Recent findings based on the phase 1b COSMIC-021 trial in  Journal of Clinical Oncology demonstrated that treatment with the multikinase inhibitor cabozantinib (Cabometyx) plus the immune checkpoint inhibitor atezolizumab (Tecentriq) showed promising efficacy in patients with both clear cell (cc) and non–clear cell (ncc) renal cell carcinoma (RCC), according to findings from the phase 1b COSMIC-021 trial.¹ The combination reached an objective response rate (ORR) as high as 58% across two ccRCC cohorts and an ORR of 31% in patients with nccRCC.

“Cabozantinib plus atezolizumab demonstrated encouraging clinical activity in patients with advanced RCC regardless of histology. The safety profile with the combination was tolerable with dose modification and comparable to previous reports,” first author Sumanta K. Pal, clinical professor, Department of Medical Oncology & Therapeutics Research; co-director, Kidney Cancer Program, City of Hope, and coinvestigators wrote.

The multicenter, open-label phase 1b COSMIC-021 trial (NCT03170960) enrolled 102 patients with advanced RCC. Patients with ccRCC received atezolizumab plus either 40 mg (n = 34) or 60 mg (n = 36) of cabozantinib. Patients with nccRCC (n = 32) received atezolizumab plus 40 mg of cabozantinib.

In the 40-mg cabozantinib ccRCC group, the median age was 68 (range, 39-87), 79% of patients were male, and 71% were White. The ECOG performance status was 0 for 79% of patients and 1 for 21% of patients. Regarding IMDC risk, 21% were favorable, 76% were intermediate, and 3% were poor. Twenty-six percent of the cohort had a sarcomatoid component, which was significantly higher than the other 2 study arms. The PD-L1 status by CPS was ≥1 for 26% of patients, <1 for 44% of patients, and unknown for 29% of patients. Fifty-three percent of patients had ≥3 tumor sites. Metastatic sites included lung (79%), lymph node (47%), liver (15%), and bone (12%). One patient had received prior systemic anticancer therapy, 3 patients had prior radiotherapy, and 85% of patients had prior nephrectomy.

In the 60-mg cabozantinib ccRCC group, the median age was 60 (range, 42-82), 72% of patients were male, and 94% were White. The ECOG performance status was 0 for 69% of patients and 1 for 31% of patients. Regarding IMDC risk, 39% were favorable, 58% were intermediate, and 3% were poor. Six percent of the cohort had a sarcomatoid component. The PD-L1 status by CPS was ≥1 for 22% of patients, <1 for 50% of patients, and unknown for 28% of patients. Thirty-nine percent of patients had ≥3 tumor sites. Metastatic sites included lung (75%), lymph node (42%), liver (8%), and bone (11%). One patient had received prior systemic anticancer therapy, 4 patients had prior radiotherapy, and 89% of patients had prior nephrectomy.

In the nccRCC group, the median age was 62 (range, 37–78), 81% of patients were male, and 72% were White. The ECOG performance status was 0 for 75% of patients and 1 for 25% of patients. Regarding IMDC risk, 38% were favorable, 47% were intermediate, and 16% were poor. Thirteen percent of the cohort had a sarcomatoid component. Regarding histology subtype, 47% were papillary, 28% were chromophobe, and 22% were others. The PD-L1 status by CPS was ≥1 for 13% of patients, <1 for 56% of patients, and unknown for 31% of patients. Fifty-six percent of patients had ≥3 tumor sites. Metastatic sites included lung (50%), lymph node (59%), liver (16%), and bone (16%). Seven patients had received prior systemic anticancer therapy, 2 patients had prior radiotherapy, and 69% of patients had prior nephrectomy.

The median follow-up for the 40-mg ccRCC arm was 25.8 months and the ORR was 53%, including a complete response (CR) rate of 3%. The median progression-free survival (PFS) was 19.5 months. In the 60-mg ccRCC arm, the median follow-up was 15.3 months and the ORR was 58%, including an CR of 11%. The median PFS was 15.1 months. Among patients with nccRCC, the ORR was 31%, comprising all partial responses. The median PFS was 9.5 months.

Regarding safety, grade 3/4 treatment-related adverse events (TRAEs) occurred in 71% and 67% of patients in the 40-mg and 60-mg ccRCC groups, respectively. TRAE-related discontinuation of both drugs occurred in 15% and 6% of these 2 arms, respectively. In the nccRCC arm, 38% of patients had grade 3/4 TRAEs and TRAEs led to discontinuation of both drugs in 3% of patients. No treatment-related death occurred in the trial.

“These results support further evaluation of cabozantinib plus atezolizumab in patients with advanced RCC in the phase III trial setting, including those with non–clear cell histology. Patients with non–clear cell RCC have limited treatment options, and prospective data on tyrosine kinase inhibitor plus immune checkpoint inhibitor combinations are lacking for this population,” the authors wrote.

Reference

1. Pal SK, McGregor B, Suárez C, et al. Cabozantinib in combination with atezolizumab for advanced renal cell carcinoma: results from the COSMIC-021 study [published online ahead of print September 7, 2021]. J Clin Oncol. doi: 10.1200/JCO.21.00939

The post Combo of cabozantinib plus atezolizumab active across kidney cancer subtypes first appeared on GUcancers.

• Researchers found that clinical trials conducted largely outside the United States were much less likely to enroll Black participants.
• On average, non-U.S. trials enrolled less than half the proportion of Black patients.
• Experts say that study researchers can take several steps to boost black enrollment participation in clinical trials by building trust levels in that community.

The racial disparity in cancer drug trials are not uncommon. Low participation rates of Black participants in clinical trials has long been an issue for researchers. Over these years, there is widespread under-representation of African Americans and Native Americans in clinical trials for cancer drugs, even when the type of cancer disproportionately affects them. This is partly due to the fact that FDA, the agency responsible for new drug approvals, has been reluctant to force drugmakers to enroll more minority patients, and the failure of most manufacturers to do so voluntarily, Recent data by the FDA indicates that fewer than 5 percent of the patients were black in trials for 24 of the 31 cancer drugs approved since 2015 although African-Americans make up 13.4 percent of the U.S. population.

Source: U.S. Food and Drug Administration; National Cancer Institute 

Globalization impact on clinical trials

Pharmaceutical companies and research centers have been moving a significant number of drug clinical trials overseas in recent years to cut down the costs and speed up the drug approvals. Such globalization of cancer clinical trials is associated with a widening racial enrollment disparity gap in the United States. widening racial disparities in cancer clinical trials, according to a new study published online this month in Cancer, a peer-reviewed journal of the American Cancer Society. The study was led by a team of researchers at the Icahn School of Medicine at Mount Sinai in New York City, including Matthew Galsky, a professor of medicine specializing in oncology and hematology, and Serena Tharakan, a third-year medical student.

Similarly, other recent study published in the Annals of Internal Medicine, found that among 61,763 overall participants, African-American representation was only 7.44%. Samer Al Hadidi, MD, MS, of Baylor College of Medicine, a lead author of this study mentioned that factors impeding representational participation among Blacks in cancer clinical trials include distrust of the medical system and bias against African Americans by those running such trials, as well as socioeconomic factors.

Expansion of trials for new drug applications abroad “broadens the already existing gap in racial disparities in patient enrollment in cancer clinical trials,” said Gail Trauco, a registered nurse and clinical research consultant based in the Atlanta area. The popular destinations for conducting such drug trials are Canada, Australia, Spain, the United Kingdom, and Israel — nations where the population is overwhelmingly white. “The goal of a trial should be to inform about the efficacy of a drug,” said Tharakan, noting that generalization is important when doing trials or it might be difficult to speak to potential side effects for a subset of the population. “It might be applicable for a certain population but not the whole population.”

“Diversity within clinical trials is important for a number or reasons,” said Sanjeev Luther, president and CEO of Rafael Pharmaceuticals, an East Windsor, New Jersey-based company specializing in cancer therapies. “The findings can be skewed or non-encompassing of an entire population as a result of the lack of diversity, resulting in an incomplete understanding of drug safety and efficacy.” He continued, “Diversity is important in studying cancer, orphan, and rare diseases because they are difficult to treat, but all conditions require the lens of inclusivity because they can affect all parts of our communities.”

What it means for the efficacy of drug in people of color

Recent study raises concerns about the generalization of the efficacy of the drugs developed during these trials. Without more Black participants the authors question whether or not the findings about the efficacy and safety of cancer drugs will hold for people of color.

What can be done

Dr. Rajbir Singh, an internal medicine specialist and director of clinical and translational research at Meharry College of Medicine, a historically black medical school in Nashville, called the study groundbreaking. “This is a good study. It hasn’t been done before,” he said, adding that more studies of this nature are needed and that future studies should consider looking at data from 2018 to 2020 as well. Singh said researchers could take several steps to boost Black enrollment participation in clinical trials by building trust levels in that community. This could involve doing more to educate the community about ethical practices and safeguards in clinical trials, and advertising on social media platforms and television.

He said the healthcare industry should work at developing more Black physicians and researchers to help raise trust levels in that community. He said researchers should consider taking the trials to the community as part of the education process. “There should be community advisory boards looking at how trials are presented to the community,” he said. “There should be patient stakeholder meetings talking how about how trials can help them and how they work.” In addition, researchers should consider assisting black participants with transportation to trial sites as well as compensating them when they miss work.

Diversity in clinical trials is important to ensure that drugs meet patients’ needs. The issue “is not elevated high enough in the discussion on clinical studies,” said John Maraganore, chair of the industry group Biotechnology Innovation Organization. But he added that enrolling minorities is challenging, often for reasons beyond the manufacturer’s control, and that it would require a “public-private partnership, working with the FDA and NIH [National Institutes of Health].”

Not enrolling in clinical trials is just one of many ways that African Americans trail white Americans in the quality of their health care. From diagnosis to death, they often experience inferior care and worse outcomes. Because some black Americans can’t afford the health insurance mandated under the Affordable Care Act, they remain less likely to have coverage than non-Hispanic white Americans.

There appear to be gaps in participation of other minority groups as well. Asians were well represented in trials held in some foreign countries, but they made up only 1.7 percent of patients for drugs for which at least 70 percent of trials were conducted within the U.S. By comparison, about 6 percent of the U.S. population identifies as Asian. Almost two-thirds of the trials didn’t report any Native Americans or Alaska Natives, who together make up about 2 percent of the U.S. population. ProPublica’s analysis excluded Hispanics, because the FDA reports did not have a separate category for them until 2017 and do not distinguish between white and non-white Hispanics.

The very relationship of race to drug development is fraught with controversy. Race is primarily seen as a social concept, rather than as a product of measurable biological traits. Yet there’s growing evidence that, whether for environmental or genetic reasons, drugs may have different effects on different populations.

Inadequate minority representation in drug trials means that “we aren’t doing good science,” said Dr. Jonathan Jackson, founding director of the Community Access, Recruitment and Engagement Research Center at Massachusetts General Hospital in Boston. “If we aren’t doing good science and releasing these drugs out into the public, then we are at best being inefficient, at worst being irresponsible.

Diversity Trade-offs

Well, Diversity has its trade-offs too. Clinical trials already cost hundreds of millions of dollars, and drugmakers say that requiring participants to be racially representative would likely add more time and expense. “If you have a significant delay in enrollment, that would delay the medication advancing to the whole patient population, hurting everybody including the black population,” said Maraganore, who is also CEO of drugmaker Alnylam Pharmaceuticals Inc.

To offset costs caused by these delays, manufacturers might reduce the number of drugs in development, depriving some patients of experimental treatments, or raise prices, which would translate into higher insurance premiums and make new drugs even less affordable for the uninsured. Maraganore favors improving diversity through patient education — “a carrot-based approach” — rather than government regulation.

Dr. Rachel Sherman, the FDA’s principal deputy commissioner, said that she’s “not entirely satisfied” with minority enrollment but that clinical trials have become more diverse in other ways. Two decades ago, women and children were rarely included in drug studies. Now those groups are better represented and the FDA is working on including more minorities, she said.

The globalization of cancer clinical trials may have the unintended consequence of further exacerbating existing racial disparities in cancer clinical trial representation and ultimately the generalizability of trial results. The impact of global trials on domestic clinical trial generalizability warrants further consideration from a regulatory and policy standpoint.

The post Black people and Native Americans are under-represented in Cancer Drug trials of new drugs first appeared on GUcancers.

By Christopher Brown

Substances linked to bladder cancer found in the urine of e-cigarette users

Recently published scientific studies found six substances that have a strong link to bladder cancer in the urine of people who had used electronic cigarettes and sometimes other tobacco products. Researchers from the University of North Carolina Lineberger Comprehensive Cancer Center and NYU Langone Health reported in the journal European Urology Oncology.

In this recent study, researchers compiled the results of 22 different studies that analyzed the urine of people who used e-cigarettes or other tobacco products, including cigarettes, to check for evidence of cancer-linked compounds or biomarkers of those compounds. They found six biomarkers or compounds with a strong link to bladder cancer.

Smoking is the No.1 modifiable behavioral risk factor for bladder cancer. There is now evolving literature showing that people who vape may have similar carcinogens in their urine as combustible cigarette users.”

Marc Bjurlin, DO, MSc, associate professor of urology in the UNC School of Medicine

While public health agencies including the U.S. Food and Drug Administration and the Centers for Disease Control and Prevention have warned that there are health risks of vaping, including for e-cigarette-associated lung injury, their safety profile has not been “definitively characterized,” according to Bjurlin and his colleagues.

“The first and foremost side effects that we’re seeing from electronic cigarette use are lung and pulmonary related,” Bjurlin said. “We won’t see the side effects for these other kinds of carcinogenic pathways until much later down the exposure pipeline.”

To develop a better understanding of the long-term risks of vaping, including cancer, researchers investigated possible exposure to substances that can cause bladder cancer in particular since carcinogens could be processed in the body and then passed in urine.

In their review, Bjurlin and his colleagues found 40 different parent compounds that can be processed in the body to produce 63 different toxic chemicals or carcinogenic metabolites, which are substances that remain after in the body after processing.

Six of those chemicals have a strong link to bladder cancer, according to researchers’ analysis of carcinogens databases of the International Agency for Research on Cancer and the Collaborative on Health and the Environment Toxicant and Disease Database.

They found evidence in some studies that e-cigarette users had “significantly” higher levels of several carcinogens that can be metabolized into substances linked to bladder cancer in their urine compared to people who had never used them.

“This finding shows us that people who vape will be exposed to a variety of different carcinogens,” Bjurlin said. “People who have decades of exposure to these carcinogens from vaping may be at risk for developing malignancies, especially bladder cancer.”

There were several limitations to the study, including that researchers did not know the levels of all of the cancer-causing substances in the urine of users from the studies.

In addition, some studies included people who were “dual users,” or people who both smoked and vaped e-cigarettes. There were also cases when users smoked cigarettes and switched to e-cigarettes.

“The study population was quite heterogeneous, meaning that often studies looked at dual users, meaning those who used e-cigarettes and combustible cigarettes,” Bjurlin said. “That made it difficult to assess whether the carcinogen found in the urine was actually from the e-cigarette use or from the cigarette use.”

Further research is needed, said Bjurlin, who wants to determine the threshold of exposure to carcinogens that would lead to development of bladder cancer or other cancer types. He plans to lead a study that will evaluate carcinogens in the urine of e-cigarette users, smokers and non-users.

“Although there is no definitive case yet linking bladder cancer to vaping, it may be reasonable to suspect that decades down the road after exposure to these byproducts, people who vape may be at risk of developing bladder cancer,” he said.

Source: UNC Lineberger Comprehensive Cancer Center

Journal reference:

Bjurlin, M.A., et al. (2020) Carcinogen Biomarkers in the Urine of Electronic Cigarette Users and Implications for the Development of Bladder Cancer: A Systematic Review. European Urology Oncology. doi.org/10.1016/j.euo.2020.02.004.

The post Study Discovers Link Between Electronic Cigarette Use and Bladder Cancer first appeared on GUcancers.

• Christoph Baker

Mar 29 | 2021

National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines to include FOTIVDA^® (tivozanib) as a recommended regimen for third- or fourth- line therapy in patients with clear cell renal cell carcinoma.

National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines to include FOTIVDA^® (tivozanib) as a recommended regimen for third- or fourth- line therapy. The subsequent therapy category follows the first-line treatment regimen recommendations for patients with clear cell histology renal cell carcinoma (ccRCC)), according to AVEO Oncology, the developer of the oral, next-generation VEGF tyrosine kinase inhibitor – FOTIVDA.¹

US FDA approval of tivozanib on March 10, 2021² in the relapsed/ refractory RCC setting based on data from phase 3 TIVO-3 trial, the FDA approved tivozanib for the treatment of adult patients with relapsed or refractory advanced RCC who have received 2 or more prior systemic therapies, based on data from the phase 3 TIVO-3 trial.

On the heels of the recent TIVO-3 results presented during the 2020 ASCO Virtual Scientific Program³ which demonstrated treatment with tivozanib led to a significant improvement in progression-free survival (PFS) compared with sorafenib (Nexavar), US FDA approval of tivozanib on March 10, 2021² in the relapsed/ refractory RCC setting

The findings showed that the final hazard ratio (HR) for OS was 0.97 (P = .78). Moreover, an updated analysis of the data found that, with a median follow-up of 38 months for tivozanib and 40 months for sorafenib, the median OS was 16.4 months for tivozanib and 19.2 months for sorafenib. A subset analysis showed the greatest benefit was derived by the cohort of patients who previously received a checkpoint inhibitor and VEGF inhibitor, with an HR of 0.55, or 2 VEGF TKIs, with an HR of 0.57.

Prior findings showed an increased median PFS for tivozanib when compared with sorafenib at 5.6 months versus 3.9 months, respectively (HR, 0.73; P = .016).

“Fotivda’s addition to the NCCN Guidelines provides further validation for its potential to serve as an important evidence-based, well tolerated treatment option for patients with relapsed or refractory advanced RCC. As previously announced, launch efforts are now underway, and we are committed to bringing this promising therapy to as many appropriate patients as possible.” Michael Bailey, president and chief executive officer of AVEO, stated in a press release.

In the multicenter, open-label, randomized TIVO-3 trial, 350 patients were split evenly between the 2 drugs and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy.³ These patients had to progress on 2 or 3 prior systemic regimens, at least 1 of which had to be a VEGFR tyrosine kinase inhibitor other than sorafenib or tivozanib.

Patients either received 1.5 mg of tivozanib mg orally once a day on 4-week cycles or sorafenib at 400 mg orally twice a day continuously. The primary end point was PFS by independent review in the intention-to-treat population.

The most common grade 3/4 treatment-related adverse events (TRAEs) in the originally published data were hypertension in 20% of patients receiving tivozanib and 14% of patients receiving sorafenib. Serious TRAEs were observed in 11% versus 10% of patients respectively, but no treatment-related deaths were reported.

Tivozanib is now being investigated in combination with the PD-1 inhibitor nivolumab (Opdivo) in the phase 3 TiNivo-2 trial in patients with relapsed/refractory RCC .⁴

BACKGROUND INFORMATION:

The NCCN Clinical Practice Guidelines are the recognized standard for clinical policy in cancer care and are developed through review of evidence and recommendations from physicians and oncology researchers. The current NCCN RCC guidelines categorically make treatment recommendations for first-line or subsequent therapy options for RCC patients. FOTIVDA is now recommended by the NCCN Guidelines as a subsequent therapy for patients with ccRCC who have received two or more prior systemic therapies (Category 2a). FOTIVDA’s addition to the NCCN Guidelines follows its recent U.S. FDA approval, which was based on AVEO’s pivotal Phase 3 study, TIVO-3, comparing FOTIVDA to sorafenib in relapsed or refractory advanced RCC following two or more prior systemic therapies. The approval was also supported by three additional trials in RCC and included safety data from over 1,000 clinical trial subjects.

About FOTIVDA^® (tivozanib)

FOTIVDA^® (tivozanib) is an oral, next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). It is a potent, selective inhibitor of VEGFRs 1, 2, and 3 with a long half-life designed to improve efficacy and tolerability. AVEO received U.S. Food and Drug Administration (FDA) approval for FOTIVDA on March 10, 2021 for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. FOTIVDA was approved in August 2017 in the European Union and other countries in the territory of its partner EUSA Pharma (UK) Limited for the treatment of adult patients with advanced RCC. FOTIVDA was discovered by Kyowa Kirin.

INDICATIONS

FOTIVDA is indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies.

References

1. AVEO Oncology Announces Addition of FOTIVDA® (tivozanib) into National Comprehensive Cancer Network Clinical Practice Guidelines. Published online March 29, 2021. Accessed March 29, 2021. https://bwnews.pr/3w9zecY.

2. AVEO Oncology Announces U.S. FDA Approval of FOTIVDA® (tivozanib) for the Treatment of Adult Patients with Relapsed or Refractory Advanced Renal Cell Carcinoma. Published online March 10, 2021. Accessed March 10, 2021. https://bwnews.pr/3vbdRY4.

3. Pal SK, Escudier B, Atkins MB, et al. TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). Presented at: 2020 ASCO Virtual Program; May 27, 2020. Abstract 5062.

4. AVEO Oncology Announces Collaboration with Bristol Myers Squibb to Evaluate FOTIVDA® (tivozanib) in Combination with OPDIVO® (nivolumab) in Pivotal Phase 3 TiNivo-2 Trial in IO Relapsed Renal Cell Carcinoma. Posted online March 12, 2021. Accessed March 12, 2021. https://bit.ly/3ldIasp

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A list of global guidelines for kidney cancer are provided in this section. These guidelines provide evidence-based recommendations to serve as a guide and support best quality standards of care.

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Background Information

CenterWatch, an online resource that lists more than 80,000 active clinical trials, allows you read an overview of clinical trials online, while also providing information on volunteering for a clinical trial and understanding informed consent. 

Search for Clinical Trials

Studies at the National Institutes of Health: This page allows you to search for government-funded clinical research studies being conducted by the various National Institutes of Health. More information about clinical trials from the National Institutes of Health can be found online.

National Cancer Institute (NCI) Clinical Trials: This page provides a searchable database of government-funded clinical research studies being conducted by the National Cancer Institute. More information about clinical trials from the National Cancer Institute can be found online.

ClinicalTrials.gov: This page provides a searchable database of federally and privately supported clinical research trials conducted in the United States and around the world. This page provides information about a trial’s purpose, who may participate, and locations and contact phone numbers for further details.

CenterWatch.com Clinical Trials Listing: This page allows you to search for thousands of privately supported clinical trials. Users may narrow their search by medical condition, therapeutic area (such as urology) or location. CenterWatch also provides an email notification service, which will send you an alert when a clinical trial is happening in your interest area or geographic location.

Clinical Trial Results

Listing of FDA-Approved Drugs, Urology: This page, provided by CenterWatch, lists drugs that have been approved by the FDA since 2005 to treat urologic conditions.

Research Center Information:
Research Center Profiles, Urology: This page, provided by CenterWatch, lists institutions conducting research in urology, with a profile of their services, including a description of their facilities and information on the experience of their clinical investigators and research staff.

For Researchers

Mentored research training awards for young investigators.

Why a Clinical Trial Might Be Right for You

Learn how a clinical trial may be a good option for you with this informative video.

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