ASCO 2011: news from the front line against cancer
Pharmafocus presents selected highlights from the American Society of Clinical Oncology’s annual meeting in Chicago, beginning with non-small cell lung cancer (NSCLC).
Pfizer’s targeted NSCLC treatment crizotinib was one of the highlights of ASCO last year and now looks set to gain approval in record time, and is likely to hit the market by early 2012.
Crizotinib targets the 3- 5% of patients who carry the ALK mutation, and new data presented at ASCO this year shows it doubled survival time compared with average survival rates.
Two more late-stage studies are under way in patients who have failed other therapies and those who are new to treatment.
Pfizer completed its filing for the drug with the FDA and Japan’s regulator in May.
Meanwhile Roche’s EURTAC study is the first phase III trial of Tarceva in a Western population with a genetically distinct form of advanced lung cancer.
EURTAC showed that first line Tarceva nearly doubled the time people with NSCLC with EGFR activating mutations lived, without their disease getting worse compared with chemotherapy (median progression-free survival: 9.7 months compared with 5.2 months).
Tarceva significantly reduced the risk of the disease getting worse by 63% compared with standard chemotherapy.
Finally, Roche’s MetMab has shown huge promise in phase II trials in lung cancer – but only in patients with ‘high Met’ tumours.
Results from the study of 137 patients suggest the drug could be a major breakthrough in extending the lives of this sub-group of patients with NSCLC.
Around 50% of NSCLC patients are high Met, meaning that many could benefit from the drug. Met is a receptor, expressed on the surface of some cells, which is thought to play a role in numerous cancers, including lung cancer. By blocking the action of Met, the drug inhibits the growth, replication and spread of the tumour.
High Met patients benefited greatly from the drug, showing an average doubling of their progression-free survival (PFS) from 1.5 months to 2.9 months.
Most exciting of all, the drug tripled the length of overall survival in these patients, from 3.8 months to 12.6 months. This was, however, only a secondary endpoint of the study, and will require larger trials to back up the findings.
High Met lung cancer patients currently have a particularly poor prognosis, but if the drug is able to replicate the results in larger trials, these patients could see their prognosis become better than other NSCLC patients.
As with other targeted cancer therapies, patients must have a diagnostic test to establish if they have a high or low Met tumour.
The company plans to start a phase III study later this year.
In contrast to patients with high Met tumours, those with low Met tumours on the trial actually fared worse with the drug than those who did not receive it.
When all the results from the trials’ patients with high and low Met expression were combined, the MetMab and Tarceva combination did not show a statistically significant improvement in PFS compared to Tarceva alone, confirming the drug’s specific action on the Met marker.
The wave of new treatments for melanoma was undoubtedly one of the highlights at this year’s ASCO, with Bristol-Myers Squibb’s recently approved Yervoy leading the pack.
Yervoy (ipilimumab) is the first melanoma treatment to increase overall survival, and could be a major step forward in treating the disease – but it also carries a risk of very serious side effects.
Yervoy has gained US approval as a first and second line treatment for advanced, inoperable or metastatic melanoma, the deadliest and most aggressive form of skin cancer. It looks set for European approval following a recommendation from the EMA’s medicines committee in May.
Analysts forecasts for the drug range from $820 million (£513 million) to $1.7 billion by 2015.
The approval was based on impressive phase III results in which Yervoy (ipilimumab) increased median overall survival, the gold standard in oncology trials, by 10 months, compared with just over six months when compared to GP-100. GP-100 is an investigational cancer vaccine under phase II trials by the National Cancer Institute, but has so far only shown an increase in progression- free survival in its own clinical studies.
“Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment,” he said.
The drug is given in a 90-minute infusion every three weeks for a total of four doses, costing $120,000 for a full course of treatment, making it one of of the most expensive drugs on the US market.
Despite the benefits of the drug, it also carries significant safety risks for patients. The FDA has issued a ‘black box’ warning on the drug after severe to fatal autoimmune reactions were seen in 13% of patients treated with Yervoy. These included enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.
Due to the unusual and severe side effects associated with Yervoy, the FDA has approved the drug alongside a Risk Evaluation and Mitigation Strategy to inform healthcare professionals about these serious risks.
A new study presented at ASCO showed the drug conferred an overall survival (OS) benefit in patients with metastatic melanoma, as reported by Jedd Wolchok, MD, of Memorial Sloan-Kettering Cancer Center.
The results are the second phase III trial to show an OS benefit for the drug, and look set to change the treatment landscape for metastatic melanoma, establishing ipilimumab as the first line therapy of choice in place of dacarbazine.
Another melanoma drug, Roche’s vemurafenib, was also the centre of much attention at the meeting, having also produced spectacular results in patients.
The late-stage BRIM3 study showed vemurafenib significantly improved overall survival in patients with previously untreated BRAF V600 mutation-positive metastatic melanoma, compared to chemotherapy alone.
In the study, the risk of death was reduced by an unprecedented 63% for those taking vemurafenib, compared to patients on the chemotherapy arm.
Roche said that median overall survival (OS) rates couldn’t yet be estimated because of the small number of patients in long-term follow-up. However, it has released median OS estimates from an earlier BRIM3 study in January, which saw patients receiving vemurafenib living 9.2 months compared to 7.8 months for those receiving chemotherapy.
After an additional two months of follow-up, median OS increased to 10.5 months for patients receiving vemurafenib, while the median OS estimate for patients receiving chemotherapy remained at 7.8 months.
Further data will be released later this year after the long-term follow up study is completed.
Roche expects US and European regulatory decisions before the end of the year, and analysts have forecast annual vemurafenib to achieve annual sales of $452 million by 2015.
Other companies in the field include GSK, which recently started late-stage trials of two new drugs for advanced or metastatic melanoma patients who are also expressing the BRAF V600 mutation, with top line results expected later this year.
New data from Roche’s Avastin and AstraZeneca’s olaparib show promise in the hard-to-treat ovarian cancer, but both drugs still fall short of proving overall survival (OS) benefits.
A phase III study of Avastin has shown that women with previously untreated advanced ovarian cancer who received the drug in combination with chemotherapy, followed by Avastin alone, had a 39% improvement in progression-free survival compared to chemotherapy alone.
The study (known as GOG 0218), was conducted by a network of researchers led by the Gynecologic Oncology Group (GOG).
GOG 0218 demonstrated that women with advanced ovarian cancer who received front line (first line following surgery) Avastin in combination with chemotherapy (paclitaxel and carboplatin), and continued use of Avastin alone for a total duration of up to 15 months, had a median PFS of 14.1 months compared to 10.3 months in women who received chemotherapy alone (hazard ratio = 0.72, p=<0.0001, a 28% reduction in the risk of cancer progression or death, which corresponds to a 39% improvement in the likelihood of living longer without the disease worsening). The study also investigated Avastin in combination with chemotherapy but without the continuation of Avastin alone.
Women who received this shorter duration of Avastin did not have a statistically significant increase in PFS compared with chemotherapy alone.
Meanwhile, AstraZeneca released encouraging results from a phase II study in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) who had received maintenance treatment with olaparib, after the completion of chemotherapy.
In this phase II study olaparib 400 mg twice daily significantly extended progression-free survival by RECIST compared to placebo Median PFS: 8.4 versus 4.8 months respectively. The study evaluated 265 patients who had received two or more previous platinum regimens and who were in a partial or complete response following their last platinum-containing regimen.
Olaparib also significantly prolonged the secondary endpoint of time to progression (TTP) by CA-125 or RECIST Median TTP 8.3 versus 3.7 months respectively.
However, OS data at the time of data cut off were too immature for analysis.
A second phase II ovarian cancer study (study 41, olaparib in combination with carboplatin/paclitaxel followed by maintenance olaparib treatment for patients with platinum sensitive SOC) is expected to report in late 2011 and a decision will be based on all of the available data.
Olaparib is the latest in the Poly ADP ribose polymerase (PARP) inhibitor class of drugs. Another drug in the class, Sanofi’s iniparib, failed to meet its endpoints in a phase III trial of triple negative breast cancer patients in early 2011.
Metastatic soft-tissue or bone sarcomas
Merck is to submit its cancer drug ridaforolimus to European and US regulators later this year following encouraging phase III results.
The filings will be based on the SUCCEED trial, the results of which were presented at ASCO.
The mTOR inhibitor improved progression-free survival compared to placebo in patients with metastatic soft-tissue or bone sarcomas, who had previously responded well to chemotherapy.
If brought to market, it would compete with Novartis’ own oral mTOR inhibitor Afinitor, which has a licence as a second line treatment for advanced renal cell carcinoma.
Patients took oral ridaforolimus 40 mg five days out of seven each week, and 552 out of 711 patients experienced PFS, with a 28% reduction in the risk of progression or death compared to placebo.
Median PFS was 17.7 weeks for those treated with ridaforolimus compared to 14.6 weeks in the placebo group. An investigator assessment analysis of PFS showed a 31% reduction by ridaforolimus in the risk of progression or death compared to placebo, with median PFS rising to 22.4 weeks versus 14.7 weeks.
The independent radiological committee review analysis showed that the proportion of patients with PFS in the ridaforolimus group versus placebo was 70% versus 54% after three months, and 34% versus 23% after six months.
Secondary endpoints included trends in overall survival (with data so far favouring ridaforolimus) and best target lesion response (average lesion size reduction of 1.3% versus average increase of 10.3% with placebo).
Gastrointestinal stromal tumours (GIST)
Finally, Novartis announced new data showing a significant improvement in both recurrence-free survival and overall survival for patients taking Glivec (imatinib) for three years after surgery to remove KIT (CD117)-positive gastrointestinal stromal tumours (GIST) compared to one year of treatment.
At five years, 66% of patients taking Glivec for three years remained free of cancer recurrence (primary endpoint) compared to 48% who had received Glivec for only one year. Moreover, 92% of patients taking Glivec for three years were alive (secondary endpoint) compared to 82% who had received Glivec for only one year. Median patient follow-up was 54 months.
The 400-patient phase III trial is the first prospective large scale trial to show a survival benefit of adjuvant Glivec therapy for KIT+ GIST, with extended three years of therapy relative to one year of therapy. ‘‘This study confirms the hypothesis that extending the duration of Glivec treatment for patients following surgery improves recurrence-free survival. For the first time, an effect on overall survival was found,” said Heikki Joensuu, professor, oncology, University of Helsinki and principal investigator of the study.
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