Australian early-stage lung cancer study lauded in Madrid

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For patients with few treatment options, mutation-targeting alectinib offers survival benefits in early stage ALK+ NSCLC.

Patients with resectable stage IB-IIIA ALK+ non-small cell lung cancer are more likely to survive if they get alectinib after surgery than chemotherapy, according to interim two-year findings.  

Professor Ben Solomon, from Melbourne’s Peter MacCallum Cancer Centre, presented the data at the European Society for Medical Oncology Congress in Madrid last month to “sustained applause from the audience”. 

His research showed that at median follow-up of almost 28 months, patients with stage IB through to IIIA NSCLC who received the alternative treatment were 76% less likely to have disease recurrence than those on standard adjuvant care.  

For all stages, two-year disease-free survival was more than 94% in the experimental treatment groups, compared with 63% of those who received treatment as usual.  

And patients in the intention-to-treat population were 78% less likely to develop brain metastasis, which people with ALK-positive NSCLC are susceptible to, during follow-up.  

“The effect on distant recurrences was particularly profound, with marked effects not just in the brain but also at extracranial sites including bone,” said Professor Solomon.  

The findings were hailed as “practice changing” by many attending the conference.   

The phase III ALINA trial randomly assigned 257 patients with completely resected ALK-positive cancer to receive either up to four, 21-day cycles of standard intravenous platinum-based chemotherapy or 600mg twice daily oral alectinib for up to two years or until disease recurrence.  

Early-stage cancers comprise around 40% of all new diagnoses and have a high recurrence rate of 45-76%. ALK mutations exist in 4-5% of NSCLC cases, affecting mainly patients under 55 years of age and non-smokers, and immunotherapy does not seem to work for them. 

Alectinib, a drug that targets the ALK mutation, is already used as a first-line treatment for more advanced ALK+ NSCLC. These findings suggest the anaplastic lymphoma kinase inhibitor is also an effective treatment for stages IB-IIIA, Dr Solomon told delegates.  

A similar number of participants, around 30%, reported adverse events (grade 3-4) in both the alectinib and chemotherapy arms of the trial. Only 2% of patients who received alectinib reported serious treatment-related adverse events and 7% reported adverse events that led to withdrawal from the trial.  

In the chemotherapy arm, 8% reported serious treatment-related adverse events and 15% reported an event that led to withdrawal from the trial. There were no grade 5 events. 

Professor Marina Garassino, a US thoracic tumour expert, told delegates it was not yet time to give up on chemotherapy in this group of patients. 

“I think that we should discuss it with the patients because we have to remember that the chemotherapy is the regimen that showed an increase in terms of overall survival in the overall population. And we know that pemetrexed is a good ALK inhibitor and the results in the adjuvant setting can be even better,” she said. 

At two years, it was too early to tell what the effect would be on overall survival, she said, pointing to varied results in other trials – some of which translated to overall survival benefit (the ADAURA trial showed that three years of osimertinib led to a “very meaningful overall survival benefit”) and others which did not (RADIANT, erlotinib adjuvant for two years). 

Toxicity with adjuvant treatment was also a consideration, she said. Patients with potentially successful surgery then had to take eight capsules a day for two years, 27% experiencing adverse events that led to discontinuation, compared to only four months of chemotherapy, with only 14% having adverse events leading to discontinuation. 

“I asked some patients to describe to me what is their life on alectinib in the metastatic setting. … They say that they have [in]ability to focus on large tasks, they have difficulty to focus, they have decrease of appetite and neuropathy, sound sensitivity, they have constipation – and they are potentially patients that are cured,” she told delegates. 

“So what I will do tomorrow, I will ask the patients if they want to have this kind of toxicity in the absence of a clear overall survival benefit.” 

Dr Malinda Itchins, medical oncologist and the Lung Cancer Chair of the Clinical Oncology Society of Australia, told ARR the results offered “great promise”. Her hunch was that it would be practice-changing, “but not yet”.  

The effect on relapses, locoregionally, distantly and in the central nervous system was “incredibly meaningful”, she said.  

“ALK lung cancers have a great propensity to metastasise, and cure, even with surgical resection, is unlikely. Adjuvant alectinib and its potential to eradicate micro-metastatic disease and provide a personalised approach to these patients will address a large unmet need.” 

But with new data came new questions about patterns of recurrence, salvage and identifying other biomarkers to see who would benefit most.  

“Absolutely more is to be understood with ongoing important perioperative trials, including neoadjuvant ALK-inhibitor therapy which could bring a greater impact. Furthermore, the use of plasma, such as ctDNA positivity perioperatively, may be an important negative prognostic group who stand to make great gains from heightened adjuvant therapy including prolonged ALK-inhibitor treatment. 

“The next question is do we need to wait three to five years and longer to prove the impact stands across the array of oncogenes, including novel and rarer, or has ADAURA shifted the needle and we embrace the change in paradigm across the board?”  

For today’s patients, the data “cannot mature fast enough,” said Dr Itchins, unless the TGA and PBS approval system were to change for rare cancers and consider surrogate data.  

“Of course, these data need to be shared with the patients of today,” she said, “but for most this will be too high a cost financially.”  

Alectinib was already in use for advanced lung cancers, and strategies for dealing with side effects were well established, said Dr Itchins.  

Treatment was “dynamic”, she said, and decisions could be made to reduce, interrupt or stop treatment, though few did the latter.  

Many of her patients were “mostly comfortable” with it, she said. “When you ask them, they are happy to take this number of tablets if their quality of life is preserved and extended in controlling their cancer and preventing decline. 

“I get the sense most fitting the ALINA criteria will want to try these tablets if they have a greater chance of living longer and even being cured. They probably do, based on these results.   

“What is important is a discussion with the patient and caregivers in front of us around risks and benefits, toxicity and efficacy and a mutual decision can then be made encompassing their values,” she said. 

Unfortunately, the majority of cases oncologists dealt with were not early stage, she pointed out. “Seventy five percent of ALK+ lung cancers present with advanced incurable disease however, so our next step is diagnosing early with opportunity to cure.”  

Professor Brian Oliver, head of the Respiratory, Cellular and Molecular Biology Group at the Woolcock Institute of Medical Research, told OR the results were encouraging and that this was “game-changing therapy” for people with lung cancer.

“Sometimes you can get results which are hard to replicate outside the clinical trials. But in this case, this particular treatment will do wonders for the right patient.”

Annals of Oncology 2023, online October 

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