Study: Alectinib 600 mg more effective than standard therapy in Asian ALK positive NSCLC patients

In continuation of my update on crizotinib and alectinib

 and  

A subanalysis of the phase III ALEX study has shown that alectinib 600 mg twice daily is more effective than standard of care crizotinib in Asian patients with anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC), researchers report at the ESMO Asia 2017 Congress.

The J-ALEX study demonstrated that alectinib 300 mg twice daily improved progression-free survival compared to crizotinib in Japanese patients with ALK positive NSCLC. (3) The ALEX study subsequently showed improvement in progression-free survival with alectinib 600 mg twice daily compared to crizotinib in a global population of ALK positive NSCLC patients. (4)

This subanalysis of the ALEX study investigated the efficacy and safety of alectinib 600 mg twice daily compared to crizotinib in Asian versus non-Asian patients with ALK positive NSCLC. As previously reported, the ALEX study included 303 patients who were randomised in a 1:1 ratio to receive alectinib or standard of care crizotinib. There were 69 Asian patients in each treatment group. The primary endpoint was progression-free survival.

A distinguishing feature of the study was that all patients underwent magnetic resonance imaging (MRI) of the brain every six months, regardless of whether or not they had brain metastases at the start of the study. The time to progression in the brain was measured and compared between the two treatment groups.

"Around 50% of NSCLC patients with ALK mutations will develop brain metastases so it is very important to demonstrate the efficacy of alectinib in the brain," said lead author Professor Tony S.K. Mok, Chairman, Department of Clinical Oncology, The Chinese University of Hong Kong.

The subanalysis showed similar efficacy and safety with alectinib in Asian and non-Asian patients. Progression-free survival was longer with alectinib compared to crizotinib in Asian and non-Asian populations, with hazard ratios (HRs) of 0.46 and 0.49, respectively. Alectinib reduced central nervous system (CNS) progression compared to crizotinib in the Asian and non-Asian groups, with cause-specific HRs of 0.21 and 0.16, respectively. Median overall survival was not reached in either subgroup.

Response rates to alectinib and crizotinib were 81.2% versus 76.8%, respectively, for the Asian subgroup and 84.3% versus 74.4%, respectively, for the non-Asian subgroup.

The rates of nausea, vomiting, and grade III toxicities overall were lower with alectinib compared to crizotinib, and similar between the Asian and non-Asian subgroups. Liver toxicity due to alectinib was slightly higher in the Asian compared to the non-Asian subgroup.

Mok said: "Alectinib 600 mg twice daily was similarly effective in Asian and non-Asian patients in the ALEX study in terms of progression-free survival, CNS progression, and response rate. The rates of toxicities were also comparable. The findings suggest that 600 mg should be the standard dose of alectinib across Asia."

Commenting on the research, Dr Pilar Garrido, Head of the Thoracic Tumour Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain, said: "ALK rearrangements emerged as important therapeutic targets in NSCLC in 2007, defining a distinct molecular subset of tumours. Around 5% of NSCLC patients harbour ALK mutations and are highly sensitive to ALK tyrosine kinase inhibitors, which efficiently induce apoptosis. Patients wih advanced ALK positive NSCLC have a high lifetime risk of CNS metastases and a high frequency of brain metastases at diagnosis, with the CNS being the most common site of disease progression."

Lorlatinib Superior to Crizotinib for ALK-Positive NSCLC

In continuation of my update on lorlatinib and  crizotinib

                                                                 lorlatinib

                                                               crizotinib

Among patients with previously untreated advanced ALK-positive non-small cell lung cancer (NSCLC), progression-free survival is significantly longer for those who receive first-line therapy with lorlatinib versus crizotinib, according to a study published in the Nov. 19 issue of the New England Journal of Medicine.

Alice T. Shaw, M.D., Ph.D., from the Massachusetts General Hospital Cancer Center in Boston, and colleagues conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who were previously untreated for metastatic disease.

The researchers found that 78 and 39 percent of patients in the lorlatinib group and crizotinib group, respectively, were alive without disease progression at 12 months (hazard ratio for disease progression or death, 0.28). An objective response occurred in 76 and 58 percent of those in the lorlatinib and crizotinib groups, respectively. Among those with measurable brain metastases, an intracranial response occurred in 82 and 23 percent, respectively; an intracranial complete response occurred in 71 percent of those who received lorlatinib. Hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects were the most common adverse events associated with lorlatinib. Compared with crizotinib, lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels; 72 versus 56 percent).

"Among patients with previously untreated, advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival, a higher overall and intracranial response, and better quality of life than those who received crizotinib," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including Pfizer, which manufactures lorlatinib and funded the study.

https://en.wikipedia.org/wiki/Lorlatinib

https://en.wikipedia.org/wiki/Crizotinib

Added benefit of crizotinib drug for first-line treatment of advanced bronchial carcinoma not proven

In continuation of my update on crizotinib

The drug crizotinib (trade name: Xalkori) has been available since 2012 for patients with advanced non-small cell lung cancer (bronchial carcinoma) who have a high activity of the enzyme anaplastic lymphoma kinase (ALK) and have already received another treatment. In November 2015, the approval was extended to first-line treatment.

After its assessment in 2013, the German Institute for Quality and Efficiency in Health Care (IQWiG) therefore now reassessed the added benefit of the drug in comparison with the appropriate comparator therapy - and found out: An added benefit of crizotinib for the first-line treatment of advanced bronchial carcinoma is not proven.

Carboplatin only in advanced risk of cisplatin side effects

Advanced bronchial carcinoma can only be treated palliatively. The Federal Joint Committee (G-BA) specified several appropriate comparator therapies for this. Either cisplatin in combination with a third-generation cytostatic agent was to be used in the control arm, or - in case of an increased risk of cisplatin side effects - carboplatin with a third-generation cytostatic agent. Monotherapy with gemcitabine or vinorelbine was an alternative option for patients with already severe limitations.

Use of carboplatin attached to condition

The drug manufacturer did not use the latter option and only submitted data from a randomized study in which crizotinib was directly compared with cisplatin or carboplatin, each in combination with the cytostatic agent pemetrexed. Carboplatin is not approved for the treatment of advanced non-small cell lung cancer, but can be prescribed in so-called off-label use. This is only the case for patients with an advanced risk of cisplatin side effects, e.g. in neuropathy, hearing impairment or susceptibility to nausea, renal insufficiency or cardiac failure.

The only submitted study did not fulfil the condition

Almost half of the participants received carboplatin in the control arm of the PROFILE 1014 study; the criteria for this individual medical decision were not comprehensible. A large proportion of the patients in the control arm did not correspond to the criteria of the Pharmaceutical Directive for the off-label use of carboplatin. Patients with neuropathy, renal insufficiency or cardiac failure were excluded from participation in the study and only about two and six per cent of the participants had notable hearing impairment or nausea as accompanying disease.

Hence the control group of the study did not adequately represent the appropriate comparator therapy. The data submitted were therefore unsuitable for the derivation of an added benefit of crizotinib in comparison with this comparator therapy.

Added benefit of crizotinib drug for first-line treatment of advanced bronchial carcinoma not proven: The drug crizotinib (trade name: Xalkori) has been available since 2012 for patients with advanced non-small cell lung cancer (bronchial carcinoma) who have a high activity of the enzyme anaplastic lymphoma kinase (ALK) and have already received another treatment. In November 2015, the approval was extended to first-line treatment.

FDA Approves Alecensa (alectinib) as First-Line Treatment for ALK-Positive Metastatic Non-Small Cell Lung Cancer

Genentech, a member of the Roche Group  announced that the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) for Alecensa (alectinib) for the treatment of people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. The approval is based on results from the Phase III ALEX study, which showed Alecensa significantly reduced the risk of disease worsening or death (progression-free survival, PFS) by 47 percent (HR=0.53, 95 percent CI: 0.38, 0.73, p<0.0001) compared to crizotinib as assessed by independent review committee (IRC). Median PFS was 25.7 months (95 percent CI: 19.9, not estimable) for people who received Alecensa compared with 10.4 months (95 percent CI: 7.7, 14.6) for people who received crizotinib. The safety profile of Alecensa was consistent with that observed in previous studies.

The study also showed that Alecensa significantly reduced the risk of the cancer spreading to or growing in the brain or central nervous system (CNS) compared to crizotinib by 84 percent (HR=0.16, 95 percent CI: 0.10, 0.28, p<0.0001). This was based on a time to CNS progression analysis in which there was a lower risk of progression in the CNS as the first site of disease progression for people who received Alecensa (12 percent) compared to people who received crizotinib (45 percent).

“Our goal is to develop medicines that have the potential to significantly improve upon the standard of care,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “In our pivotal study, Alecensa significantly extended the time that people lived without their disease worsening compared to crizotinib and also showed a marked reduction in the risk of their cancer spreading to the brain.”

“ALK-positive lung cancer is often found in younger people, who tend to have more advanced disease at the time of diagnosis, and comes with a unique set of challenges," said Bonnie J. Addario, a lung cancer survivor and founder of the Bonnie J. Addario Lung Cancer Foundation (ALCF). “We applaud advancements in care, like the approval of Alecensa, which provides a new initial treatment option for people with this type of lung cancer.”

Alecensa received Breakthrough Therapy Designation from the FDA in September 2016 for the treatment of adults with advanced ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible. Results from the Phase III ALEX study were simultaneously presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine. Subsequently, Alecensa was recommended in the National Comprehensive Cancer Network (NCCN) guidelines as a treatment option for first-line ALK-positive metastatic NSCLC (Category 1, Preferred).

In addition to today’s approval, the FDA also converted Alecensa’s initial accelerated approval in December 2015 for the treatment of people with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib (second-line) to a full approval.

Crizotinib drug effectively halts growth of ROS1-positive lung tumors

In continuation of my update on crizotinib

Treatment with the targeted therapy drug crizotinib effectively halts the growth of lung tumors driven by rearrangements of the ROS1 gene. In an article receiving Online First publication in the New England Journal of Medicine to coincide with a presentation at the European Society for Medical Oncology meeting, an international research team reports that crizotinib treatment led to significant tumor shrinkage in 36 of 50 study participants and suppressed tumor growth in another 9.

"Prior to this study, there were a handful of reports describing marked responses to crizotinib in individual patients with ROS1-positive lung tumors," says Alice Shaw, MD, PhD, of the Massachusetts General Hospital (MGH) Cancer Center, lead author of the NEJM report. "This is the first definitive study to establish crizotinib's activity in a large group of patients with ROS1-positive lung cancer and to confirm that ROS1 is a bona fide therapeutic target in those patients."

Crizotinib currently is FDA-approved to treat non-small-cell lung cancers (NSCLC) driven by rearrangments in the ALK gene, which make up around 4 percent of cases. An MGH Cancer Center report published in 2012 reported that 1 to 2 percent of NSCLCs are driven by rearrangements in ROS1, which encodes a protein with significant structural similarities to that encoded by the ALK gene.

Crizotinib drug effectively halts growth of ROS1-positive lung tumors

FDA Expands Use of Xalkori (crizotinib) to Treat ROS-1 Positive Non-Small Cell Lung Cancer

In continuation of my update on Xalkori (crizotinib) 

The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration. Xalkori is the first and only FDA approved treatment for patients with ROS-1 positive NSCLC.

Lung cancer is the leading cause of cancer-related deaths in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute. ROS-1 gene alterations, thought to lead to abnormal cells, have been identified in various cancers, including NSCLC. ROS-1 gene alterations are present in approximately 1 percent of patients with NSCLC. The overall patient and disease characteristics of NSCLC with ROS-1 gene alterations appear similar to NSCLC with anaplastic lymphoma kinase (ALK) gene alterations, for which crizotinib use was previously approved. Xalkori was approved to treat certain patients with late-stage NSCLC that expresses an abnormal ALK gene in 2011.

“Lung cancer is difficult to treat, in part, because patients have different mutations, some of which are rare,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded use of Xalkori will provide a valuable treatment option for patients with the rare and difficult to treat ROS-1 gene mutation by giving health care practitioners a more personalized way of targeting ROS-1 positive NSCLC.”

Xalkori is an oral medication that blocks the activity of the ROS-1 protein in tumors that have ROS-1 gene alterations. This effect on ROS-1 may prevent NSCLC from growing and spreading.

The safety and efficacy of Xalkori for the treatment of patients with ROS-1 positive tumors were evaluated in a multi-center, single-arm study of 50 patients with ROS-1 positive metastatic NSCLC. Patients received Xalkori twice daily to measure the drug’s effect on their lung cancer tumors. The studies were designed to measure overall response rate, the percentage of patients who experienced complete or partial shrinkage of their tumors. Results showed 66 percent of participants experienced a complete or partial shrinkage of their NSCLC tumors, an effect that lasted a median of 18.3 months.

FDA Expands Use of Xalkori (crizotinib) to Treat ROS-1 Positive Non-Small Cell Lung Cancer

ALK fusion variants could influence NSCLC crizotinib response

In continuation of my update on crizotinib

In non-small-cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) rearrangement treated with crizotinib, progression-free survival (PFS) varies according to the ALK fusion variant.

ALK gene rearrangements result in the formation of the EML4-ALK fusion oncogene, the variants of which differ on the basis of which exon of EML4 is fused to ALK exon 20, explain Tatsuya Yoshida and co-workers, from Aichi Cancer Center Hospital in Japan, who explored the link between the ALK fusion variants and response to crizotinib.

Among 55 patients given the ALK tyrosine kinase inhibitor, median PFS was 11.0 months for the 54% of patients with ALK variant 1 (with exon 13 of EML4). This was significantly longer than the 4.2 months for the remaining participants who harbouredALK variants other than variant 1.

And in multivariate analysis, the presence of variant 1 and advanced stage were the only two factors significantly associated with PFS duration, with the former exerting a positive and the latter a negative effect (hazard ratios of 0.350 and 4.646, respectively).

"Therefore, the treatment strategy for ALK-positive NSCLC should be determined on the basis of the ALK variant status of the patient", Yoshida et al conclude in the Journal of Clinical Oncology.

Ref : http://jco.ascopubs.org/content/early/2016/06/22/JCO.2015.65.8732.abstract

Crizotinib Shows Dramatic Results for Shrinking Tumors (lung cancer)....

Patients with a specific kind of lung cancer may benefit from a Phase III clinical trial offered by the Moores UCSD Cancer Center. The new drug, crizotinib (structure), under development by Pfizer, showed dramatic results in reducing lung cancer tumors in some patients during Phase I and II clinical trials.

"The results of the first two trials have been very encouraging," said Lyudmila Bazhenova, MD, assistant clinical professor at UC San Diego School of Medicine and a member of the Moores UCSD Cancer Center...

According to a preliminary study,  57% of patients had their tumors reduced and at eight weeks of the treatment, 87% showed disease stabilization.

The Phase III clinical trial will compare crizotinib with standard-of-care chemotherapy in the treatment of ALK-positive recurrent NSCLC. Through a randomized selection process, patients will either be treated with chemotherapy or crizotinib. If the patients who are given the chemotherapy do not respond to treatment, they will be given crizotinib at the end of the trial....

Ref : http://ucsdnews.ucsd.edu/newsrel/health/06-22ShrinkingTumors.asp

IASLC lauds FDA approval of alectinib for lung cancer treatment

The International Association for the Study of Lung Cancer (IASLC) is once again gratified to see the approval of a new second-generation lung cancer treatment that can help many patients in their battle against the disease. Lung cancer patients got another round of hope with the FDA's rapid progression of lung cancer drug approvals - this time for alectinib (Alecensa, Roche/Genenetech) for patients with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) if their disease deteriorated after treatment with another therapy called crizotinib (Xalkori, Pfizer). Patients who could not tolerate treatment with crizotinib also qualify for use of alectinib.

Lung cancer is the leading cause of cancer deaths around the world, responsible for claiming more lives than prostate, colon and breast cancer combined. Medications that target the individual characteristics of a patient's disease continue to create new options and hope for those with lung cancer. For example, tumor cells in about 5 percent of lung cancer patients with NSCLC contain the ALK (anaplastic lymphoma kinase) genetic mutation. In patients with metastatic cancer, the disease spreads to new part of the body. For ALK-positive NSCLC metastatic patients, the disease often spreads to the brain.

Many ALK-positive patients benefit from treatments called ALK inhibitors, such as crizotinib which blocks the activity of the ALK protein and can prevent NSCLC cells from growing and spreading. Alectinib is an oral medication that performs similarly. Patients can also develop resistance to ALK inhibitors such as crizotinib, so alectinib gives health professionals a new option to continue to extend their patients' life span. The FDA previously approved ceritinib (Novartis) in the same treatment setting.

"These types of medications that take advantage of a patient's specific genetic mutations are the future of lung cancer treatments and these treatments create a blueprint of how we can turn some cancers into a chronic disease and eventually create a cure," said Fred R. Hirsch, MD, PhD, Professor of Medicine and Pathology at the University of Colorado Cancer Center and School of Medicine and CEO of the IASLC.

Alectinib is the fifth lung cancer treatment approved by the FDA since early October. The others include:

Necitumumab in combination with standard chemotherapy to treat patients with advanced squamous NSCLC who did not previously received systemic therapy;

Two immunotherapy treatments: nivolumab and pembrolizumab;

And osimertinib, a 3rd-generation EGFR TKI.

IASLC lauds FDA approval of alectinib for lung cancer treatment

EMA has accepted Pfizer's regulatory submissions for review of two investigational compounds crizotinib and bosutinib

European Medicines Agency (EMA) has accepted Pfizer's regulatory submissions for review of two investigational compounds  crizotinib, an oral first-in-class anaplastic lymphoma kinase (ALK) inhibitor, for the treatment of patients with previously treated ALK-positive advanced non-small cell lung cancer (NSCLC); and bosutinib for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase. 

Crizotinib

                                                                                               Bosutinib

Dr. Andreas Penk, president of Pfizer Oncology Europe, claims that,

"With the EMA submissions for crizotinib and bosutinib, we are one step closer to potentially bringing two promising agents to patient populations in areas of significant unmet medical need"......

Scientists develop new strategy to overcome drug-resistant childhood cancer

Researchers at The Institute of Cancer Research in London have found a way to overcome the resistance of cancer cells to a drug called crizotinib, which recently showed positive early results in its first trial in children with cancer.

Crizotinib (see structure) has already been licensed by the US Food and Drug Administration for use in adult cancers, but early experience suggests tumours eventually stop responding to treatment, after developing additional mutations in the ALK gene targeted by the drug.

Brigatinib drug shows promise against ALK non-small cell lung cancer in phase I/II clinical trial

Phase I/II clinical trial results reported at the American Society for Clinical Oncology (ASCO) Annual Meeting 2015 show promising results for investigational drug brigatinib against ALK+ non-small cell lung cancer (NSCLC), with 58 of 78 ALK+ patients responding to treatment, including 50 of 70 patients who had progressed after previous treatment with crizotinib, the first licensed ALK inhibitor. Progression-free survival (PFS) in patients previously treated with crizotinib was 13.4 months.

"Although still only in an early phase trial, brigatinib is showing an objective response rate in approximately 70 percent of ALK-positive patients post-crizotinib and it's showing about a year of progression-free survival. These results are among the best in the field, offering a lot of hope to people with ALK-positive lung cancer," says D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado Cancer Center and the trial's principal investigator.

In addition, robust data is emerging on drug activity in patients with brain involvement of the disease. Many lung cancer trials have traditionally excluded patients with brain metastases at baseline, expecting that the presence of metastases would create negative results that could in turn create the appearance of drug failure. Following early recognition of the importance of the brain as a potential differentiator between the activity of new drugs, the brigatinib trial includes patients with untreated brain metastases, showing a greater than 30 percent decrease in size of brain tumors in 8 of 15 patients with brain tumors greater than 10 mm and disappearance of brain metastases in 11 of 33 patients with smaller lesions only. Brain metastases remained controlled for a median 15.6 months.

Based on these promising early results, brigatinib, developed by Ariad Pharmaceuticals, Inc., recently received Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ALK+ metastatic NSCLC whose tumors are resistant to crizotinib (below structure)

Brigatinib drug shows promise against ALK non-small cell lung cancer in phase I/II clinical trial

Alecensa (alectinib) approved for treatment of people with advanced ALK-positive NSCLC

The U.S. Food and Drug Administration today approved Alecensa (alectinib) to treat people with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) whose disease has worsened after, or who could not tolerate treatment with, another therapy called Xalkori (crizotinib).

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute. An ALK (anaplastic lymphoma kinase) gene mutation can occur in several different types of cancer cells, including lung cancer cells. ALK gene mutations are present in about 5 percent of patients with NSCLC. In metastatic cancer, the disease spreads to new parts of the body. In ALK-positive NSCLC metastatic patients, the brain is a common place for the disease to spread.

 Crizotinib

"Today's approval provides a new therapy for a group of patients who would have few treatment options once their disease no longer responds to treatment with Xalkori," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "In addition to the primary effect on tumors in the lung, Alecensa clinical trials provide evidence of an effect on tumors that had spread to the brain, which is an important effect for clinicians to understand."

Alecensa is an oral medication that blocks the activity of the ALK protein, which may prevent NSCLC cells from growing and spreading.

Alecensa (alectinib) approved for treatment of people with advanced ALK-positive NSCLC

Early treatment with lorlatinib improves survival in some lung cancer patients: Lung cancer patients with a specific genetic alteration lived longer and were protected against metastasis to the brain when treated early with lorlatinib

In continuation of my update on Lorlatinib

Non-small-cell lung cancer (NSCLC) accounts for 87% of all cases of lung cancer. Some 5% of NSCLC cases are ALK-positive, which means they have a genetic abnormality in the anaplastic lymphoma kinase gene. ALK-positive NSCLC, which is not associated with smoking, is a particularly aggressive form of lung cancer.

"When ALK is turned on abnormally, it's like stepping on the gas pedal -- it drives uncontrolled proliferation and survival of cancer cells," says investigator Alice Shaw, MD, PhD, who was formerly director of the Center for Thoracic Cancers at MGH and led the NEJM study. Notably, ALK-positive patients tend to be 10 to 15 years younger than other lung cancer patients. They are also at high risk for developing brain metastasis.

A new class of drugs that block ALK, known as ALK inhibitors, was discovered in 2008. "Turning off ALK with an ALK inhibitor is like putting on the brakes," agrees Justin Gainor, MD, of the Mass General Cancer Center, who worked with Shaw on the study. "It can lead to rapid killing of cancer cells and cause tumors to shrink dramatically." Both first and second generation ALK inhibitors have been developed, including crizotinib (Xalkori), alectinib (Alecensa), and brigatinib (Alunbrig), which can be very effective, but patients eventually relapse. What's more, patients treated with these drugs can still develop metastatic spread of cancer to the brain.

Lorlatinib belongs to a third-generation of this drug class and is even more effective at blocking ALK. It's currently approved by the Food and Drug Administration for treating ALK-positive patients whose cancer has progressed despite taking older-generation ALK inhibitors.

Shaw and her co-investigators wanted to know if lorlatinib improved the likelihood of long-term remission in ALK-positive patients when administered as first-line therapy. To find out, she and colleagues at 104 medical centers in 23 countries recruited 296 patients with advanced, previously untreated ALK-positive NSCLC. Half of the patients received lorlatinib, while the remainder were treated with crizotinib, which was the standard of care for these patients when the trial began.

The results were striking. Compared to patients who received crizotinib, those given lorlatinib had a 72% reduction in the risk of cancer progression or death. Importantly, lorlatinib also reduced the risk of new or recurrent brain metastases by 93%. Serious side effects were more common in the lorlatinib group, but more than half were increases in blood cholesterol and triglycerides, which were manageable with medication.

The investigators will continue to follow patients in this study to track their long-term outcomes, but "these results support lorlatinib as a potential first-line option for ALK-positive patients," says Shaw.

Shaw is now global head of Translational Clinical Oncology at the Novartis Institutes for BioMedical Research

https://en.wikipedia.org/wiki/Lorlatinib

Early treatment with lorlatinib improves survival in some lung cancer patients: Lung cancer patients with a specific genetic alteration lived longer and were protected against metastasis to the brain when treated early with lorlatinib -- ScienceDaily

Xalkori Approved For Rare Genetic Form of Lung Cancer

In continuation of my update on Xalkori (crizotinib)

Xalkori (crizotinib) has been approved by the U.S. Food and Drug Administration to treat advanced non-small cell lung cancer (NSCLC) with tumors that have a rare ROS-1 gene mutation.The drug was approved in 2011 to treat advanced NSCLC that was related to an abnormal ALK gene, the agency said Friday in a news release.

Lung cancer is the leading cause of cancer death in the United States. Last year, more than 221,000 cases were diagnosed and more than 158,000 people died from it, the FDA said.

Clinical studies of 50 people with ROS-1-positive NSCLC found that about two-thirds of participants treated with Xalkori had their tumors partially or completely shrink for an average of 18 months, the agency said.

The drug's most common side effects include nausea, diarrhea, vomiting, swelling, constipation, elevated liver enzymes, fatigue, loss of appetite and upper respiratory infection. More serious adverse reactions could include liver problems, lung inflammation, abnormal heartbeat and loss of vision.

Xalkori Approved For Rare Genetic Form of Lung Cancer 

Existing drugs could help prevent deadly familial stomach and lobular breast cancers

Deadly familial stomach and lobular breast cancers could be successfully treated at their earliest stages, or even prevented, by existing drugs that have been newly identified by cancer genetics researchers at New Zealand's University of Otago.

The researchers, led by Professor Parry Guilford, show for the first time that the key genetic mutation underlying the devastating conditions also opens them to attack through drug therapies targeting other cellular mechanisms.

There is currently no treatment for this kind of gastric cancer other than surgical removal of the stomach as a preventive measure in those identified as carrying the mutated gene. Lobular breast cancer is hard to detect by mammography and mastectomies are also undertaken by some carriers.

The researchers' findings appear in the US journal Molecular Cancer Therapeutics.

The team used genomic screening to search for vulnerabilities in the cancer cells that lack the tumour-suppressor protein E-cadherin. The genetic mutation that causes this protein to be lost is common in hereditary diffuse gastric and lobular breast cancers.

E-cadherin is not a traditional drug target for these forms of cancer because the protein is present in healthy cells but absent in malignant ones. However, Professor Guilford and his team predicted that its loss might create other vulnerabilities in these cancer cells. 

Professor Guilford says the research team used an approach of searching for 'synthetically lethal' combinations of E-cadherin loss with inactivation of other proteins, which together cause cell death.

 (Saracatinib)   (Crizotinib)

 (Crizotinib)     (Alisertib)

(Gandotinib)

Existing drugs could help prevent deadly familial stomach and lobular breast cancers