Cabozantinib and Lenvatinib for Kidney Cancer Get OK in EU

Patients with kidney cancer in Europe who are not responding to treatment will soon have two new options to try, as cabozantinib (Cabometyx, Ipsen Pharma) and lenvatinib (Kisplyx, Eisai Europe Ltd) have been recommended for approval by the European Medicines Agency (EMA).

Both of these drugs are tyrosine kinase inhibitors, and both are recommended for use in patients with kidney cancer who have been previously treated with a vascular endothelial growth factor (VEGF) inhibitor. Cabozantinib is to be used as monotherapy, whereas lenvatinib is to be used in combination with everolimus (Afinitor, Novartis).

The drugs are already approved for this indication in the United States.

In its announcement, the EMA notes that the most common form of kidney cancer in adults is renal cell carcinoma (RCC). Advanced RCC includes both metastatic disease and locally advanced disease that cannot be removed by surgery. Despite the recent approval of new therapies for advanced RCC, many patients who do not respond to the existing treatments have a poor prognosis. Therefore, new treatment options are needed, the agency comments.

The EMA considers the kidney cancer indications for cabozantinib and lenvatinib to be accelerated approvals because both drugs were felt to address an unmet medical need.

The EMA also notes that both of these drugs are also used in thyroid cancer but are marketed for that indication under different trade names. Cabozantinib (as Cometriq) was approved in the EU in December 2013 for adults with medullary thyroid cancer, while lenvatinib (as Lenvima) was recommended for approval for patients with thyroid carcinoma in March 2015.

Clinical Data to Support Approval

Cabozantinib was recommended for approval mainly on the basis of a phase 3 trial (known as METEOR) involving 658 patients with metastatic RCC that had progressed after prior VEGF receptor tyrosine kinase inhibitor therapy. As previously reported by Medscape Medical News, this study showed the longest progression-free survival (PFS) ever seen in this setting, with 7.4 months on cabozantinib compared with 3.8 months on everolimus, which is the usual standard second-line therapy. In addition, preliminary results show an improved overall survival, with a median of 21.4 months on cabozantinib vs 16.5 months on everolimus.
The EMA notes that the most frequent adverse reactions associated with cabozantinib include diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (hand and foot redness, swelling, and pain), hypertension, and vomiting.

Lenvatinib was recommended for approval mainly on the basis of a phase 1b/2 trial involving 153 patients with metastatic or unresectable RCC who received at least one prior VEGF targeted therapy and were treated with lenvatinib plus everolimus or with one of these agents used alone. In this study, progression-free survival was 12.8 months on average for patients receiving the combination of lenvatinib and everolimus, compared with 5.6 months for patients treated with everolimus alone, based on independent review of radiologic images. In addition, encouraging signs of prolonged overall survival were seen in patients given the combination therapy. The most frequent adverse reactions include diarrhea, fatigue, decreased appetite, vomiting, nausea, and hypertension. Severe diarrhea occurred at a higher frequency in the combination group than in the everolimus group.

When assessing these data, the EMA’s Committee for Medicinal Products for Human Use considered that the benefits of lenvatinib plus everolimus outweigh its risks but requested that postauthorization studies be conducted to collect further data to complement data from the phase 1b/2 trial.

Rare kidney tumor provides insights on role of metabolic changes in cancer

Researchers in The Cancer Genome Atlas (TCGA) Network have made a number of new findings about the biology and development of a rare form of kidney cancer. They found that the disease – chromophobe renal cell carcinoma (ChRCC) – stems in part from alterations in genes in the mitochondria, the cell’s energy supplier. They also discovered that the tumor is characterized by genetic rearrangements near a gene important in DNA repair and in maintaining telomerase, the enzyme which determines a cell’s lifespan. Finally, investigators also found that ChRCC is a distinct disease and shares few genomic characteristics with other kidney cancers.

In the study – the most extensive genomic view of ChRCC to date – investigators led by Chad Creighton, Ph.D., Baylor College of Medicine, Houston, and Kimryn Rathmell, M.D., Ph.D., University of North Carolina, Chapel Hill, performed a complex array of analyses, including examining the entire genomes of 50 of the 66 ChRCC tumors studied, a high number for a rare cancer. The study revealed increased numbers of mitochondria as well as mutations in mitochondrial DNA. This led researchers to discover that ChRCC tumors favor a different energy-generating process than that used by the more common clear cell kidney cancer. In addition, their findings are the first to show specific alterations affecting the TERT gene that could affect cancer development, and might help explain its increased expression – and deregulation – in cancer. Overall, the findings provide new insights into the development of more common forms of kidney cancer, and shed light on the role of mitochondria and metabolic pathways in cancer. The results also support the growing realization that both the cancer’s genomic characteristics and cell of origin matter, as many cancers consist of several individual diseases that require specific therapies. TCGA is a collaboration jointly supported and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.Cancer Cell.

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Reduced Kidney Function Linked With Higher Risk Of Kidney And Urothelial Cancers.

Individuals with poor kidney function may require more intensive screening for these cancer types

Reduced kidney function may increase the risk of developing kidney and urothelial cancers, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). The findings suggest that patients with kidney disease may benefit from more intensive screenings for these types of cancer.

Chronic kidney disease and cancer are both major and growing public health problems. “While multiple studies have observed higher risks of cancer in persons with end-stage renal disease, the association of less severe kidney disease with cancer remains poorly understood,” said Alan Go, MD (Kaiser Permanente Northern California).

To investigate, Dr. Go and his colleagues analyzed information from nearly 1.2 million adult members of Kaiser Permanente in Northern California who were at least 40 years of age and who had no history of cancer, dialysis, or kidney transplantation. Kidney function was measured by estimated glomerular filtration rate (eGFR), with normal kidney function being over 60 ml/min/1.73m2 and kidney failure being below 15 ml/min/1.73m2.

During more than 6 million person-years of follow-up, 72,875 individuals developed cancer. (A person-year is the number of years of follow-up multiplied by the number of people in the study.) Among the major findings during follow-up:

Individuals with an eGFR of 45 to 59 had a 39% increased risk of kidney cancer (or renal cell carcinoma).
Individuals with an eGFR of 30 to 44 had an 81% increased risk of kidney cancer.
Individuals with an eGFR below 30 had a 100% (or a 2-fold) increased risk of kidney cancer.
Individuals with an eGFR below 30 had a 48% increased risk of urothelial cancer, which includes tumors in the bladder and ureters.
There were no significant links between eGFR and other cancer types such as prostate, breast, lung, and colorectal cancers.

The researchers noted that various biologic mechanisms may help to explain the links observed in this study. For example, kidney dysfunction causes a state of chronic inflammation and oxidative stress. “These and other mechanisms deserve further study in order to better define the link between kidney function and site-specific cancer risk,” said lead author Will Lowrance, MD, MPH (University of Utah).

In an accompanying editorial, Jonathan Hofmann, PhD and Mark Purdue, PhD (National Cancer Institute) noted that the study is “an important step forward in characterizing the relationship between chronic kidney disease and risk of renal cell carcinoma and other malignancies. Studies such as this further support an etiologic role of impaired renal function in the development of renal cell carcinoma.”


Source: American Society of Nephrology


If You Are a Cancer Survivor, This Is a Must Read .

Getting through cancer treatment successfully is something to celebrate. To stay in good health, doctors say you need to watch for other symptoms, including vision changes, headaches and problems with balance.

What many cancer survivors don’t realize is that 25 percent of people who survive some common cancers go on to develop a brain tumor. These brain tumors don’t originate in the brain but are actually cancerous cells from the original tumor that travel to the brain through the bloodstream. When this happens, doctors call these tumors brain metastases.

“About one-third of patients with the most common cancers — lung, breast and kidney cancer and melanoma — are at risk of developing brain metastases,” says Cleveland Clinic neurosurgeon Gene Barnett, MD.

When this happens, the resulting growth needs early treatment. Dr. Barnett says early detection can help people get the right treatment at the right time to avoid serious complications. This is why you need to be vigilant and pay attention to your symptoms.

Watch for these 9 signs

If you’ve had cancer and experience these symptoms, be sure to tell your doctor:

  1. Vision changes (such as double vision or partial vision loss)
  2. Headaches (possibly with nausea)
  3. Numbness or tingling in part of the body
  4. Paralysis or difficulty moving any part of the body
  5. Inability to walk
  6. Difficulty with balance and an increased incidence of falls
  7. Difficulty speaking (including slurred words or incoherent speech)
  8. Problems with mental acuity (such as not being able to read or tell time)
  9. Seizure or convulsions

Metastatic brain tumors tend to develop gradually, although severe episodes can occur. No matter what, it’s important to tell your doctor immediately so he or she can evaluate you and treat you early as needed.

Treatable brain tumors

For years, doctors believed that brain metastases were uniformly fatal. Treatment could only to relieve symptoms. Today, they know that such tumors are treatable, thanks to technological and medical advances. The key is early detection.

To help in this fight, Cleveland Clinic teamed with the Northern Ohio American Cancer Society to establish the B-Aware Program. “Our goal is to educate at-risk cancer patients so that brain metastases are detected as early as possible, when they have the greatest number of treatment options,” says Dr. Barnett.

Many treatments available

We’ve come a long way from the days when the only treatment option available for brain metastases was whole brain radiation. This often failed to control the tumors. Today, aggressive and precisely delivered treatments produce better outcomes with fewer side effects.

Treatment options depend on the location, type and extent of the tumor, and include:

  • Radiosurgery. Radiosurgery directs highly focused beams of radiation at the tumor with extreme precision. This will not destroy the tumor, but may succeed in stopping tumor growth. Surgeons deliver this radiation so precisely that they can spare the surrounding brain tissue. Gamma Knife surgery is a common form of radiosurgery.
  • Minimal access surgery. This type of surgery allows doctors to remove the tumor in a faster, simpler way. Surgeons make a very small incision in the skull or hidden in a nearby structure. This reduces postoperative complications, minimizes pain and scarring, and shortens recovery time.
  • Localized radiotherapy, or radiation therapy. Radiotherapy exposes the cancerous cells to ionizing radiation that injures or destroys them. Doctors often use radiotherapy before or in addition to radiosurgery.
  • Medical therapies. Chemotherapy uses drugs to kill tumor cells that are dividing most rapidly. Many drugs used successfully for tumors in the body cannot penetrate into the brain. However, in certain cases, chemotherapy or other medical treatments may secure control of certain brain metastases.

“We want to help patients ‘be aware’ of all management options, so they don’t blindly agree to a proposed treatment which may not be in their best interest,” says Dr. Barnett. “They always have the right to seek a second opinion.”

Study Offers Insight into “Obesity Paradox” in Kidney Cancer.

Kidney cancer affects more than 55,000 people in the United States each year.
Kidney cancer affects more than 55,000 people in the United States each year.

For years, kidney cancer specialists have puzzled over two seemingly contradictory research findings: Obesity is associated with an increased risk of kidney cancer, yet obese and overweight people have better odds of surviving kidney cancer than normal-weight people.

A new study by a team from Memorial Sloan Kettering has uncovered a possible biological explanation for the phenomenon known as the “obesity paradox.”

A genetic analysis of tumor samples from patients with renal cell carcinoma, a common form of kidney cancer, found normal-weight patients had higher expression of a gene associated with faster-growing tumors than obese patients. Previous studies have shown that the gene, FASN, is overexpressed in aggressive tumors in several types of cancer.

The activity of FASN may help to explain why obese kidney cancer patients tend to fare better than normal-weight patients, says epidemiologist Helena Furberg, a coauthor of the study. With less activity in a cancer-promoting gene, tumors in obese people may grow more slowly than in normal-weight people.

By understanding what drives the progression of these tumors, the research, published online in December in the Journal of the National Cancer Institute, could ultimately lead to better therapeutic strategies.

Metastatic Disease More Likely in Slim Patients

The study included 2,119 kidney cancer patients who underwent surgery at Memorial Sloan Kettering between 1995 and 2012. As had been noted in previous research, this study found that normal-weight people are more likely to have their cancer discovered at advanced stages than obese people.

Obese patients also had a 25 percent lower risk of cancer-related death than normal-weight patients. (Obesity is defined as a body mass index, or BMI, of 30 or greater; normal weight is a BMI of under 25. BMI is an estimate of body fat based on a person’s height and weight.)

But the team’s analysis showed that obesity alone didn’t explain the difference in the risk of death, Dr. Furberg notes. Instead, the risk of death was associated with the stage at which the cancer was detected — and normal-weight people were more likely to have metastatic disease at the time of diagnosis.

These findings led researchers to wonder if there was something different about the tumors themselves in obese patients versus normal-weight patients influencing the cancer’s growth.

Honing In on the Tumor Genome

For answers, Dr. Furberg and her colleagues turned to The Cancer Genome Atlas (TCGA), a project funded by the National Institutes of Health to map the genetic mutations and alterations that occur in cancer cells.

The team’s analysis of genetic data available through TCGA revealed an overexpression of the FASN gene in the tumors of normal-weight patients. “FASN is an oncogene, which are genes that are the gas pedal driving cancer progression,” Dr. Furberg says.

In a normal cell, FASN is involved in the regulation of fatty acids, or fat production and breakdown, explains urologic oncology fellow Ari Hakimi, a coauthor of the study. “Cancer cells hijack that mechanism, and use it to fuel growth,” Dr. Hakimi says.

Their findings suggest that obesity interferes with cancer cells’ ability to hijack the mechanism, which may help prevent tumors from spreading quickly, Dr. Hakimi adds.

Yet researchers cautioned that their findings come with caveats. First, the team didn’t prove that obesity causes decreased expression of FASN. Second, the findings shouldn’t be interpreted as advice about weight management in kidney cancer patients, or how weight gain or loss might influence survival during the course of the disease.

Insights for Future Research

Instead, the findings will guide future research on the role of obesity and FASN in tumor growth. “Our study provides mechanistic insights into the obesity paradox,” Dr. Furberg says. “It gives researchers a different place to start in terms of understanding how body size influences patients’ survival.”

Finally, even though obesity is associated with a lower risk of death from kidney cancer, the statistics don’t speak to any individual’s odds of survival, which are impacted by many factors.

“What this study indicates is a new granularity, or knowledge of cancer, and how the genetics of tumors impact the way in which tumors behave,” says kidney surgeon Paul Russo, the senior author of the study. “We are on the precipice of a better understanding of the things that power tumors, which could eventually lead to tailored treatments and novel strategies to stop tumors from spreading.”