;7:137-155]

In preclinical assays, brigatinib maintained substantial activity against 17 secondary ALK mutant variants tested, including the recalcitrant G1202R mutation, and exhibited a superior inhibitory profile compared with crizotinib, ceritinib and alectinib at clinically achievable concentrations. [Clin Cancer Res 2016;22:5527-5538]

“These findings can be translated to the clinic, as demonstrated by results from a phase I/II trial and the ALTA study,” explained Ahn. “Patients with secondary ALK mutations, including G1269A, L1196M, F1174L and G1202R, responded well to brigatinib treatment. Interestingly, brigatinib activity was maintained independently of secondary ALK mutations.” [J Clin Oncol 2016;34:9060]

Optimal sequencing of next-generation ALK TKIs

Ahn pointed out that patients who received initial chemotherapy (or crizotinib) followed by at least one ALK TKI in subsequent lines of treatment have prolonged overall survival compared with those who received follow-up therapy other than ALK TKI, suggesting the importance of sequential treatment. [J Clin Oncol 2018;36:2251-2258]

“Sequential treatment with ALK TKIs promotes the stepwise accumulation of ALK mutations. Hence, repeat biopsies and genotyping upon disease progression are vital for identifying these heterogeneous resistance mechanisms and choosing the most effective therapeutic strategies,” noted Ahn. [Cancer Discov 2018;8:714-729]

“To date, no studies have addressedthe optimal treatment sequencefor ALK TKIs in NSCLC,” she continued. “The ongoing National Cancer Institute [NCI]-NRG ALK Protocol phase II randomized trial, designed to evaluate different biomarker/ALK TKI combinations in ALK-positive NSCLC, will help generate clinical evidence regarding sequencing of ALK TKIs in the future.” [https://clinicaltrials.gov/ct2/show/NCT03737994]

Summary

Results of the MAIC suggest that brigatinib may prolong post-crizotinib PFS vs other second-generation ALK TKIs in NSCLC. Brigatinib exhibited in vivo anti-tumour activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumours of patients who have progressed on crizotinib.




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Most Read Articles
14 Feb 2020
The phase III CASTOR and POLLUX studies previously demonstrated benefit of daratumumab plus bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) vs standard-of-care (SoC) Vd or Rd regimen in relapsed or refractory multiple myeloma (R/R MM). The latest efficacy and safety results after 4 years of follow-up from CASTOR and POLLUX were presented at the American Society of Hematology (ASH) 61st Meeting & Exposition 2019 held in Orlando, Florida, US.  
Natalia Reoutova, 20 May 2020

Cancer patients infected with coronavirus disease 2019 (COVID-19) appear to be at higher risk of severe outcomes, including death, but cancer type and treatment serve as better predictors, according to recent research presented at the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting I.

At the time of writing, COVID-19 has spread to more than 200 countries and territories, affecting an estimated 4.5 million people and killing over 300,000. Cancer, on the other hand, is newly diagnosed in 18 million people and takes the lives of 10 million every year.

“We have invited physician scientists who are at the epicentre of the COVID-19 pandemic, taking care of patients with cancer. They gathered prospective information to understand the effects of COVID-19 on patients with cancer, are testing new treatments, and are making this knowledge available to the global research community, so we can all benefit from their experience,” said Professor Antoni Ribas from UCLA Medical Center, Los Angeles, California, US, chairperson of the COVID-19 and cancer plenary session of the meeting.

Natalia Reoutova, 28 May 2020

Fasting-mimicking diet (FMD) cycles in combination with endocrine therapy (ET) cause metabolic changes in hormone receptor (HR)-positive breast cancer patients analogous to those observed in animal models, where they are associated with anticancer activity.

Dr. Jason Butler, 01 Apr 2020
Proteasome inhibitors have become a cornerstone of therapy for multiple myeloma (MM). At the Hong Kong Society of Myeloma Annual Scientific Meeting 2019, Dr Jason Butler of the Icon Cancer Care & Royal Brisbane and Women’s Hospital, Brisbane, Australia, reviewed current evidence for the use of proteasome inhibitors in the management of relapsed/refractory MM (R/R MM), with a focus on the efficacy and safety profile of carfilzomib.