Two ground-breaking EORTC trials headlined at the recent annual meeting of the American Association for Cancer Research (AACR)

In the first, Alexander M.M. Eggermont, Director General of the Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, and investigators from 23 countries across the world, found that giving a one-year course of 18 doses of the immunotherapy drug pembrolizumab (Keytruda) significantly reduced the risk of the cancer returning for adult patients with stage III melanoma who were at high risk of recurrence after surgery. Patients with stage III melanoma have metastatic disease in one or more regional lymph nodes. Giving a dose of 200 milligrams of pembrolizumab every three weeks after surgery for up to a year significantly reduced the risk of recurrence for these patients the investigators found.

Pembrolizumab works by blocking a protective mechanism of cancer cells, thus allowing the immune system to destroy them. Of the 1,019 patients recruited to the double-blind trial, 514 were randomised to pembrolizumab, and the others to placebo. For all those randomised to pembrolizumab, the 12-month recurrence-free survival rate was 75.4 percent, compared with 61.0 percent for all those randomised to placebo. The estimated hazard ratio was 0.57, indicating that risk of recurrence or death was reduced by 43 percent in patients randomised to pembrolizumab as compared to those randomised to placebo.

After a median follow-up of 1.25 years, 135 of the 514 patients randomised to pembrolizumab and 216 of the 505 patients randomised to placebo had been diagnosed with recurrent disease or had died. Patients randomised to placebo who had recurrence were offered access to pembrolizumab. “This cross-over design is unique in the world of adjuvant trials in melanoma and will permit us to analyse if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse,” says Eggermont.  “We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients.”

The trial results are published in the New England Journal of Medicine.

Abstract no CT001 : Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial

In the second trial, investigators from eight European countries, headed by Patrick Schöffski from KU Leuven, Belgium, found that treatment with a targeted cancer drug achieved complete or partial tumour shrinkage in 50% of patients with inflammatory myofibrobastic tumour (IMFT), a very rare type of soft tissue sarcoma. Soft tissue sarcomas in themselves are very rare, accounting for just 1% of all solid tumour diagnoses, and IMFT so uncommon that there are no reliable statistics for its incidence or for mortality rates.

Many IFMTs have rearrangements of the ALK gene. Recently discovered as a target for cancer therapies, the ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional copies or through mutations of the actual DNA code for the gene itself.

Schöffski and colleagues therefore set out to see whether the ALK inhibitor crizotinib might be a potential treatment for patients with IMFT.  “Inflammatory myofibroblastic tumours are usually resistant to conventional chemotherapy and radiotherapy, so patients with unresectable or locally recurring disease have few treatment options,” he says.

Because IMFT is so rare, only 35 patients with a local diagnosis of inflammatory myofibroblastic tumour could be recruited to the trial. Twenty of these patients were confirmed centrally to have the disease and received crizotinib.

Nineteen patients were evaluable for response. The objective response rate among the 12 evaluable patients with ALK-positive IFMTs who received crizotinib was 50 percent (95% confidence interval : 21.1-78.9%); two had a confirmed complete response and four had a confirmed partial response. Among the seven evaluable patients with ALK-negative IFMTs, the rate was 14.3 percent (95% confidence interval: 0.0-57.9%). In the group of patients with ALK-positive IFMT, crizotinib activity met the pre-specified response rate criteria set by the protocol.

« Limitations of the trial include that it is a noncomparative, single-arm study with a relatively small number of patients. Given the disease prevalence, a more definitive, randomised, comparative trial would not be possible, » says Schöffski.

« However, our study highlights how identifying the genetic drivers of a rare type of cancer can be used to find a new precision medicine for patients who otherwise have few treatment options,” he adds. “The inclusion in our trial of a group of patients with ALK-negative inflammatory myofibroblastic tumors provides valuable insight into the selectivity of crizotinib and our understanding of this rare disease, even if we cannot formally compare the outcomes for the ALK-positive and -negative groups.”

The trial results are published in The Lancet Respiratory Medicine.

Abstract no CT045 :Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 “CREATE”

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