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

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

Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer

Pfizer Inc.    announced encouraging new data from a Phase 1/2 study of lorlatinib, the proposed generic name for PF-06463922, Pfizer’s investigational, next-generation ALK/ROS1 tyrosine kinase inhibitor. The study showed clinical response in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. These data were presented today in an oral presentation at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

lorlatinib

The results presented are from the dose escalation component of an ongoing Phase 1 study of patients with ALK-positive or ROS1-positive NSCLC, with or without brain metastases, who were treatment-naïve or had disease progression after at least one prior tyrosine kinase inhibitor (TKI). Among patients with ALK-positive metastatic NSCLC, the overall response rate (ORR) with lorlatinib was 46 percent, with three patients achieving complete responses and 16 patients achieving a partial response (95% CI: 31-63). The median progression free survival (PFS) was 11.4 months (95% CI: 3.4 – 16.6). The majority of patients had received two or more prior ALK TKIs. Additionally, lorlatinib showed the ability to decrease the size of brain metastases in patients with ALK-positive or ROS1-positive metastatic NSCLC.

“Many patients with ALK-positive or ROS1-positive metastatic NSCLC will progress beyond initial therapy and potentially develop brain metastases,” said Benjamin Solomon, MBBS, Associate Professor, Peter MacCallum Cancer Centre, Australia. “These early data suggest lorlatinib may be effective in a broad range of patients, including those who are heavily pre-treated or develop brain metastases. We are encouraged by these results and look forward to further investigating the full effects of lorlatinib in ALK-positive and ROS1-positive NSCLC.”

“We are excited by these data and the potential of lorlatinib to overcome resistance to ALK inhibitors, which remains a significant challenge for patients with ALK-positive NSCLC,” said Mace Rothenberg, MD, senior vice president, head of development, Pfizer Oncology. “Pfizer pioneered precision medicine in ALK-positive advanced NSCLC through the introduction of XALKORI® (crizotinib), which is widely recognized as a first-line standard of care for these patients, and we are committed to developing next-generation treatments that meet these patients’ evolving needs.”

In the phase 1 portion of the study, patients received lorlatinib on a continuous basis, once or twice daily. The primary objective was to identify the maximum tolerated dose and recommended Phase 2 dose. Patients were treated across 10 dose levels (10–200 mg). The recommended Phase 2 dose was 100 mg once daily. Other objectives included safety and efficacy by RECIST v1.1 including intracranial activity. Of 54 patients treated as of January 15, 2016, 41 were ALK-positive, 12 were ROS1-positive and one was unconfirmed. The majority of patients were previously treated with a TKI, including 20 with one prior TKI and 27 with more than one TKI. Additionally, 39 patients had brain metastases at baseline.

The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade 3 or higher treatment-related AE and the most frequent reason for dose delay or reduction. No patients discontinued due to treatment-related AEs. At the recommended Phase 2 dose, 4 out of 17 patients (24%) experienced a treatment-related AE of any grade that led to a dose delay or hold.

The ongoing Phase 2 study is expected to enroll a total of 240 patients across six cohorts (five for ALK-positive and one for ROS1-positive patients with NSCLC), with enrollment defined by degree and type of prior treatment.

About Lorlatinib

Lorlatinib, the proposed generic name for PF-06463922, is an investigational next-generation ALK/ROS1 tyrosine kinase inhibitor that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of both ALK and ROS1. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier. A Phase 1/2 clinical trial of lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC is currently ongoing. Lorlatinib has not yet been approved by any regulatory agency.

Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer