Trial shows apple allergen as effective treatment option for birch pollen-related apple allergy

In continuation of my update on Osimertinib

Osimertinib improves progression-free survival compared to standard first line therapy in Asian patients with EGFR-mutated non-small-cell lung cancer (NSCLC), according to the Asian subset analysis of the FLAURA trial presented at the ESMO Asia 2017 Congress, sumultaneously published in The New England Journal of Medicine.

EGFR mutations occur in 30-40% of NSCLC in Asian populations compared to 10-15% in Western populations. The phase III FLAURA trial compared osimertinib, a third generation EGFR-tyrosine kinase inhibitor (TKI), to standard of care EGFR-TKIs (erlotinib or gefitinib) as first line therapy in NSCLC patients with EGFR mutations. A total of 556 patients from Asia, Europe, and North America were randomized 1:1 to treatment with osimertinib or standard of care. Osimertinib improved progression-free survival by 54%.

This subset analysis included the 322 Asian patients in the FLAURA trial, of whom 46 were Chinese, 120 were Japanese, and 156 were from other parts of Asia.

The median progression-free survival was 16.5 months with osimertinib compared to 11.0 months for the standard therapy, with a hazard ratio of 0.54 (95% confidence interval, 0.41-0.72; p<0.0001).

The median duration of response was two-fold higher for patients treated with osimertinib (17.6 months) compared to standard of care (8.7 months). The overall response rate was 80% with osimertinib compared to 75% with standard of care treatment. Median overall survival was not reached. The incidence of grade 3 or higher toxicities was lower for osimertinib (40%) than the standard treatment (48%).

Lead author Professor Byoung Chul Cho, Yonsei Cancer Center, Seoul, Korea, said: "As in the overall trial population, osimertinib provided a significant progression-free survival benefit in Asian patients with EGFR-mutated NSCLC. Asian patients had similar toxicities with osimertinib as the overall FLAURA population. Osimertinib should be the preferred first line treatment for EGFR-mutant NSCLC in Asia."

Commenting on the findings Professor James CH Yang, Chairman, Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan, said: "The results of this subset analysis are quite compatible with the findings in the overall population presented at the ESMO 2017 Congress in Madrid. We can therefore conclude that osimertinib can be considered as the standard of care for the first line treatment of Asian advanced NSCLC patients with EGFR mutations."

"The proportion of patients having adverse events that caused them to stop taking osimertinib was similar in the overall (13%) and Asian (15%) populations," added Yang. "We tend to think osimertinib is a well tolerated drug so these discontinuation rates were surprisingly high and need further investigation."

Yang continued: "Although there was no statistical difference between the hazard ratios for progression-free survival, it was numerically lower in non-Asians (0.34) compared to Asians (0.54). There is an ongoing debate as to whether Asian and non-Asian patients with EGFR mutations have distinct responses to EGFR-TKIs. This might be due to variations in clinical practice rather than biology. A meta-analysis of all relevant studies could shed light on this issue."

"It will also be important to know whether Asian and non-Asian patients in the FLAURA trial with brain metastases had similar outcomes," said Yang.

Trial shows apple allergen as effective treatment option for birch pollen-related apple allergy

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."

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.

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

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  

Novel combination therapy shows strong response in phase 1 trial

In continuation of my update on Sorafenib, Premetrexed,  Vandetanib
"Though phase 1 studies are designed to evaluate the safety of a new therapy, we had strong preclinical evidence suggesting this novel drug combination could work against a variety of cancers, so we hoped that we would see a response in our patients in this early phase trial," said Andrew Poklepovic, M.D., lead investigator on the study. "With this trial, we established a safe dosing schedule, and we will now be testing the efficacy of the therapy in the phase 2 study."

The results of the clinical trial were recently published online by the journal Oncotarget (PMID: 27213589). The study enrolled 37 patients between October 2011 and December 2014. Of those patients, 36 received treatment and 33 were evaluated for response. One patient had a complete response, meaning all detectable traces of the tumor disappeared, while four patients had a partial response, which means that the tumor volume shrank by at least 30 percent. The therapy stabilized disease progression in an additional 15 patients, with some of these patients responding for up to a year. The therapy was found to be particularly active in breast cancer patients.

"Some dose-limiting toxicities associated with pemetrexed were observed in one cohort of patients, but those who were eligible were switched to the dosing schedule of the second cohort, which was found to safe and tolerable," says Poklepovic, medical oncologist and member of the Developmental Therapeutics research program at Massey as well as assistant professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.

The trial is based on pre-clinical research conducted by a team of Massey scientists led by Paul Dent, Ph.D., who is the Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey, and Richard Moran, Ph.D., who recently retired after 22 years at Massey and more than four decades in the field. Pemetrexed was co-developed by Moran, and is now a first-line therapy for non-small cell lung cancer (NSCLC) and mesothelioma. Sorafenib is used to treat liver, kidney and thyroid cancer. In 2011, a research team led by Dent and including Moran discovered that the two drugs synergize to induce profound killing of cancer cells through a toxic form of autophagy, a process that normally re-cycles components of cells to provide energy for maintaining cell growth and survival. The drug combination hyper-activated the autophagy process within cancer cells, causing them to literally eat themselves to death (PMID: 21622715).

 Sorafenib  Pemetrexed

  Vandetanib    Lapatinib

The phase 2 study is not the only continuation of the research. Because the initial results of the phase 1 study were so promising, Dent started a new project to discover the best "third drug" that could act to further enhance the anti-cancer properties of the pemetrexed and sorafenib combination. This work has also recently been published in Oncotarget, and it showed that the combination therapy could be enhanced by a class of drugs known as ERBB1/2/4 inhibitors (PMID: 27015562).

"We discovered in mouse models of breast cancer that the drugs lapatinib and vandetanib significantly enhanced the anti-tumor effect of the pemetrexed and sorafenib therapy without any apparent toxicity to normal tissue. We made a nearly identical observation when adding the drug afatinib in experiments involving non-small cell lung cancer," says Dent. "Based on this data, we will be submitting a grant application to the National Cancer Institute for funding that will hopefully provide data that could allow us to open a future phase 1 trial testing the addition of an ERBB1/2/4 inhibitor to pemetrexed and sorafenib in patients with advanced solid tumors."

Dent was able to determine that ERBB1/2/4 inhibitors could increase the effectiveness of the combination therapy by using a novel technology called a multiplex assay. The multiplex assay is a broad, unbiased screening approach that allows researchers to simultaneously examine the levels of multiple hormones in the blood and determine the activities of enzymes in cancer cells. Using this technology, the researchers discovered that the enzyme ERBB1 was activated in response to the pemetrexed and sorafenib therapy.

"Unlike alternative methods where a certain degree of guesswork is required, the multiplex assay allowed us to observe exactly how the cancer cells responded to therapy," says Dent. "We were surprised to see that the enzyme ERBB1 was activated because it is ordinarily thought to protect cancer cells from chemotherapy. We went on to successfully use ERBB1/2/4 inhibitors as our third drug because of this unexpected data."

The multiplex assay provided Dent's team with such invaluable additional information about how the sorafenib and pemetrexed combination worked in the mouse models that they will now be using the assay in several of their clinical trials moving forward, including the new phase 2 trial of pemetrexed and sorafenib.

"The multiplex assay will allow us to track specific levels of hormones in the blood as patients undergo treatment, which could potentially give us a molecular 'fingerprint' of the point at which tumors develop resistance to the therapy," says Dent. "Ongoing preclinical experiments show that it could be possible to pinpoint exactly how the cancer cells are developing resistance to therapies, which might eventually allow oncologists to develop in real time a personalized therapy designed to overcome drug resistance in an individual patient's tumor."

Ref : http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=9434

FDA Approves Gilotrif (afatinib) for Patients with Squamous Cell Carcinoma of the Lung

I continuation of my update on Afitinib

Boehringer Ingelheim  announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Gilotrif® (afatinib) tablets for the treatment of patients with advanced squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy. The U.S. approval follows the recent marketing authorization of Gilotrif in this patient population by the European Commission. Gilotrif, an oral, once-daily EGFR-directed therapy, is currently approved in the U.S. for the first-line treatment of specific types of EGFR mutation-positive NSCLC.

 afatinib

“We are pleased to bring a proven therapy to patients suffering from advanced squamous cell carcinoma of the lung who have progressed despite chemotherapy,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “This approval is further evidence of Boehringer Ingelheim’s strong commitment to bringing new treatment options to the lung cancer community.”

Squamous cell carcinoma (SqCC) of the lung is associated with a poor prognosis, limited survival and symptoms like cough and dyspnea. The median overall survival (OS) after diagnosis of advanced SqCC is around one year.

LUX-Lung 8 clinical trial investigator Shirish Gadgeel, MD, leader of the Thoracic Oncology Multidisciplinary Team at the Karmanos Cancer Center, Detroit, commented: “The overall survival data and significant delay in lung cancer progression seen in the global head-to-head Phase III trial demonstrated that Gilotrif is an effective new treatment option in this patient population.”

The sNDA was based on results of the head-to-head LUX-Lung 8 trial in patients with SqCC of the lung whose tumors progressed after first-line chemotherapy. Gilotrif, compared to erlotinib, demonstrated:

• Significant delay in progression of lung cancer (PFS, progression-free survival, primary endpoint), reducing the risk of cancer progression by 18%
• Significant improvement in overall survival (OS, key secondary endpoint), reducing the risk of death by 19%
• Significantly improved disease control rate (51% vs 40%; P=0.002)

The most common adverse reactions observed with Gilotrif (reported in at least 20% of study patients) were diarrhea (75%), rash or acne (70%), stomatitis (mouth sores) (30%), decreased appetite (25%), and nausea (21%).

LUX-Lung 8 (NCT01523587) is part of the Gilotrif LUX-Lung program – the largest collection of clinical trials of any EGFR tyrosine kinase inhibitor (TKI), with over 3,760 patients across eight studies conducted around the world. The comprehensive LUX-Lung program includes two pivotal studies in the first-line setting for EGFR mutation-positive patients, LUX-Lung 3 and LUX-Lung 6, which compared Gilotrif to chemotherapy regimens. In addition, the program included two head-to-head studies (LUX-Lung 7 and LUX-Lung 8) of Gilotrif versus first-generation EGFR TKIs gefitinib and erlotinib, respectively. The LUX-Lung program has involved over 680 sites in 40 countries, reflecting the strong partnership between Boehringer Ingelheim and the lung cancer specialist community.

Investigational drug abemaciclib shows durable clinical activity for variety of cancer types

In continuation of my  updates on palbociclib (Ibrance)  and letrozole

Bottom Line: The investigational anticancer therapeutic abemaciclib, which targets CDK4 and CDK6, showed durable clinical activity when given as continuous single-agent therapy to patients with a variety of cancer types, including breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, and melanoma, according to results from a phase I clinical trial.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Senior authors: Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas, and Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute in Boston.

Background: In February 2015, the U.S. Food and Drug Administration (FDA) approved the CDK4/6 inhibitor palbociclib (Ibrance) for use in combination with the aromatase inhibitor letrozole for treating postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer.

  letrozole  palbociclib

The oral CDK4/6 inhibitor abemaciclib is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity, according to Shapiro. For example, abemaciclib has greater selectivity for CDK4 compared with palbociclib, which may explain why it does not affect white blood cell counts as severely, allowing it to be taken on a continuous schedule without treatment holidays, he said. Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors, he added.

 abemaciclib

How the Study Was Conducted and Results: Patnaik, Shapiro, and colleagues enrolled 225 patients with a variety of types of advanced cancer in the phase I clinical trial designed to evaluate the safety and preliminary efficacy of abemaciclib. In the dose escalation phase, the researchers determined that the maximum tolerated dose was 200 milligrams (mg) every 12 hours; the dose-limiting toxicity was grade 3 fatigue.

In the expansion phase, single-agent abemaciclib was administered to 47 patients with breast cancer, 68 with NSCLC, 17 with glioblastoma, 26 with melanoma, and 15 with colorectal cancer. Among these patients, the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts.

Radiographic responses were observed for some patients with breast cancer, NSCLC, and melanoma. Among the 36 patients with hormone receptor-positive breast cancer, 11 had a partial response, with four of the 11 responders having continued prior endocrine therapy, and an additional 18 patients had stable disease. Among the 68 patients with NSCLC, two had a partial response and 31 had stable disease; one patient who had a partial response and 12 who had stable disease were known to have KRAS-mutant NSCLC. Among the 26 patients with melanoma, one had a partial response and six had stable disease. Three of the 17 patients with glioblastoma had stable disease, with two of them continuing to receive treatment without disease progression for 19 and 23 cycles, respectively.

Author Comment: "These data show that abemaciclib is an oral drug that can be taken on a continuous schedule and achieve durable clinical activity against multiple tumors including breast and lung cancers," said Shapiro.

"The results of the trial supported the FDA decision to grant breakthrough therapy designation to abemaciclib (previously known as LY2835219) for patients with refractory hormone receptor-positive advanced or metastatic breast cancer," added Patnaik.

Limitations: Patnaik explained that because this study included 225 patients with different types of cancer, confirmatory clinical trials in specific patient populations are necessary to precisely define the role of abemaciclib in cancer care. Multiple clinical trials have already been initiated to evaluate abemaciclib as a treatment for certain groups of patients with breast cancer and NSCLC, as well as children with primary brain tumors and adults with brain metastases, she noted.

AstraZeneca reports new Phase I extended follow-up data on osimertinib in NSCLC patients at ELCC 2016

AstraZeneca today reported new Phase I extended follow-up data on osimertinib in both first- and second-line treatment of patients with non-small cell lung cancer (NSCLC), at the European Lung Cancer Conference (ELCC) 2016. Late-breaker presentations reinforced the efficacy and safety profile for osimertinib previously seen in the AURA clinical trials programme.

osimertinib

Phase I data from the AURA trial on osimertinib investigated as first-line treatment in 60 patients (pooled 80mg and 160mg dose cohorts) with epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC showed an objective response rate (ORR, a measurement of tumour shrinkage) of 77% (95% confidence interval (CI): 64%-87%) and a progression-free survival (PFS) of 19.3 months, with 55% of patients remaining progression-free at 18 months (95% CI: 41%-67%).1 Median duration of response (DoR) was non-calculable (NC) (95% CI: 12.5 months to NC) at the time of data cut off, with 53% of patients continuing to respond at 18 months (95% CI: 36%-67%).1 Of the 60 first-line patients, five had tumours also harbouring the T790M mutation at diagnosis (known as de novo patients) and all five of these patients showed durable responses. The most common adverse events were rash (78% overall; 2% ≥Grade 3), diarrhoea (73% overall; 3% ≥Grade 3), dry skin (58% overall; 0 ≥Grade 3) and paronychia (50% overall; 3% ≥Grade 3). All of the Grade 3 or above events in these categories occurred at the 160mg dose.

Klaus Edvardsen, Vice President, Clinical Oncology and Interim Head of Oncology, Global Medicines Development at AstraZeneca said:

In a Phase I study with osimertinib as first-line therapy in EGFR-mutation positive NSCLC, we are seeing consistently durable responses. In many cases, responses continue for at least 18 months including in a small group of patients with the T790M mutation detectable at diagnosis. The ongoing Phase III FLAURA trial will further characterise the potential of osimertinib 80mg in the first-line EGFRm setting.

AstraZeneca reports new Phase I extended follow-up data on osimertinib in NSCLC patients at ELCC 2016: AstraZeneca today reported new Phase I extended follow-up data on osimertinib in both first- and second-line treatment of patients with non-small cell lung cancer (NSCLC), at the European Lung Cancer Conference (ELCC) 2016. Late-breaker presentations reinforced the efficacy and safety profile for osimertinib previously seen in the AURA clinical trials programme.

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 

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

Afatinib a better choice for EGFR-mutated lung cancer in first-line treatment

In continuation of my update on Afatinib

Patients with EGFR-activating mutations in advanced lung cancer seem to benefit more from afatinib than gefitinib as first-line treatment, researchers report at the first ESMO Asia 2015 Congress in Singapore.

In the global, randomised, open-label Phase IIb LUX-Lung 7 (LL7) trial1, the irreversible ErbB family blocker afatinib significantly improved efficacy versus gefitinib across a range of clinically relevant endpoints, such as progression-free survival, time-to-treatment failure and objective response rate. "Based on these results I would consider afatinib as the EGFR tyrosine kinase inhibitor (TKI) of choice for the first-line treatment for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC)," lead author, Professor Keunchil Park, head of the Division of Hematology/Oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, said.

NSCLC is the most common type of lung cancer: activating epidermal growth factor receptor (EGFR) gene mutations are more frequently observed in non-smokers and women, and occur in 50% of Asians and only 10% of non-Asians. The targeted agents afatinib and gefitinib block key pathways involved in tumour growth and spread. They have both been approved for the treatment of naive patients, based on the results of Phase III trials, confirming their superiority compared to chemotherapy. Unlike the first-generation EGFR inhibitor gefitinib, the irreversible ErbB family blocker afatinib is suggested to be active in prolonging tumour response and delaying disease progression.

Afatinib a better choice for EGFR-mutated lung cancer in first-line treatment - Medical News Today

FDA Approves Alecensa (alectinib) for ALK-Positive Non-Small Cell Lung Cancer

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.

“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.

The safety and efficacy of Alecensa were studied in two single-arm clinical trials of patients with metastatic ALK-positive

FDA Approves Alecensa (alectinib) for ALK-Positive Non-Small Cell Lung Cancer

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

TIGER-X study reviews efficacy of rociletinib therapy in patients with EGFR mutant-positive NSCLC

Oncology & Hematology Review, the peer-reviewed journal, has published a review highlighting recent data around rociletinib, an investigational therapy in patients with previously treated EGFR mutant-positive non-small cell lung cancer.

Treatment for patients with non-small cell lung cancer (NSCLC) is being guided increasingly by driver mutations and, routinely, tumors from patients with adenocarcinoma are screened for mutations in the kinase domain of the epidermal growth factor receptor (EGFR) as well as for other genomic abnormalities (i.e. anaplastic lymphoma kinase [ALK] and ROS1 translocations). Effective, well-tolerated treatment options that specifically target the EGFR T790M mutation (the "gatekeeper" residue) in patients with NSCLC remains an unmet need. Rociletinib is an oral, irreversible, potent, covalent inhibitor of the activating EGFR mutations (del19 and L858R) and the T790M resistance mutation; it also spares wild-type EGFR. TIGER-X is the first of the TIGER trial series, which is a clinical development program for rociletinib in patients with mutant EGFR NSCLC. This phase I-II study is evaluating rociletinib in patients who have progressed following their first and only EGFR-directed tyrosine kinase inhibitor (TKI) therapy who have developed the T790M mutation and in later-line T790M positive patients who have progressed on their second or later TKI therapy or subsequent chemotherapy. In the ongoing TIGER-X study, rociletinib has shown encouraging activity in patients with EGFR mutant-positive NSCLC and is well tolerated. Future aims of the ongoing TIGER programme include to investigate rociletinib treatment in other lines of therapy, determine whether rociletinib treatment can lead to an improvement in overall survival (OS) and to explore the potential benefits of combining rociletinib with other anti-cancer agents such as anti-programmed cell death protein and programmed cell death 1 ligand 1 monoclonal antibodies, mitogen-activated protein kinase enzyme inhibitors, vascular endothelial growth factor inhibitors, and c-Met inhibitors. Other aims include evaluating the outcome of progression-free survival associated with rociletinib treatment and determining the efficacy of rociletinib in patients with T790M negative status.

TIGER-X study reviews efficacy of rociletinib therapy in patients with EGFR mutant-positive NSCLC

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