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.

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

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

New targeted therapy shows promise in patients with ALK-positive advanced NSCLC

An international study involving Manchester researchers has found that for previously untreated lung cancer patients with a particular genetic change, a new targeted therapy is better than standard chemotherapy.

Some patients with non-small cell lung cancer (NSCLC) have changes in the anaplastic lymphoma kinase (ALK) gene, which can drive the development of their cancer. A drug recently developed by Pfizer, crizotinib (see structure), targets ALK and is currently given to patients with ALK positive lung cancer when their cancer has worsened after initial chemotherapy. Now doctors have investigated the use of crizotinib in patients with ALK positive lung cancer who have not yet received any chemotherapy treatment.

New targeted therapy shows promise in patients with ALK-positive advanced NSCLC

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.

Experimental Drug Helps Fight Some Childhood Cancers, Study Finds

In continuation of my update on Crizotinib

Experimental Drug Helps Fight Some Childhood Cancers, Study Finds:  A new targeted drug therapy may help treat certain advanced cancers in children, a new preliminary study indicates.In some cases, the oral medication even made tumors disappear after regular cancer treatments had failed, the...

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"......

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