FDA Approves Lenvima (lenvatinib) for the Treatment of Patients with Advanced Renal Cell Carcinoma

In continuation of my update on Lenvatinib

 Lenvatinib

Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) approved Lenvima (lenvatinib), the company's multiple receptor tyrosine kinase inhibitor, in combination with everolimus for the treatment of patients with advanced renal cell carcinoma(aRCC) who were previously treated with an anti-angiogenic therapy. This approval was based on the impressive results of the registration study (Study 205), in which the once daily combination of 18 mg Lenvima and 5 mg everolimus demonstrated a substantial improvement in progression-free survival (PFS), powerful objective response rate (ORR) and clinically meaningful overall survival (OS) when compared with everolimus alone, a standard of care for patients with aRCC who have received prior anti-angiogenic therapy.

"Lenvatinib plus everolimus is the first and only FDA-approved regimen that successfully combines treatments that employ tyrosine kinase and mTOR inhibition, the primary targets of advanced RCC treatment for the past decade," said Robert Motzer, M.D., Memorial Sloan Kettering Cancer Center, New York, and the principal investigator of the study. "This combination regimen led to enhanced efficacy and helped patients with advanced RCC live longer without disease progression or death than those treated with everolimus alone. These noteworthy findings advance the treatment paradigm for this patient population."

Lenvima was granted Breakthrough Therapy designation by the FDA for this indication, and the application received Priority Review, which is assigned to drugs the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition.

In Study 205, a Phase 2 trial, Lenvima and everolimus (LEN+EVE) resulted in a median PFS nearly three times that of everolimus alone. The median PFS, or the length of time from randomization until disease progression or death, in patients treated with the combination (n=51) was 14.6 months (95% CI: 5.9–20.1) compared with 5.5 months (95% CI: 3.5–7.1) for those treated with everolimus alone (n=50) (HR 0.37; 95% CI: 0.22–0.62). The combination regimen resulted in a 63% reduction in the risk of disease progression or death compared with everolimus alone. The treatment effect of the combination on PFS was supported by a retrospective independent review.

The objective response rate was 37% (95% CI: 24–52) in patients treated with the combination regimen (35% partial response + 2% complete response) compared to 6% (all partial response, 95% CI: 1–17) in patients treated with everolimus alone.

The patients who received LEN+EVE experienced a 10.1-month increase in median OS compared with those who received everolimus monotherapy (25.5 months [95% CI: 16.4–32.1] versus 15.4 months [95% CI: 11.8–20.6]; HR 0.67; 95% CI: 0.42–1.08). This OS analysis was conducted when 63% of deaths had occurred in the combination arm and 74% of deaths had occurred in the everolimus arm.

The safety of this combination regimen was also examined in Study 205. Serious risks from treatment with the combination of Lenvima and everolimus may include hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid-stimulating hormone suppression/thyroid dysfunction, and embryofetal toxicity. The most common adverse reactions observed in study patients treated with Lenvima and everolimus (greater than 30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events and proteinuria. The most common serious adverse reactions (greater than or equal to 5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%) and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients receiving Lenvima and everolimus and 54% in patients receiving everolimus. The most common adverse reactions (greater than or equal to 5%) resulting in dose reductions in patients treated with Lenvima and everolimus were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%) and proteinuria (5%).

Treating physicians are likely to be familiar with many of the adverse reactions observed for this combination regimen based on their prior experience with these types of drugs. Prescribers may be able to manage certain adverse reactions (such as nausea, vomiting, diarrhea and hypertension) with a proactive plan that includes concomitant medications and/or dose reductions, interruptions and/or discontinuations.

"Rates of renal cell carcinoma have been on the rise over the past several decades, and unfortunately, advanced RCC remains an incurable disease. Since the VEGF pathway is known to be involved in the growth of renal cell tumors, it is important to have a diverse offering of therapeutic options, including treatments that continue to target VEGF inhibition," said Sumanta Kumar Pal, M.D., Assistant Professor, Department of Medical Oncology & Therapeutics Research and Co-Director, Kidney Cancer Program at City of Hope in Duarte, Calif. "The combination regimen of lenvatinib and everolimus provides a new treatment for patients with advanced RCC whose disease continues to progress despite prior treatment with an anti-angiogenic therapy."

Lenvima was first approved in the U.S. on February 13, 2015, for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

"By bringing this breakthrough treatment to patients with advanced RCC, Eisai now offers an efficacious option in a second difficult-to-treat tumor type, just 15 months after its initial approval, and we look forward to continued exploration of LENVIMA in additional malignancies," said Alton Kremer, M.D., Ph.D., Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "This also marks the second time in four months that one of Eisai's oncology treatments has been granted a new indication following Priority Review from the FDA. These milestones, as well as the ongoing development of innovative agents in our pipeline, underscore our steadfast commitment to Eisai's human health care (hhc) mission of identifying and addressing the unmet needs of people living with cancer."

About Study 205

Study 205, the Phase 2 study, was a multicenter, randomized trial in patients (n=153) with unresectable advanced or metastatic RCC who were previously treated with an anti-angiogenic therapy and randomized 1:1:1 to receive a combination of 18 mg LENVIMA plus 5 mg everolimus once a day, LENVIMA only (24 mg once a day) or everolimus only (10 mg once a day) administered orally in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary efficacy endpoint of this study was investigator-assessed PFS. Other endpoints of the study included ORR, OS and safety.

The results of this study were published online in The Lancet Oncology in October 2015, following an oral presentation at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.

RADIANT-3 study results show everolimus significantly extends progression-free survival in patients with advanced pancreatic neuroendocrine tumors...

We know that Everolimus (RAD-001, marketed by Novartis under the  tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine and Afinitor in oncology) is the 42-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

The FDA has approved everolimus for the treatment of advanced kidney cancer on March 30, 2009 and for organ rejection prophylaxis on April 22, 2010. Now Novartis Pharmaceuticals Corporation announced that the  Phase III study of Afinitor® (everolimus, see structure) tablets plus best supportive care met its primary endpoint, showing the drug significantly extended progression-free survival, or time without tumor growth, in patients with advanced pancreatic neuroendocrine tumors (NET). The study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), is part of the largest clinical trial program of its kind. 

Everolimus is approved under the trade name Afinitor® (everolimus) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.  

As  per the claim by   Herve Hoppenot, President, Novartis Oncology, Everolimus was developed to inhibit the mTOR protein, which is a critical target in treating various cancers, including NET. Results from RADIANT-3 demonstrate that everolimus has the potential to become an important treatment option for patients with advanced pancreatic NET, where there is a major unmet need.

"These study results will serve as the basis of worldwide regulatory filings for everolimus and bring us one step closer to our goal of offering these patients a new therapy."...says Herve Hoppenot...

Ref : http://www.novartis.com/newsroom/media-releases/en/2010/1421290.shtml

Everolimus combined with standard R-CHOP therapy shows promise in treating DLBCL patients

In continuation of my update on everolimus

The targeted therapy everolimus may be safely combined with R-CHOP for new, untreated diffuse large B-cell lymphoma according to the results of a pilot study by Mayo Clinic researchers published in the Lancet Haematology. R-CHOP is a combination of drugs used to treat lymphoma. The combination includes rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

"There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma," says Patrick Johnston, M.D., Ph.D., a hematologist at Mayo Clinic and lead author. "This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial."

The everolimus, R-CHOP combination was well-tolerated by patients with no dose-limiting toxicity reached within the planned dose escalation. The vast majority of patients (96 percent) achieved an overall response, and all responders achieved a complete metabolic response to the treatment. The findings indicate that drugs targeting the P13K-mTOR pathway — a cascade of molecules involved in cell growth and survival — add benefit when combined with standard R-CHOP therapy.

Lymphoma is the sixth most common cancer in the U.S., and diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. The standard accepted treatment for DLBCL is a combination R-CHOP delivered in a 21-day cycle for six cycles. However, this regimen typically cures only approximately 60 percent of patients.

Dr. Johnston and his colleagues scoured the scientific literature in search of ways to improve the cure rate. Two lines of evidence pointed toward targeting the P13K-mTOR pathway. First, numerous studies have demonstrated the importance of this pathway in the pathogenesis of DLBCL cells in the laboratory. Second, clinical studies have documented the single-agent efficacy of everolimus (an mTOR inhibitor) in relapsed DLBCL. Therefore, Mayo Clinic researchers decided to test a regimen that combined the standard R-CHOP with everolimus.

They conducted a phase 1 and feasibility study in 24 patients with new, previously untreated DLBCL in the Alliance for Clinical Trials in Oncology, a National Cancer Institute cooperative group. Patients received everolimus for 14 days in combination with R-CHOP-21. A large proportion of patients achieved an overall response (96 percent) and a complete metabolic response as assessed by positron emission tomography imaging (96 percent). No relapses with DLBCL occurred and all patients achieved the predictive milestone of being event-free at 12 months from enrollment. The treatment was well-tolerated, and the most common adverse events were hematological in nature, such as grade 4 neutropenia (75 percent) and grade 3 febrile neutropenia (21 percent).

"This study is the first to integrate a P13K-mTOR agent with standard RCHOP," says Dr. Johnston. "The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients."

Exelixis Announces FDA Approval of Cabometyx (cabozantinib) for Patients with Advanced Renal Cell Carcinoma

In continuation of my update on  cabozantinib

Exelixis, Inc.   announced that the U.S. Food and Drug Administration (FDA) has approved Cabometyx (cabozantinib) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. RCC is the most common form of kidney cancer in adults. Cabometyx, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first therapy to demonstrate in a phase 3 trial for patients with advanced RCC, robust and clinically meaningful improvements in all three key efficacy parameters — overall survival, progression-free survival and objective response rate.

“With  this announcement, patients with previously treated advanced kidney cancer now have a new option, the first and only approved product demonstrated to help patients live longer while also delaying the progression of their cancer,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “We are proud to bring new hope to this community, who are looking for more therapies that can help extend lives. Exelixis is committed to making Cabometyx available to patients in need within the next couple weeks.”

“The efficacy profile demonstrated by Cabometyx in the METEOR trial, now complemented by the overall survival benefit, is highly compelling,” said Toni Choueiri, MD, Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “Cabometyx is distinct from other approved treatment options, as it targets multiple tyrosine kinases involved in the development of RCC, including MET, AXL and three VEGF receptors. At the same time, physicians are very familiar with this class of drug and how to use dose adjustments to balance safety and efficacy. The approval of Cabometyx is wonderful news for physicians who are looking for a new option for their previously treated patients with advanced kidney cancer.”

The approval of Cabometyx is based on results of the phase 3 METEOR trial, which met its primary endpoint of improving progression-free survival. Compared with everolimus, a standard of care therapy for second-line RCC, Cabometyx was associated with a 42 percent reduction in the rate of disease progression or death. Median progression-free survival for cabozantinib was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). Cabometyx also significantly improved the objective response rate compared with everolimus. These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.

As announced in February 2016, Cabometyx also demonstrated a statistically significant and clinically meaningful increase in overall survival in the METEOR trial. Compared with everolimus, Cabometyx was associated with a 34 percent reduction in the rate of death. Median overall survival was 21.4 months for patients receiving Cabometyx versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).

Drug shrinks brain tumors in children with tuberous sclerosis complex, study suggests

In continuation of my update on Everolimus

 "Every patient in this study experienced a decrease in size of their tumors, and no patient required surgery for their tumors after treatment with everolimus," says Dr. Franz, co-director of the TSC Clinic at Cincinnati Children's and the study's main author. "Thirty-five percent of patients in this study on everolimus had at least a 50 percent reduction in tumor volume after an average of 42 weeks on medication."

The phase III study was conducted among 117 patients with TSC who were randomly assigned to either everolimus or a placebo. Patients were 9 ½ years old on average but ranged from infants to adults. No patient on placebo showed improvement in their tumors. Tumor volume was measured by MRI assessment of the brain.

Dr. Franz conducted an earlier, phase II study of everolimus published in The New England Journal of Medicine in 2010. Based on that data, the U.S. Food and Drug Administration granted accelerated approval of everolimus for patients with these tumors, known as subependymal giant cell astrocytomas, or SEGAs. The new, placebo controlled study was conducted to confirm these earlier results.

Prior to FDA approval, surgery was considered standard therapy for SEGAs, but everolimus is a potential alternative to surgery and the first targeted medical therapy for TSC, says Dr. Franz.

"Children and teens may not only avoid surgery but they also may see improvement in other aspects of this disease, including a reduction or even elimination of hydrocephalus  a buildup of fluid inside the skull leading to increased intracranial pressure. Hydrocephalus is commonly associated with these tumors because they are located deep within the brain in spinal fluid pathways, or ventricles."

In Dr. Franz's 2010 study, patients reported their quality of life, as measured by a validated quality of life and neuropsychological assessments, improved at three months and six months after treatment with everolimus...

Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61134-9/fulltext

Drug shrinks brain tumors in children with tuberous sclerosis complex, study suggests

Researchers uncover two-drug combo that halts the growth of cancer cells

                       Everolimus

Neratinib

In continuation of my update on Neratinib  and Everolimus

UT Southwestern Simmons Cancer Center researchers have discovered a two-drug combo that halts the growth of cancer cells that carry HER2 mutations.

The findings, published today in the journal Cancer Cell, were prompted by the observation that, after an initial response, patients with cancers harboring HER2 mutations eventually develop resistance to a promising new cancer drug currently in clinical trials.

The scientists found that another drug, already on the market, counters that resistance and blocks the cancer, thereby providing the basis for a novel drug combination against cancers with mutations in the HER2 gene.

Dhivya Sudhan, Ph.D., a postdoctoral research fellow in the Harold C. Simmons Comprehensive Cancer Center, and collaborators evaluated data from a molecularly guided trial where patients with tumors with HER2 mutations were treated with the HER2 inhibitor neratinib. In this study, patients' cancers were sequenced as the disease progressed during treatment. Based on this analysis, Sudhan discovered in the laboratory that an effective way to offset eventual resistance to neratinib is with everolimus, a TORC1 inhibitor commonly used to treat other types of breast cancer.

"This finding may give clinicians an effective response to neratinib resistance. That could make a real difference for patients with breast, ovarian, lung, and other cancers harboring HER2 mutations," says Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center at UT Southwestern and corresponding author of the study.

HER2 mutations have long been identified as a key driver in breast and other cancers. The authors of this study zeroed in on a signaling network driven by TORC1, which they showed is the pathway through which HER2-mutant cancers become neratinib-resistant.

"We consistently noted activation of TORC1 signaling as a mechanism of resistance to neratinib across different types of HER2-mutant cancers. Different cancer types used different strategies to escape neratinib, but they all converged on TORC1 signaling," Sudhan says.

In addition to studying tumor sequencing data from HER2-mutant cancer patients across the country who are in clinical trials for neratinib, Sudhan also studied neratinib-resistant cells and tumors that continue to live and grow in the laboratory.

The sequencing of the patients' cancer before and during the clinical trial showed that some patients already had a mutation that could activate the TORC1 pathway. Others would develop it eventually, but they could benefit from everolimus which is currently used as a TORC1 inhibitor to address the other roles TORC1 plays in cancer. Everolimus would allow the patient to continue benefiting from neratinib's inhibition of HER2.

Sudhan says the combination of neratinib and everolimus worked in cell lines, organoids established from patient-derived tumors, and in mice harboring HER2 mutant tumors. The next step will be testing this two-drug combo in humans.

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

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

https://www.sciencedirect.com/science/article/abs/pii/S1535610819305835?via%3Dihub

Everolimus, 177Lu-dotatate extend neuroendocrine tumour PFS

 

Positive progression-free survival (PFS) results from the RADIANT-4 and NETTER-1 trials extend the armamentarium for physicians treating patients with neuroendocrine tumours (NETs).

The studies, indicating efficacy for the mTOR inhibitor everolimus and the peptide receptor radionuclide therapy lutetium (Lu)177-dotatate, respectively, were presented at the European Cancer Congress held in Vienna, Austria.

The primary endpoint of PFS in the RADIANT-4 trial, as determined by central radiological review, was 11.0 months in the 205 patients with non-functional NETs of the gastrointestinal tract or lung who were randomly assigned to receive everolimus 10 mg/day compared with 3.9 months in the 97 patients given placebo, with a significant hazard ratio (HR) of 0.48.

The “robust benefit” was confirmed by investigator assessment, with PFS of 14.0 months versus 5.5 months in the everolimus and placebo groups, and a significant HR of 0.39.

The first planned interim overall survival analysis showed a 36% reduction in the risk of death in favour of everolimus and, although this was not statistically significant, the researchers believe that analysis of mature data in 2016 may show a significant result.

“Although we knew from previous studies that everolimus could delay the growth of pancreatic NETs, this is the first time we have been able to conclusively show that it is effective in other NET sites”, said James Yao, from the University of Texas MD Anderson Cancer Center in Houston, USA, and RADIANT-4 co-investigators in a press release.

Everolimus, 177Lu-dotatate extend neuroendocrine tumour PFS

Hard-to-treat Myc-driven cancers may be susceptible to drug already used in clinic

In continuation of my update on Everolimus

Hard-to-treat Myc-driven cancers may be susceptible to drug already used in clinic

Treatment with everolimus led to tumor regression and  gnificantly improved survival compared  with placebo in mice with established lymphomas. However,  all  of  these  mice  eventually  relapsed as a result   of the growth of lymphoma  cells  resistant to the effec ts  of everolimus.

"These data confirmed our hypothesis that mTORC1 inhibition could suppress Myc-driven tumor initiation and growth," said McArthur. "The surprise was found in how mTORC1 inhibition led to tumor regression. We had expected that it would trigger cancer cells to die by a cellular process known as apoptosis, but we found that this was not the case."

Detailed analysis of the tumors indicated that everolimus caused tumor regression by inducing cellular senescence.

According to McArthur, normal cells protect themselves when cancer-driving genes are switched on is by entering a state called senescence. When cancers develop, they have found ways to overcome this safeguard. "Our data indicate that one way in which cancers bypass senescence, in particular senescence induced by Myc, is through a signaling pathway involving mTORC1," he said.

Resistance to everolimus treatment in mice with established lymphomas was associated with loss of the function of p53, a protein known to help suppress tumor formation and growth.

"The loss of effectiveness of everolimus therapy against lymphoma cells deficient in p53 function has important clinical implications," said McArthur. "Everolimus could be a useful new string to the bow for clinicians treating patients with Myc-driven cancers, in particular B cell lymphomas, but that it would be helpful only to those patients with functional p53."

Ref : http://cancerdiscovery.aacrjournals.org/content/early/2012/12/13/2159-8290.CD-12-0404.abstract?sid=79f94616-1798-4c19-92c2-26e76ad12905 

Sunitinib versus everolimus trial highlights non-clear cell RCC patient response heterogeneity

In continuation of my update on Sunitinib

Sunitinib offers significantly longer progression-free survival (PFS) than everolimus for patients with metastatic non-clear cell renal cell carcinoma (RCC), phase II trial results indicate, but treatment effect appears to depend upon key patient characteristics.

“Based on the present study and previous clinical studies, decisions on therapeutic choice between sunitinib and everolimus for patients with metastatic non-clear cell [RCC] should be based on prognostic risk criteria, histological subtype, and the known, expected side-effects”, say Andrew Armstrong, from Duke University in Durham, North Carolina, USA, and co-workers.

“Future clinical trials in these patients should also consider this heterogeneity of outcome when assessing novel agents”, they recommend in The Lancet Oncology. PFS was 8.3 months for the 51 patients randomly assigned to receive open-label, 6-week cycles of treatment with the VEGF receptor inhibitor sunitinib 50 mg/day compared with 5.6 months for the 57 patients given the mTOR inhibitor everolimus 10 mg/day, giving a significant hazard ratio (HR) of 1.41.

Sunitinib versus everolimus trial highlights non-clear cell RCC patient response heterogeneity: Sunitinib offers significantly longer progression-free survival than everolimus for patients with metastatic non-clear cell renal cell carcinoma, phase II trial results indicate, but treatment effect appears to depend upon key patient characteristics.

Drug shows dramatic reduction in seizures in patients with tuberous sclerosis complex

In continuation of my update on Everolimus

Newest study, led by a physician-scientist at Cincinnati Children's in collaboration with a team at Texas Children's Hospital in Houston, has been accepted by the journal Annals of Neurology, and is available online.

"Everolimus treatment reduced seizure frequency and duration in the majority of TSC epilepsy patients whose seizures previously did not respond to treatment," says Darcy Krueger, MD, PhD, a pediatric neurologist at Cincinnati Children's and lead author of the study. "This improvement in seizure control was associated with a better quality of life, and side effects were limited. Work is already underway to confirm these results in a follow-up, phase III clinical study."

"This has been positively life-changing for the patients involved and is nothing short of transformative in the treatment of epilepsy associated with cellular growth disorders, such as TSC," says Angus Wilfong, MD, director of the comprehensive epilepsy program at Texas Children's Hospital and associate professor of pediatrics and neurology at Baylor College of Medicine.

The study included 20 patients who were treated with everolimus. Their median age was 8. Half of the patients were enrolled at Cincinnati Children's and half at Texas Children's Hospital in Houston.

The researchers found that everolimus reduced seizure frequency by at least 50 percent in 12 of the 20 participants. The drug also reduced seizures in 17 of the 20 TSC patients by a median rate of 73 percent. Four patients were free of seizures and seven had at least a 90 percent reduction in seizure frequency.

Overall quality of life, as reported by the participants' parents, also improved. Parents reported several positive changes, including attention, behavior, social interaction and physical restrictions.

Ref: http://onlinelibrary.wiley.com/doi/10.1002/ana.23960/abstract;jsessionid=5F1A5FDF269D16EDA880D9A0CE57B8CC.d03t03

Drug shows dramatic reduction in seizures in patients with tuberous sclerosis complex

Liver Cancer Drug Fails to Live Up to Early Promise...

In continuation of my update on everolimus

Although it looked promising in early studies, the drug everolimus didn't improve survival for people with advanced liver cancer in its latest trial, a new study found.

The findings from the phase 3 clinical trial are disappointing because earlier research suggested that everolimus (Afinitor) prevented tumor progression and improved survival for in advanced liver cancer. Normally, these patients can expect a median overall survival of less than one year.

The only drug currently shown to significantly improve survival of advanced liver cancer patients is sorafenib (Nexavar). But that drug's benefits are temporary and the cancer eventually progresses, according to background information in the new study.

The current study included 546 adults with advanced liver cancer whose disease progressed during or after treatment with sorafenib, or who could not take sorafenib. The patients were divided into two groups, with 362 given everolimus and 184 given a placebo.

Liver Cancer Drug Fails to Live Up to Early Promise 

Patients with advanced kidney cancer benefit from cabozantinib treatment

In continuation of my update on cabozantinib

Patients with advanced kidney cancer live for nearly twice as long without their disease progressing if they are treated with cabozantinib, a drug that inhibits the action of tyrosine kinases - enzymes that function as an "on" or "off" switch in many cellular processes, including cancer.

In the second of two late-breaking presentations of research that is predicted to change the way kidney cancer patients are treated, Professor Toni Choueiri will tell the presidential session of the 2015 European Cancer Congress, about results from the first 375 patients out of a total of 658 patients recruited to the phase III clinical METEOR trial comparing cabozantinib with everolimus, the current standard treatment for the disease.

Analysis of results in July 2015 showed that the estimated median (average) progression-free survival time for patients with advanced clear cell kidney cancer, randomised to receive cabozantinib, was 7.4 months, while it was 3.8 months for those receiving everolimus. The objective response rate (the proportion of patients whose tumours shrank, assessed up to 17 months) was 21% for cabozantinib and 5% for everolimus.

An interim analysis of overall survival among all of the 658 patients found that it was a third better for patients receiving cabozantinib. The findings are published simultaneously with the ECC2015 presentation in the New England Journal of Medicine.

Prof Choueiri, who is Associate Professor of Medicine at Harvard Medical School and Clinical Director and Kidney Cancer Center Director at The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, USA, said: "I am very excited about the outcome of the study since the results may change the standard of care in patients with advanced kidney cancer who have received prior standard therapy that targets the vascular endothelial growth factor receptor (VEGFR).

"Although treatment with VEGFR-targeted drugs has been very effective in the first line of therapy for patients with advanced kidney cancer, in many cases tumour cells find ways to escape control by these drugs. Cabozantinib is a new drug that targets possible escape mechanisms of tumour cells, including the tyrosine kinases MET, VEGFR and AXL. The results of the METEOR trial indicate that cabozantinib is able to shrink tumours and slow down tumour growth much better than current standard treatment in patients who previously received VEGFR-targeted drugs. This has resulted in a significant reduction in the rate of disease progression or death in the cabozantinib arm as compared with the everolimus arm. Regaining tumour control after prior targeted therapy may reduce symptoms related to kidney cancer and eventually help patients live longer.

Patients with advanced kidney cancer benefit from cabozantinib treatment

FDA approves Afinitor drug for tuberous sclerosis complex

We know that Everolimus (RAD-001), marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine and Afinitor in oncology is the 42-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. The FDA has approved everolimus for the treatment of advanced kidney cancer on March 30, 2009 and for organ rejection prophylaxis on April 22, 2010. Now the same drug has been approved for Tuberous sclerosis or tuberous sclerosis complex (TSC a rare, multi-system genetic disease that causes benign tumours to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin ) ….more

Novartis announces FDA approval of Afinitor for progressive, nonfunctional neuroendocrine tumors of GI

 

In continuation of my update  on Everolimus 

Novartis today announced that the United States Food and Drug Administration (FDA) approved Afinitor® (everolimus) tablets for the treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Afinitor received a priority review designation providing a shortened review period for drugs that treat serious conditions and offer a significant improvement in safety or effectiveness.

"Afinitor is the first treatment approved for progressive, nonfunctional NET of lung origin, and one of very few options available for progressive, nonfunctional GI NET, representing a shift in the treatment paradigm for these cancers," said Bruno Strigini, President, Novartis Oncology. "We are proud of our Afinitor development program, which has translated to meaningful benefits for patients with several different cancers and rare diseases."

Neuroendocrine tumors are a rare type of cancer that originate in neuroendocrine cells throughout the body, and are most often found in the GI tract, lungs or pancreas. NET can be defined as functional or nonfunctional. Functional NET are characterized by symptoms caused by the oversecretion of hormones and other substances. Nonfunctional NET may be characterized by symptoms caused by tumor growth, such as intestinal obstruction, pain and bleeding for GI NET, and asthma, chronic obstructive pulmonary disease and pneumonia for lung NET. More than 70% of patients with NET have nonfunctional tumors. At the time of diagnosis, 5%-44% (depending on site of tumor origin) of patients with NET in the GI tract and 28% of patients with lung NET have advanced disease, meaning the cancer has spread to other areas of the body, making it difficult to treat. Progression, or the continued growth or spread of the tumor, is typically associated with poor outcomes.

Novartis announces FDA approval of Afinitor for progressive, nonfunctional neuroendocrine tumors of GI

Everolimus treatment option for tuberous sclerosis patients

In continuation of my update on Everolimus

Everolimus treatment option for tuberous sclerosis patients

Cabozantinib extends advanced RCC overall survival

In continuation of my update on Cabozantinib

Patients with advanced or metastatic renal cell carcinoma (RCC) derive a significant overall survival (OS) benefit from second-line treatment with the multi-tyrosine kinase inhibitor (TKI) cabozantinib relative to everolimus.

These findings come from the final analysis of the phase III METEOR trial in which 330 participants were randomly assigned to receive cabozantinib 60 mg/day and 328 allocated to the mammalian target of rapamycin inhibitor everolimus at a dose of 10 mg/day. All patients had received at least one previous vascular endothelial growth factor receptor TKI.

After a median follow-up of 18.7 and 18.8 months in the cabozantinib and everolimus arms, respectively, the corresponding median OS times were 21.4 and 16.5 months, a significant difference equating to a hazard ratio for death of 0.66.

Progression-free survival was also significantly improved in the cabozantinib arm, as was the objective response rate - findings that were consistent with the previously reported results for the first 375 randomly assigned patients, report Toni Choueiri (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and team.

They conclude in The Lancet Oncology: "Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma."

Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.

Ref : http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2816%2930107-3/abstract

Novartis drug Afinitor® approved by FDA as first medication to treat patients with non-cancerous kidney tumors associated with TSC

In continuation of my update on AFINITOR^®(everolimus)...

Novartis Pharmaceuticals Corporation ("Novartis") announced today that the US Food and Drug Administration (FDA) approved Afinitor® (everolimus) tablets* for the treatment of adult patients with kidney tumors known as renal angiomyolipomas and tuberous sclerosis complex (TSC), who do not require immediate surgery. This marks the first approval of a medical treatment in this patient population......

Media Release...

Ref : http://www.novartisoncology.com/media/press-releases.jsp?id=1606656&year=2012&page=1

FDA approves cancer drug Afinitor for treatment of rare genetic disorder

 We know that Afinitor ( see structure) is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Afinitor is specifically indicated for the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Afinitor is supplied as a 5 mg or 10 mg tablet designed for oral administration. The recommended initial dose of the drug is 10 mg, to be taken once daily at the same time every day, either with or without food. Afinitor tablets should be swallowed whole with a glass of water; they should not be chewed or crushed....Now FDA approves the drug....

 FDA approves cancer drug Afinitor for treatment of rare genetic disorder   

Combination of Two Drugs Reverses Liver Tumors.....

The combination of two inhibitors of protein mTOR stops the growth of primary liver cancer and destroys tumour cells, according to a study by researchers of the Group of Metabolism and Cancer at Bellvitge Biomedical Research Institute (IDIBELL).  

The study led by IDIBELL researchers compared the effects in mice of two inhibitors of mTOR. The first was a derivative of rapamycin, called everolimus (RAD001 - see structure below left),
which is already used as an immunosuppressant and to treat specific cancers. The second is a new generation drug that inhibits mTOR called BEZ235 (see right side structure). 

During the study, researchers found unexpectedly that the combination of the two drugs had a more potent effect than any of the two drugs separately. Coadministration of BEZ235 and RAD001 limits the development of tumour and causes the self-destruction of tumour cells.

Based on these results a clinical trial, funded by Novartis, has started in the United States to evaluate the efficacy of the combination of these two inhibitors of mTOR in humans. The study coordinator, Sara Kozma, noted that

"because rapamycin and its derivatives are already approved for the treatment of other diseases, their combination to BEZ235, would be a rapid strategy to test the efficacy of this drug and fast track its approval for clinical use."

Ref :1. http://www.idibell.cat/modul/news/en/362/combination-of-two-drugs-reverses-liver-tumours
2.http://stm.sciencemag.org/content/early/2012/04/27/scitranslmed.3003923

FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

In continuation of my update on lenvatinib

Woodcliff Lake, NJ and Kenilworth, announced today that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor Lenvima (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT (Study 304), where Lenvima demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

“Unresectable hepatocellular carcinoma is an extremely difficult-to-treat cancer, with no new first-line systemic therapy options for more than a decade,” said Dr. Ghassan Abou-Alfa, medical oncologist, Memorial Sloan Kettering Cancer Center. “REFLECT is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC. The efficacy and safety data from REFLECT are important findings for oncologists and others in the multidisciplinary teams who treat liver cancer, as well as for our patients who are affected by it.”

Adverse reactions, some of which can be serious or fatal, may occur with Lenvima, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the severity of the adverse reaction, Lenvima should be monitored, withheld or discontinued. Based on its mechanism of action and data from animal reproduction studies, Lenvima can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see “Important Safety Information” below.

REFLECT showed that Lenvima achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with Lenvima experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted when 351 events had occurred in the Lenvima arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, Lenvima showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

• Median PFS was doubled with Lenvima compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with Lenvima versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77) per RECIST 1.1.
• Lenvima showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with Lenvima versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
  • Per mRECIST: Treatment with Lenvima resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with Lenvima resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
  • Per RECIST 1.1: Treatment with Lenvima resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with Lenvima resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib

In addition, median time to progression (TTP) was doubled with Lenvima compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with Lenvima versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

In REFLECT, the most common adverse reactions (≥20%) observed in patients treated with Lenvima were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism and nausea. The most common serious adverse reactions (≥2%) reported in patients treated with Lenvima were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%).

The most common adverse reactions (≥20%) observed in patients who received sorafenib were palmar-plantar erythrodysesthesia syndrome, diarrhea, fatigue, hypertension, abdominal pain, decreased appetite, rash, decreased weight and arthralgia/myalgia. The most common serious adverse reactions (≥2%) reported in patients who received sorafenib were ascites (2%) and abdominal pain (2%).

It is also important to note that the dose for Lenvima for patients with unresectable HCC is based on the patient’s weight (12 mg for patients weighing 60 kilograms or more, 8 mg for patients weighing less than 60 kilograms); the recommended dosage and dose adjustments are described in the full prescribing information.

“Eisai strives to be a leading global R&D-based pharmaceutical company, driven by our human health care (hhc) mission to improve the lives of patients and their loved ones,” said Shaji Procida, President and Chief Operating Officer, Eisai Inc., and Commercial Head of the Oncology Business Group, Americas at Eisai. “That purpose is what has propelled us toward this win for patients with unresectable hepatocellular carcinoma. Our goal is to bring monumental solutions to patients and health care providers, changing expectations for the oncology landscape, and we look forward to continuing this work in our ongoing collaboration with Merck.”

“We are pleased by the FDA approval of Lenvima as it marks an important advancement in the treatment of unresectable hepatocellular carcinoma,” said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. “With our shared mission to find solutions for difficult-to-treat cancers, we look forward to working with Eisai to help bring this needed option to patients and physicians.”

Lenvima, a kinase inhibitor, was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In May 2016, Lenvima was approved in the U.S. in combination with everolimus, for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Under the collaboration, Eisai and Merck initiated co-commercialization activities for Lenvima in the U.S. in June 2018. Since the initial launch, more than 10,000 patients were treated with Lenvima, which is approved in more than 50 countries worldwide.

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FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)