Lung cancer

Novel therapies begin to ‘outsmart’ ALK-positive NSCLC


Rare ALK+ non-small cell lung cancer (NSCLC) can achieve an ‘impressive’ overall survival of almost four years (46 months) when aggressively managed, Australian clinicians have shown.

A study of 35 patients identified between 2010 and 2016 at the Royal North Shore Hospital found most patients (54%) were managed on a single line of therapy, typically crizotinib. The overall response rate in these patients was 83%.

Other available treatments included certitinib, alectinib, brigatinib and loratinib.

“Three patients were managed on a second generation ALK inhibitor in the first line setting and 15 (47%) achieved at least two lines of therapy; 13 (37%) remaining on their first line agent still responding,” the study authors said in the Asia Pacific Journal of Clinical Oncology.

In patients receiving at least two lines of tyrosine kinase inhibitor therapy, median overall survival was estimated to be 53. 5 months.

The study found the subgroup of patients with CNS disease had similar survival rates – ostensibly related to improved CNS penetration of second-generation ALK inhibitors.

“Close CNS surveillance from diagnosis and aggressive multidisciplinary management with informed radiation oncologist, availability of stereotactic radiosurgery and educated neurosurgeons performing elective craniotomies in selected patients with low morbidity is expected to have contributed to this favorable survival.”

Medical oncologist Dr Malinda Itchins told the limbic the standard of care was moving rapidly with ‘an embarrassment of riches’ available – about 10 ALK inhibitors under investigation in clinical trials and treatments very effective.

Since its listing on the PBS in January and with superior efficacy and better tolerated than crizotinib, alectinib was currently the standard of care.

Dr Itchins said the sequencing of drugs was now the important issue.

“Should we hold on to some? Because we don’t fully understand the mechanisms of resistance to each of the drugs, if we use the best one first, we might find they develop more obnoxious resistance mechanisms.”

“Historically in advanced cancers, you treat until the cancer grows and then go onto the next treatment which may not be as good but is a different treatment. We’re looking at whether if you give fixed alternating doses of two ALK inhibitors, does it actually delay the emergence of drug resistance because it doesn’t give the cancer a chance to outsmart the therapy.”

She added about 70% of patients will develop CNS metastases at some point in their disease.

“So a huge priority with second and next generation inhibitors has been penetration into the brain as we know they also play a role in preventing the development of brain metastases.”

“There are far fewer relapses in brain and if they have brain mets, they can have dramatic responses. Because our drugs can work dramatically well in the brain, we are doing things we didn’t otherwise do. They are amenable to surgery, they are amenable to more aggressive focal therapy.”

She said each of the ALK inhibitors had different side effect profiles but were all much better than chemotherapy.

“It’s a no-brainer”, she said.

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