Nav: Home

Alectinib potential new standard of care for ALK-positive non-small lung cancer

June 06, 2017

Results of a 303-patient, multi-national phase III clinical trial known as ALEX published today in the New England Journal of Medicine and presented concurrently at the American Society for Clinical Oncology (ASCO) Annual Meeting 2017 argue for alectinib replacing crizotinib as first-line standard of care in advanced ALK-positive non-small cell lung cancer.

The primary endpoint of the study was progression free survival (PFS), the time that a patient can live with a cancer without it getting worse. Overall, patients given alectinib saw 53 percent reduction in the risk of progression compared with those given crizotinib. As many alectinib patients had not yet progressed at the time the data were analyzed, it was not yet possible to define median PFS values for this arm of the trial. However, median data were available from an Independent radiology review committee who reported the median PFS on crizotinib to be 10.4 months, compared with median PFS of 25.7 months on alcetinib. At one year of treatment, 68.4 percent of patients treated with alectinib remained progression-free, compared with 48.7 percent of patients treated with crizotinib. Overall, 82.9 percent of patients with ALK-positive non-small cell lung cancer responded to alectinib, compared with 75.5 percent responding to crizotinib.

When ALK-positive lung cancer progresses after crizotinib, it often does so in the brain due to the drug's limited ability to cross the blood-brain barrier to target the cancer inside the central nervous system. In contrast, alectinib has previously shown impressive activity on ALK+ deposits within the brain. In light of this, the ALEX trial actively included patients with brain deposits (regardless of whether they had previously been treated with radiation). Among those patients with measurable brain lesions at baseline, the objective response rate in the brain was 81 percent with alectinib versus 50 percent with crizotinib. The median duration of intracranial response was 17.3 months versus 5.5 months, respectively. Overall, including patients with and without brain metastases at baseline, there was an 84 percent reduction in the risk of central nervous system progression in patients on alectinib compared with those taking crizotinib.

Forty-one percent of patients taking alectinib and 50 percent of those taking crizotinib experienced grade 3-5 side effects.

"We've known the benefits of alectinib given post-crizotinib for a while. Really what we wanted to learn with this study is whether it's best to start treatment with crizotinib and then follow with alectinib as a second-line therapy when the cancer progresses, or whether using alectinib as our first-line therapy could be even better than the sequential approach," says D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and director of Thoracic Oncology at the CU School of Medicine. Camidge is the trial's North American Primary Investigator.

Even though sequential therapy was not explicitly explored within the ALEX trial, previous work suggests that crizotinib followed by alectinib could give a total of 20 months of cancer control (a median PFS of 11 months from first-line crizotinib plus an additional median PFS of 9 months from second-line alectinib). With ALEX showing that alectinib alone, as a first-line therapy, is associated with a median PFS of about 25 months, Camidge believes upfront use is justified.

"At the point that resistance is manifest - at the point you can see the cancer growing on a scan after initial benefit on, say, crizotinib - that cancer has begun creating more cells and more cells means more diversity. This diversity increases the number of subtypes of the cancer present in an individual, giving the cancer more options to choose from as it evolves in the environment of any new drug. This shortens benefit from the next and the next lines of therapy," he says. On the other hand, "if you suppress more of it and in more places in the body in the first place, absolute diversity should remain lower, allowing less chance for the cancer to evolve, leading to longer benefit from the treatment," Camidge says.

Camidge loosely compares these dynamics with the treatment of HIV. "If you went on one anti-retroviral drug and then another and then another, jumping just when resistance emerged, HIV was still very much a short, lethal disease. But now, when people start on a cocktail of different HIV drugs all at the start, suppressing resistance before it emerges, you have patients who can live for decades," he says.

As applied to the current study, crizotinib fairly narrowly targets the ALK rearrangement that causes ALK-positive lung cancer, whereas alectinib targets the ALK rearrangement plus a wider spectrum of related changes that could offer resistance (plus it actively suppresses disease in the brain far better). Exactly which resistance mechanism suppressed by alectinib leads to the positive results of the ALEX trial remains uncertain and may require additional data to emerge.

Camidge points out that in addition to alectinib, several other next-generation ALK-inhibitors are also being tested in first-line clinical trials.

"Alectinib has proven the principle that going on a broader-spectrum drug first - as long as it's well tolerated - may be a key factor in the long term control of malignant disease," Camidge says.

University of Colorado Anschutz Medical Campus

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...