UCLA Jonsson Comprehensive Cancer Center

Researchers at the UCLA Jonsson Comprehensive Cancer Center analyzed gene-expression patterns in the most aggressive prostate cancer grade group — known as Gleason grade group 5 &mdash; and found that this grade of cancer can actually be subdivided into four subtypes with distinct differences. The findings may affect how people are treated for the disease.

One subtype, which accounts for about 15% of the grade group 5 cancers, has highly aggressive features and is associated with much worse outcomes than the other subtypes. Another, which makes up about 20% of the tumors, appears to be much less aggressive and may not require intensified and aggressive treatments. Traditionally, all tumors in Gleason grade group 5 have been treated in the same way.

Prostate cancer is the leading solid-tumor cancer among men in the United States and a major cause of morbidity globally. While early-stage, localized prostate cancer is curable, current treatments don't always work for everyone. To find out why standard treatment may work for some and not others, the UCLA researchers looked at tumors in the Gleason grade group 5 subset of prostate cancer. These tumors are at the highest risk to fail standard treatment, leading to metastasis and death. The researchers thought that studying the gene expression — the unique "signature" &mdash; of each cancer cell in these tumors might provide insight into how to make treatments more personalized for each patient.

The researchers first analyzed data from more than 2,100 Gleason grade group 5 tumors, looking at how the genetic blueprints differed among the tumors. They identified distinct clusters of subgroups and validated their findings by analyzing an additional cohort of more than 1,900 Gleason grade group 5 prostate cancers.

By using the genetic information from tumors in men with prostate cancer, physicians hope to one day create more personalized treatments based on the actual characteristics of the cancer. This information will help optimize quality of life and avoid overtreating subgroups of men who may not need aggressive treatments.

Articles

Researchers at the UCLA Jonsson Comprehensive Cancer Center analyze gene-expression patterns in the most aggressive prostate cancer grade group&mdash;known as Gleason grade group 5&mdash;and found that this grade of cancer can actually be subdivided into four subtypes with distinct differences.

Some Types of Prostate Cancer May Not be as Aggressive as Originally Thought

 On Air! I’m your host today, Gina Columbus.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

But today, we had the pleasure of sitting down with Beth Y. Karlan, MD, vice chair of Women’s Health Research and director of Cancer Population Genetics at University of California, Los Angeles’ David Geffen School of Medicine.

Dr. Karlan has dedicated her career to improving care for women with cancer by fast-tracking translation scientific discoveries to the bedside, shaping current standards of care, and training the next generation of physicians and scientists.

With an interest in robust tumor biorepositories for translational studies and early detection, her efforts led to the discovery of HE4. HE4 testing is now an FDA approved method to help assess women with a pelvic mass and to help monitor for recurrence in those with ovarian cancer.

Additional achievements by Dr. Karlan include serving as the co-principal investigator for the 

 Founder Outreach Study (BFOR), which is conducting population-based 

 genetic testing on 4000 eligible adults of Ashkenazi Jewish ancestry.

Moreover, in 2012, President Barack Obama appointed Dr. Karlan to the National Cancer Advisory Board. She has also served as past president of the Society of Gynecologic Oncology and currently serves as editor-in-chief for Gynecologic Oncology and Gynecologic Oncology Reports.

From hearing these accolades, it is no surprise that Dr. Karlan was recognized as the 2019 

 Giant of Cancer Care in Gynecologic Cancers.

In our exclusive interview, Dr. Karlan shared the rewarding moments and challenges she has encountered in the cancer space as a female oncologist, pivotal research she has been spearheaded that has lasting impacts on the field, and other developments in gynecologic cancers that are poised to change the landscape forever.

Podcasts

In our exclusive interview, Dr. Karlan shares the rewarding moments and challenges she has encountered in the cancer space as a female oncologist, pivotal research she has been spearheaded that has lasting impacts on the field, and other developments in gynecologic cancers that are poised to change the landscape forever.

Marvels in Medicine: Dr. Karlan on Breaking Down Gender Barriers in Gynecologic Oncology

Investigators are changing the standard randomized controlled trial (RCT) design to more expeditiously identify experimental therapies for patients with glioblastoma (GBM), the deadliest form of brain cancer.

GBM kills 95% of patients within 5 years of diagnosis, with more than half of patients dying in the first 15 months; that prognosis makes a customary RCT structure that could span 1 to 4 years in length impractical. Investigators of the first global adaptive phase 2/3 GBM Adaptive Global Innovative Learning Environment (AGILE) platform trial (NCT03970447) are implementing a multiarm, 2-stage approach to concurrently evaluate single-agent and combination regimens.

“We felt that there needed to be a way to test multiple therapies in a randomized study, determine whether or not there are signals, confirm those signals, and move forward with new drug applications,” said Timothy F. Cloughesy, MD, global principal investigator of the GBM AGILE trial and director of the Neuro-Oncology Program of the Brain Research Institute at the University of California, Los Angeles.

GBM AGILE is recruiting 550 patients with 

 R132H wild-type newly diagnosed (ND) grade IV GBM or recurrent GBM (

). Investigators will stratify patients by 3 subtypes of GBM: ND methylated GBM, ND unmethylated GBM, or recurrent disease, and randomize them to a treatment arm in the trial’s first stage.

At present, GBM AGILE investigators are evaluating treatment interventions in patients either with ND unmethylated GBM or recurrent disease.

Figure. Multiple Regimens in Newly Diagnosed and Recurrent GBM Study (Click to Enlarge)

For those with recurrent disease, participants in the control arm will be treated with lomustine (Gleostine) started at 110 mg/m

 per day on day 1 of a 42-day cycle for a maximum of 6 cycles; in the experimental arm, patients with recurrent disease type will receive an investigtional therapy.

The first experimental agent to be tested is regorafenib (Stivarga), a multikinase inhibitor that the FDA has approved for metastatic colorectal cancer, metastatic gastrointestinal stromal tumor, and hepatocellular carcinoma. In the GBM AGILE trial, regorafenib will be administered at 160 mg daily for 3 weeks of every 4-week cycle.

As the study progresses, investigators will open additional treatment arms to explore other regimens. They also will assess patients for potential biomarkers that could be used to direct therapy. Across stages 1 and 2 of GBM AGILE, the primary end point of the study is overall survival (OS). Secondary end points include progression-free survival, tumor response, and duration of response.

GBM AGILE investigators will closely assess the anticancer activity of the control and experimental interventions in the ND and recurrent disease populations. In stage 1 of the study, investigators will stop enrolling patients in a treatment arm if the arm completes accrual (n ≤150) or if the arm’s therapy demonstrates futility or unacceptable toxicity.

In stage 1 of the GBM AGILE study, investigators will use a dynamic assignment strategy known as adaptive randomization to direct a higher proportion of new participants to the superior treatment arm.

“Adaptive randomization allows us to identify the therapies that are working best for patients. The randomization probabilities would adjust based on current data from the ongoing trial,” Cloughesy said.

This predefined algorithm will identify the treatments with the greatest efficacy based on the survival benefit that these therapies confer when compared with a common control. It will also select the GBM population for which these interventions are most promising. Those therapies deemed promising will “graduate” to stage 2.

For this stage, investigators will use fixed randomization to evaluate the efficacy of these therapies in the algorithm-defined population to confirm findings from the first stage of the trial. Each stage 2 cohort will enroll 50 patients.

The design of the 2-stage study supports swifter patient registration, as well as a more rapid regulatory review process and subsequent clinical adoption of the treatments that display signals in the second stage of the GBM AGILE study.

Equally important, GBM AGILE’s unique model means that investigators can more rapidly identify and expel the treatments that do not show signals indicative of therapeutic benefit than they would in traditional RCTs. “[Recognizing] early futility has huge value because if you find early futility and stop enrollment, you have determined that the therapy is not going to confer benefit, and you didn’t have to run a large, costly phase 3 study to get that answer,” Cloughesy said.

Of note, data from the treatments that do not demonstrate a sufficient survival advantage in the first stage to justify further study in stage 2, but nevertheless suggest a potential benefit, will become available to GBM specialists and can be used to support the development of biomarker hypotheses as well as further therapeutic investigations in the field.

“Our goal is to identify the effective drugs, get rid of the ineffective drugs, and also identify the drugs that have a signal, [but one] that isn’t quite as strong [as others],” Cloughesy said, adding that drug developers can draw upon data from the GBM AGILE study to determine whether they would like to appropriately power and pursue a trial of an agent that was found to have a more minimal signal in the phase 2/3 study.

The GBM AGILE study is a clinical endeavor that has been years in the making and owes its dynamic design to the collaborative interplay of more than 130 oncologists, pathologists, statisticians, imagers, neurosurgeons and academic, industry, and government researchers, who have worked collectively to cultivate this investigative model since 2015.

GBM AGILE is a “group effort” that was initiated in response to a series of unsuccessful clinical trials in GBM, according to Cloughesy. “The rationale for GBM AGILE comes from the setting of GBM, where in the [past] few years, there have been several negative phase 3 studies. They were expensive, costing several hundred million dollars, and it seemed that we weren’t [facilitating investigations] very well,” Cloughesy said. “Then, the disease gets the reputation that drugs can’t be developed in glioblastoma— that they’re just bound to fail.”

In ND GBM, the standard of care is temozolomide, which was approved for use in combination with RT and as a maintenance therapy in 2005.

 Existing data show that the median OS with temozolomide and concurrent RT is 14.6 months versus 12.1 months with RT alone, supporting the doublet regimen’s application in this setting.

Patients with ND GBM receive temozolomide with RT after maximal surgical resection, which rarely eradicates GBM tumor cells in their totality due to the invasive nature of the disease. Although adjuvant temozolomide and RT are administered to reduce the risk of disease recurrence, nearly all cases of GBM that initially respond to frontline treatment eventually recur.

In contrast to ND GBM, there is no established standard of care for recurrent disease. Interventions for recurrent GBM can include surgical resection, reirradiation, nitrosoureas, temozolomide rechallenge, or treatment with tyrosine kinase inhibitors or bevacizumab (Avastin).

Bevacizumab was indicated for use in patients with GBM in 2017, after findings from the phase 3 EORTC 26101 study (NCT01290939) showed that adding the VEGF inhibitor to lomustine reduced the risk of disease progression or death by 48%.8 Administering bevacizumab with lomustine extended the median progression- free survival versus single-agent lomustine (4.2 vs 1.5 months; HR, 0.52; 95% CI, 0.41-0.64) but notably did not result in a significant improvement in OS (HR, 0.91; 

The modest survival benefits that existing therapies afford patients with GBM, coupled with the lack of curative options, translate to a need for more efficacious treatment options for a disease that accounts for 45% of all malignant brain tumors and more than 12,000 cases annually in the United States.

GBM AGILE investigators and the trial’s broad network of clinical collaborators believe that the platform format of the study has the potential to not only identify better therapies for this deadly disease but also reduce the time and costs associated with their development around the world.

“We wanted to facilitate this evaluation in 1 environment to boost development in glioblastoma, and we also wanted to do this in multiple jurisdictions beyond the United States,” Cloughesy said. GBM AGILE is actively enrolling patients in the United States, and international locations in Canada, China, and Europe are also expected to open at a later date, according to Cloughesy.

Whereas the coronavirus disease 2019 (COVID-19) pandemic has prompted the suspension of many clinical trials across the nation, GBM AGILE has continued to accrue patients. “We have continued to add sites during this time and enrollment has remained steady, so we’ve been happy to see that,” Cloughesy said. “At their institutions, people [ask], what’s a necessary study going forward? Glioblastoma is almost 100% fatal. COVID-19 is incredibly serious, but glioblastoma will continue to be serious even after we’ve learned how to deal with COVID-19. We still need to learn how to deal with glioblastoma.”

Global Coalition For Adaptive Research. GBM AGILE website. Accessed April 13, 2020. bit.ly/2RU55M2         

Step 3: clinical research. US FDA website. Updated January 4, 2018. Accessed April 14, 2020. bit.ly/2KrezKs

A trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma (GBM AGILE). ClinicalTrials.gov identifier: NCT03970447. Updated April 14, 2020. Accessed April 15, 2020. http://www.clinicaltrials.gov/ct2/show/NCT03970447 Alexander BM, Ba Sujuan, Berger MS, et al. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. Clin Cancer Res. 2018;24(4):737-743. doi:10.1158/1078-0432.CCR-17-0764

Alexander BM, Ba Sujuan, Berger MS, et al. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. 

. 2018;24(4):737-743. doi:10.1158/1078-0432.CCR-17-0764

Temodar. Package insert. Merck; 2019. Accessed April 15, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021029s033lbl.pdf

Stupp R, Mason WP, van dan Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 

 2005;352:987-996. doi:10.1056/NEJMoa043330

Shergalis A, Bankhead A, Luesakul U, Muangsin N, Neamati N. Current challenges and opportunities in treating glioblastoma. 

. 2018;70(3):412-445. doi:10.1124/pr.117.014944

Avastin. Package insert. Genentech Inc; 2019. Accessed April 15, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125085s331lbl.pdf

Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. 

. 2017;377(20):1954-1963. doi:10.1056/NEJMoa1707358

Patients with ND GBM who are randomized to the control arm will receive radiation therapy (RT) at 60 Gy in combination with temozolomide (Temodar) at 75 mg/m

 for 6 weeks, followed by maintenance temozolomide. The maintenance phase would begin 2 to 6 weeks after RT, starting with 150 mg/m

 on days 1 to 5 of a 28-day cycle, followed by 200 mg/m

 on days 1 to 5 of the second and subsequent cycles. In the experimental arm, patients with ND GBM will also be treated with RT and temozolomide but will receive the experimental regimen instead of maintenance temozolomide.

Investigators of the first global adaptive phase 2/3 GBM Adaptive Global Innovative Learning Environment platform trial are implementing a multiarm, 2-stage approach to concurrently evaluate single-agent and combination regimens in glioblastoma.

Chasing a Cure for GBM: Investigators Test Multiple Regimens in Novel Trial



GBM kills 95% of patients within 5 years of diagnosis, with more than half of patients dying in the first 15 months; that prognosis makes a customary RCT structure that could span 1 to 4 years in length impractical. Investigators of the first global adaptive phase 2/3 GBM Adaptive Global Innovative Learning Environment (AGILE) platform trial (NCT03970447) are implementing a multiarm, 2-stage approach to concurrently evaluate single-agent and combination regimens.



“We felt that there needed to be a way to test multiple therapies in a randomized study, determine whether or not there are signals, confirm those signals, and move forward with new drug applications,” said Timothy F. Cloughesy, MD, global principal investigator of the GBM AGILE trial and director of the Neuro-Oncology Program of the Brain Research Institute at the University of California, Los Angeles.

GBM AGILE is recruiting 550 patients with 

). Investigators will stratify patients by 3 subtypes of GBM: ND methylated GBM, ND unmethylated GBM, or recurrent disease, and randomize them to a treatment arm in the trial’s first stage.

At present, GBM AGILE investigators are evaluating treatment interventions in patients either with ND unmethylated GBM or recurrent disease.

Patients with ND GBM who are randomized to the control arm will receive radiation therapy (RT) at 60 Gy in combination with temozolomide (Temodar) at 75 mg/m

Figure. Multiple Regimens in Newly Diagnosed and Recurrent GBM Study

 per day on day 1 of a 42-day cycle for a maximum of 6 cycles; in the experimental arm, patients with recurrent disease type will receive an investigtional therapy.

The first experimental agent to be tested is regorafenib (Stivarga), a multikinase inhibitor that the FDA has approved for metastatic colorectal cancer, metastatic gastrointestinal stromal tumor, and hepatocellular carcinoma. In the GBM AGILE trial, regorafenib will be administered at 160 mg daily for 3 weeks of every 4-week cycle.

As the study progresses, investigators will open additional treatment arms to explore other regimens. They also will assess patients for potential biomarkers that could be used to direct therapy. Across stages 1 and 2 of GBM AGILE, the primary end point of the study is overall survival (OS). Secondary end points include progression-free survival, tumor response, and duration of response.





GBM AGILE investigators will closely assess the anticancer activity of the control and experimental interventions in the ND and recurrent disease populations. In stage 1 of the study, investigators will stop enrolling patients in a treatment arm if the arm completes accrual (n ≤150) or if the arm’s therapy demonstrates futility or unacceptable toxicity.



In stage 1 of the GBM AGILE study, investigators will use a dynamic assignment strategy known as adaptive randomization to direct a higher proportion of new participants to the superior treatment arm.



“Adaptive randomization allows us to identify the therapies that are working best for patients. The randomization probabilities would adjust based on current data from the ongoing trial,” Cloughesy said.

This predefined algorithm will identify the treatments with the greatest efficacy based on the survival benefit that these therapies confer when compared with a common control. It will also select the GBM population for which these interventions are most promising. Those therapies deemed promising will “graduate” to stage 2.



For this stage, investigators will use fixed randomization to evaluate the efficacy of these therapies in the algorithm-defined population to confirm findings from the first stage of the trial. Each stage 2 cohort will enroll 50 patients.



The design of the 2-stage study supports swifter patient registration, as well as a more rapid regulatory review process and subsequent clinical adoption of the treatments that display signals in the second stage of the GBM AGILE study.



Equally important, GBM AGILE’s unique model means that investigators can more rapidly identify and expel the treatments that do not show signals indicative of therapeutic benefit than they would in traditional RCTs. “[Recognizing] early futility has huge value because if you find early futility and stop enrollment, you have determined that the therapy is not going to confer benefit, and you didn’t have to run a large, costly phase 3 study to get that answer,” Cloughesy said.

Of note, data from the treatments that do not demonstrate a sufficient survival advantage in the first stage to justify further study in stage 2, but nevertheless suggest a potential benefit, will become available to GBM specialists and can be used to support the development of biomarker hypotheses as well as further therapeutic investigations in the field.



“Our goal is to identify the effective drugs, get rid of the ineffective drugs, and also identify the drugs that have a signal, [but one] that isn’t quite as strong [as others],” Cloughesy said, adding that drug developers can draw upon data from the GBM AGILE study to determine whether they would like to appropriately power and pursue a trial of an agent that was found to have a more minimal signal in the phase 2/3 study.





The GBM AGILE study is a clinical endeavor that has been years in the making and owes its dynamic design to the collaborative interplay of more than 130 oncologists, pathologists, statisticians, imagers, neurosurgeons and academic, industry, and government researchers, who have worked collectively to cultivate this investigative model since 2015.



GBM AGILE is a “group effort” that was initiated in response to a series of unsuccessful clinical trials in GBM, according to Cloughesy. “The rationale for GBM AGILE comes from the setting of GBM, where in the [past] few years, there have been several negative phase 3 studies. They were expensive, costing several hundred million dollars, and it seemed that we weren’t [facilitating investigations] very well,” Cloughesy said. “Then, the disease gets the reputation that drugs can’t be developed in glioblastoma— that they’re just bound to fail.”

In ND GBM, the standard of care is temozolomide, which was approved for use in combination with RT and as a maintenance therapy in 2005.5 Existing data show that the median OS with temozolomide and concurrent RT is 14.6 months versus 12.1 months with RT alone, supporting the doublet regimen’s application in this setting.



Patients with ND GBM receive temozolomide with RT after maximal surgical resection, which rarely eradicates GBM tumor cells in their totality due to the invasive nature of the disease. Although adjuvant temozolomide and RT are administered to reduce the risk of disease recurrence, nearly all cases of GBM that initially respond to frontline treatment eventually recur.



In contrast to ND GBM, there is no established standard of care for recurrent disease. Interventions for recurrent GBM can include surgical resection, reirradiation, nitrosoureas, temozolomide rechallenge, or treatment with tyrosine kinase inhibitors or bevacizumab (Avastin).



Bevacizumab was indicated for use in patients with GBM in 2017, after findings from the phase 3 EORTC 26101 study (NCT01290939) showed that adding the VEGF inhibitor to lomustine reduced the risk of disease progression or death by 48%.

 Administering bevacizumab with lomustine extended the median progression- free survival versus single-agent lomustine (4.2 vs 1.5 months; HR, 0.52; 95% CI, 0.41-0.64) but notably did not result in a significant improvement in OS (HR, 0.91; 



The modest survival benefits that existing therapies afford patients with GBM, coupled with the lack of curative options, translate to a need for more efficacious treatment options for a disease that accounts for 45% of all malignant brain tumors and more than 12,000 cases annually in the United States.



GBM AGILE investigators and the trial’s broad network of clinical collaborators believe that the platform format of the study has the potential to not only identify better therapies for this deadly disease but also reduce the time and costs associated with their development around the world.

“We wanted to facilitate this evaluation in 1 environment to boost development in glioblastoma, and we also wanted to do this in multiple jurisdictions beyond the United States,” Cloughesy said. GBM AGILE is actively enrolling patients in the United States, and international locations in Canada, China, and Europe are also expected to open at a later date, according to Cloughesy.

Whereas the coronavirus disease 2019 (COVID-19) pandemic has prompted the suspension of many clinical trials across the nation, GBM AGILE has continued to accrue patients. “We have continued to add sites during this time and enrollment has remained steady, so we’ve been happy to see that,” Cloughesy said. “At their institutions, people [ask], what’s a necessary study going forward? Glioblastoma is almost 100% fatal. COVID-19 is incredibly serious, but glioblastoma will continue to be serious even after we’ve learned how to deal with COVID-19. We still need to learn how to deal with glioblastoma.”

Global Coalition For Adaptive Research. GBM AGILE website. Accessed April 13, 2020. bit.ly/2RU55M2

For the first time in over a decade, scientists have identified a first-line treatment that significantly improves survival for people with hepatocellular carcinoma, the most common type of liver cancer.

Researchers found that the combination of atezolizumab, an immunotherapy drug that boosts the body’s natural defenses, and bevacizumab, an anti-angiogenesis drug that inhibits the growth of tumors’ blood vessels, improved overall survival and reduced the risk of death by 42%. It also decreased the risk of the disease worsening by 41%, and the percentage of patients whose cancer shrank or disappeared more than doubled.

Results from the clinical trial were published today in the 

, and the combination is currently being reviewed for approval under the U.S. Food and Drug Administration’s Real-Time Oncology Review pilot program.

“The therapy is a real game-changer for people diagnosed with this aggressive disease,” said the study’s principal investigator and lead author, Dr. Richard S. Finn, a professor of medicine at the David Geffen School of Medicine at UCLA and director of the signal transduction and therapeutics program at the UCLA Jonsson Comprehensive Cancer Center. “We now have a new therapy that not only improves survival for people with the disease, which is very challenging to treat, but that helps them live longer while maintaining a high quality of life.”

Currently, people diagnosed with advanced liver cancer have limited treatment options, and the prognosis for survival is poor. Clinical treatment advancements have been few and far between. Until now, no new first-line therapy has been shown to improve survival since the drug sorafenib was approved in 2007.

Both atezolizumab and bevacizumab are monoclonal antibodies — specialized drugs that attach themselves to specific proteins and disable them &mdash; and they have already been used alone and in combination with other therapies to treat other cancers.

Atezolizumab targets a protein produced by cancer cells that shuts down the immune system’s infection-fighting T cells, preventing them from attacking the cancer. Bevacizumab interferes with a tumor’s blood supply, preventing the cancer from growing and spreading through the body.

“By using these two drugs with different mechanisms of action together, we have increased the number of patients who respond to this treatment and have increased the duration of these responses as compared to the standard treatment, sorafenib,” said Finn.

The trial included 501 people, aged 18 and over, from multiple centers worldwide, who had advanced metastatic or unresectable hepatocellular carcinoma. Two-thirds of participants were randomly assigned to receive the atezolizumab and bevacizumab combination, while one-third received sorafenib.

Twelve months after the start of treatment, the rate of survival with the combination was 67.2%, compared with 54.6% for the group on sorafenib.

“Liver cancer is one of the few cancers that is growing in incidence and death rate,” Finn said. “That’s why it’s so important that we now have something in the front-line setting — after more than a decade – that markedly improves survival in this very challenging disease.”

According to the American Cancer Society, liver cancer incidence rates have more than tripled, and death rates have more than doubled, since 1980. Some 800,000 people are diagnosed with this cancer each year, and it is a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths annually.

UCLA Health has a comprehensive liver cancer program with a multidisciplinary team to bring the latest treatments to people with all stages of liver cancer.

Tecentriq (atezolizumab) and Avastin (bevacizumab) are registered trademarks of Genentech, a member of the Roche Group.

When Stephen Warnock, 62, was diagnosed with liver cancer in the spring of 2018, he didn’t really have much hope. The cancer was advanced and the radiation treatment didn’t do much to shrink his tumor. By the end of summer, he was told there wasn't much left that could be done for him given it had grown significantly and was now invading the blood vessels.

That’s when he decided to take the two-hour trek from Bakersfield, California, to UCLA for a second opinion, the same place that saved his dad’s life when he was battling bone cancer.

He immediately met with Dr. Finn, who helped him enroll in the combination immunotherapy drug clinical trial.

“I didn’t have hope until I went to UCLA,” said Warnock, father to twin daughters and retired construction worker. “They made me feel like I had a chance. I was really lucky to get on this trial.”

Since Warnock enrolled in the clinical trial in September of 2018, his tumor has not progressed and his disease has been stabilized. Warnock is still part of the clinical trial and comes to UCLA for treatment every three weeks.

“I feel so fortunate that I got to start this trial. The therapy is working and I’m so grateful because there’s not very many treatment options for my disease.”

The UCLA Jonsson Comprehensive Cancer Center has approximately 500 researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the UCLA Jonsson Comprehensive Cancer Center is dedicated to promoting research and translating basic science into leading-edge clinical studies.

New Treatment Extends Lives of People With Most Common Type of Liver Cancer

For the first time in over a decade, scientists have identified a first-line treatment that significantly improves survival for people with hepatocellular carcinoma, the most common type of liver cancer.

Researchers found that the combination of atezolizumab, an immunotherapy drug that boosts the body’s natural defenses, and bevacizumab, an anti-angiogenesis drug that inhibits the growth of tumors’ blood vessels, improved overall survival and reduced the risk of death by 42%. It also decreased the risk of the disease worsening by 41%, and the percentage of patients whose cancer shrank or disappeared more than doubled.

Results from the clinical trial were published today in the 

, and the combination is currently being reviewed for approval under the U.S. Food and Drug Administration’s Real-Time Oncology Review pilot program.

“The therapy is a real game-changer for people diagnosed with this aggressive disease,” said the study’s principal investigator and lead author, Dr. Richard S. Finn, a professor of medicine at the David Geffen School of Medicine at UCLA and director of the signal transduction and therapeutics program at the UCLA Jonsson Comprehensive Cancer Center. “We now have a new therapy that not only improves survival for people with the disease, which is very challenging to treat, but that helps them live longer while maintaining a high quality of life.”

Currently, people diagnosed with advanced liver cancer have limited treatment options, and the prognosis for survival is poor. Clinical treatment advancements have been few and far between. Until now, no new first-line therapy has been shown to improve survival since the drug sorafenib was approved in 2007.

Both atezolizumab and bevacizumab are monoclonal antibodies — specialized drugs that attach themselves to specific proteins and disable them — and they have already been used alone and in combination with other therapies to treat other cancers.

Atezolizumab targets a protein produced by cancer cells that shuts down the immune system’s infection-fighting T cells, preventing them from attacking the cancer. Bevacizumab interferes with a tumor’s blood supply, preventing the cancer from growing and spreading through the body.

“By using these two drugs with different mechanisms of action together, we have increased the number of patients who respond to this treatment and have increased the duration of these responses as compared to the standard treatment, sorafenib,” said Finn.

The trial included 501 people, aged 18 and over, from multiple centers worldwide, who had advanced metastatic or unresectable hepatocellular carcinoma. Two-thirds of participants were randomly assigned to receive the atezolizumab and bevacizumab combination, while one-third received sorafenib.

Twelve months after the start of treatment, the rate of survival with the combination was 67.2%, compared with 54.6% for the group on sorafenib.

“Liver cancer is one of the few cancers that is growing in incidence and death rate,” Finn said. “That’s why it’s so important that we now have something in the front-line setting – after more than a decade – that markedly improves survival in this very challenging disease.”

According to the American Cancer Society, liver cancer incidence rates have more than tripled, and death rates have more than doubled, since 1980. Some 800,000 people are diagnosed with this cancer each year, and it is a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths annually.

UCLA Health has a comprehensive liver cancer program with a multidisciplinary team to bring the latest treatments to people with all stages of liver cancer.

Tecentriq (atezolizumab) and Avastin (bevacizumab) are registered trademarks of Genentech, a member of the Roche Group.





When Stephen Warnock, 62, was diagnosed with liver cancer in the spring of 2018, he didn’t really have much hope. The cancer was advanced and the radiation treatment didn’t do much to shrink his tumor. By the end of summer, he was told there wasn't much left that could be done for him given it had grown significantly and was now invading the blood vessels.

That’s when he decided to take the two-hour trek from Bakersfield, California, to UCLA for a second opinion, the same place that saved his dad’s life when he was battling bone cancer.

He immediately met with Dr. Finn, who helped him enroll in the combination immunotherapy drug clinical trial.

“I didn’t have hope until I went to UCLA,” said Warnock, father to twin daughters and retired construction worker. “They made me feel like I had a chance. I was really lucky to get on this trial.”

Since Warnock enrolled in the clinical trial in September of 2018, his tumor has not progressed and his disease has been stabilized. Warnock is still part of the clinical trial and comes to UCLA for treatment every three weeks.

“I feel so fortunate that I got to start this trial. The therapy is working and I’m so grateful because there’s not very many treatment options for my disease.”

The UCLA Jonsson Comprehensive Cancer Center has approximately 500 researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the UCLA Jonsson Comprehensive Cancer Center is dedicated to promoting research and translating basic science into leading-edge clinical studies.

Although fewer patients are undergoing cytoreductive nephrectomy (CN) as systemic treatments for renal cell carcinoma (RCC) improve, the modality still has a vital role to play in the treatment paradigm-even in the modern age of immune checkpoint inhibitors (ICIs), said Brian Shuch, MD.

Early results from ICI trials demonstrate safety and efficacy in patients with RCC, and ongoing trials are looking into the optimal use for neoadjuvant treatment with preoperative immunotherapy. Nonetheless, Shuch, director of the Institute of Urologic Oncology Kidney Cancer Program and the Henry Alvin and Carrie L. Meinhardt Endowed Chair for Kidney Research at the University of California, Los Angeles, said surgery is still likely to play a role in the treatment of RCC now and in the future.

"For many different eras, surgery has been relevant," he said. "Why would that change now? We just need to find the right patients, the right timing."

Shuch discussed the evolving role of surgery in advanced RCC in the context of changes in systemic therapy options (

 Interdisciplinary Prostate Cancer Congress

 and Other Genitourinary Malignancies conference.

In the cytokine era of the 1990s, clinical trial data clearly supported the superiority of CN followed by interferon-α over interferon- α alone and that approach became a standard of care for treating de novo metastatic RCC, Shuch said.

Patients with 3 or fewer preoperative risk factors have better median overall survival (OS) after CN than patients who have 4 or more risk factors (22.7 vs 12.2 months). The latter group does not appear to benefit from the surgery.

However, cytokines rarely induce a response in the primary tumor, but neoadjuvant treatment with VEGF-targeting tyrosine kinase inhibitors such as sunitinib (Sutent), pazopanib (Votrient), and axitinib (Inlyta) commonly results in tumor shrinkage, which suggested a potential change in surgical approach, Shuch said.

In 2019, Bossé et al published data from a pooled analysis of 12 phase 2/3 clinical trials of patients with metastatic RCC who received systemic therapy with tyrosine kinase inhibitors from 2003 to 2013. Data from patients with 1 target lesion in the kidney were identified as having theirprimary tumor in place (N = 565) and were evaluated. The study population included 461 (82%) patients who had not undergone treatment. Half of the patients had received first-line VEGF-targeted therapy, and 39% were poor risk as determined by International Metastatic RCC Database Consortium (IMDC) criteria. The primary end point was objective response rate (ORR) in the primary tumor.

The ORR in the primary tumor was 19% (95% CI, 16%-23%) for patients who received first-line therapy of any type compared with 28% (95% CI, 22%-33%) for those who received VEGF inhibitors in the first line and 23% (95% CI, 19%-28%) for those treated with VEGF-targeted therapy in any line. The ORR was 9% (95% CI, 5%-13%) for patients with poor risk and 20% (95% CI, 15%-27%) for those with intermediate risk.

Shuch noted that tumors shrank in the patients assigned to VEGF inhibitors, albeit slowly, and the response was mild. At 6 weeks, 60% of patients had a 7% mean reduction in tumor size. That number increased to 12% at 18 weeks and 18% at 24 weeks.

Figure. Evolution of Systemic Therapy in Advanced Renal Cell Carcinoma

CN Remains Benefical in the Right Population

Based on data from the SURTIME trial published in 2019, delayed CN does not appear to affect progression-free survival but may improve OS by eliminating patients who are harmed by surgery.

SURTIME (NCT0109942) was a randomized clinical phase 3 trial comparing immediate CN followed by sunitinib versus 3 cycles of sunitinib followed by CN and sunitinib. Recruitment was poor—investigators enrolled only 99 out of a planned 458 patients&mdash;so the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progressionfree rate instead.

Fifty patients were assigned to immediate nephrectomy, whereas surgery was deferred in 49 patients. In the deferred arm, 29% of patients never progressed to surgery.

At 28 weeks, the progression-free rate was 42% in the immediate surgery arm versus 43% in the delayed surgery arm. In the intention-to-treat population, the median OS was 15.0 months (95% CI, 9.3-29.5) in the immediate CN arm compared with 32.4 months (95% CI, 14.5- 65.3) in the deferred arm (HR, 0.57; 95% CI, 0.34-0.95; 

Choueiri et al published a retrospective review in 2011 showing that patients with metastatic RCC who had not received VEGF therapy had dramatic improvement in OS with CN compared with those who did not undergo CN (19.8 vs 9.4 months; HR, 0.44; 95% CI, 0.32-0.59; 

 <.01). However, subgroup analyses stratified for favorable-, intermediate-, or poor-risk criteria showed that patients with poor risk only derived marginal benefit (

 = .06). Overall, patients who were poor surgical candidates had poor outcomes after surgery.

In the phase 3 CARMENA trial (NCT00930033), investigators randomized 450 patients with metastatic clear cell RCC; 226 underwent CN followed by sunitinib, and 224 were assigned to sunitinib alone. In the surgery group, patients started sunitinib between 3 to 6 weeks after surgery to allow time for recovery.

Interim findings published in 2018 showed that sunitinib monotherapy was noninferior to CN followed by sunitinib. The HR for death with sunitinib monotherapy was 0.89 (95% CI, 0.71-1.10). Furthermore, monotherapy conferred a 4.5-month advantage in median OS (18.4 vs 13.9 months). Between those results and the findings from Choueiri et al, some experts wondered whether the use of CN was coming to an end.

However, Shuch said the study participants may not represent patients generally considered for surgery. He noted that 44.4% of those in the nephrectomy-sunitinib group were in the poor-risk category. He added that the median OS of 13.9 months in the surgery arm is "very low" and similar to data from EORTC/SWOG trials published before the availability of effective systemic therapies.

"This just means to me that we’re comparing different patient populations," Shuch said. "Our therapy now is better and if survival hasn’t improved, we’re just looking at a much sicker cohort. In the series of modern cytoreductive nephrectomies with carefully selected patients, we’re looking at a median OS of 15 to 24 months, so this seems to be much worse."

Final results from the CARMENA trial were presented at the 2019 American Society of Clinical Oncology Annual Meeting. In the intermediate-risk group, individuals whose only risk factor was the time from diagnosis to metastatic disease of less than 12 months— a cohort that did not have hemoglobin levels below the lower limit of normal or calcium or neutrophil levels above the upper limit of normal&mdash;the median OS was 25.2 months (95% CI, 19.6-35.4) for sunitinib alone versus 31.4 months (95% CI, 17.3-45.5) in the surgery group (HR, 1.29; 95% CI, 0.85-1.98; 

 = .232). In patients who had 2 risk factors, OS was superior in the sunitinib-alone arm (31.2 vs 17.6 months; HR, 0.63; 95% CI, 0.44- 0.97; 

Among the 40 (18%) patients who crossed over to the surgery arm, the median OS was 48.5 months compared with 15.7 months (HR, 0.34; 95% CI, 0.22-0.54) for those who did not undergo surgery.

"The updated conclusions show that [sunitinib], in this poor-risk population, is still not inferior," Shuch said. "CARMENA shows that, in [poor-prognosis] patients who should not have had surgery, surgery is really not helpful."

At present, there are 3 ICIs approved to treat patients with advanced RCC: (1) the PD-1 inhibitor nivolumab (Opdivo) as a single-agent treatment after prior antiangiogenic therapy and in combination with the CTLA-4 inhibitor ipilimumab (Yervoy) for previously untreated patients with intermediate- or poor-risk disease; (2) the PD-1 inhibitor pembrolizumab (Keytruda) in combination with axitinib as a firstline treatment; and (3) the PD-L1 inhibitor avelumab (Bavencio) in combination with axitinib as first-line therapy.

ICIs are more potent and better tolerated than other systemic therapies, Shuch said. Early study findings suggest that the adverse events from ICIs are minimal and that CN can be safely conducted in patients who have received these agents.

In a pilot study (NCT02210117), patients with metastatic RCC who had not received prior ICI and anti-VEGF therapy were randomized to receive nivolumab, nivolumab plus the VEGF inhibitor bevacizumab (Avastin), or nivolumab plus ipilimumab, followed by CN, metastasectomy, or biopsy; and subsequent nivolumab maintenance therapy for up to 2 years.

In 12-week findings, investigators observed a best overall response, including complete and partial responses, of 54% among patients in the nivolumab arm (n = 28), 48% in the nivolumab/bevacizumab arm (n = 40), and 41% in the nivolumab/ipilimumab arm (n = 29). Shuch added that the safety profile was acceptable in the perioperative setting.

In findings reported at the 2020 Genitourinary Cancers Symposium, investigators with the IMDC conducted a retrospective analysis of patients diagnosed with de novo metastatic RCC who started first-line systemic therapy with ICIs or targeted therapy from 2009 to 2019 (N = 4639). Most patients (62%) underwent CN.

The findings demonstrated that patients who underwent CN experienced improved median OS compared with those who did not have CN, respectively, both with targeted therapies (26.5 vs 10.3 months; HR, 0.48; 95% CI, 0.45-0.52; 

 <.0001) and with ICIs (53.6 vs 21.4 months; HR, 0.44; 95% CI, 0.30-0.64; 

Investigators concluded that the benefits observed with CN appear similar in the targeted therapy and ICIs eras but that patient selection remains important.

Two ongoing trials, PROSPER RCC (NCT03055013) and NORDIC-SUN (NCT03977571), will help to further clarify the role of ICIs and CN in patients with RCC. The phase 3 PROSPER trial, with an estimated enrollment of 805 participants, is randomizing patients to receive perioperative nivolumab or observation in advance of partial or radical nephrectomy. NORDICSUN, also a phase 3 trial, will evaluate initial treatment with nivolumab plus ipilimumab followed by CN in patients with 3 or fewer IMDC risk features or maintenance nivolumab in those with more than 3 risk features.

Shuch B. Evolving therapeutic strategies in renal cell carcinoma: nephrectomy vs no nephrectomy. Presented at: 13th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies hosted by Physicians’ Education Resource®, LLC (PER®); March 13-14, 2020; New York, NY.           

Culp SH, Tannir NM, Abel EJ, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? 

. 2010;116(14):3378-3388. doi: 10.1002/cncr.25046

Bossé D, Lin X, Simantov R, et al. Response of primary renal cell carcinoma to systemic therapy.

. 2019;76(6):852-860. doi: 10.1016/j.eururo.2019.08.035

Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial [erratum in 

.&#8239;2019;5(2):164-170. doi:&#8239;10.1001/jamaoncol.2018.5543

Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. 

. 2011;185(1):60-66. doi: 10.1016/j.juro.2010.09.012

Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. 

. 2018;379(5):417-427. doi: 10.1056/NEJMoa1803675

Méjean A, Thezenas S, Chevreau C, et al. Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): update on Carmena trial with focus on intermediate IMDC-risk population. 

. 37, 2019 (suppl; abstr 4508).          

Gao J, Karam JA, Tannir NM, et al. A pilot randomized study evaluating nivolumab (nivo) or nivo + bevacizumab (bev) or nivo + ipilimumab (ipi) in patients with metastatic renal cell carcinoma (MRCC) eligible for cytoreductive nephrectomy (CN), metastasectomy (MS) or post-treatment biopsy (Bx). 

 2018;36(suppl; abstr 4520). doi: 10.1200/JCO.2018.36.15_suppl.4520           

Bakouny Z, Xie W, Dudani S, et al. Cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or targeted therapy (TT): a propensity score-based analysis. 

. 2020; 38(suppl 6; abstr 608). meetinglibrary.asco.org/record/184115/abstract

"You don’t give it and the tumors shrink in a week or 2," he said. “We’re talking over 12 to 24 weeks of therapy where you get some effects—not really enough to change surgical approach."

Although fewer patients are undergoing cytoreductive nephrectomy as systemic treatments for renal cell carcinoma improve, the modality still has a vital role to play in the treatment paradigm&mdash;even in the modern age of immune checkpoint inhibitors.

New Therapeutic Era Sparks Fresh Questions About Nephrectomy in RCC

Wolfgang Fendler, MD, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, discusses the rationale for creating the 68Ga-PSMA-11 PET imaging test in prostate cancer.

The 68Ga-PSMA-11 PET test, a whole-body scan for patients with prostate cancer, offers insight into tumor location and provides other relevant information in the clinical setting. Knowing the location of the tumor is vital for many available treatments for this disease, including radiation and surgery.

What had once been an unmet need in the prostate cancer paradigm has now been filled with the the development of the 68Ga-PSMA-11 PET imaging test; this test can help improve future prostate cancer regimens, concludes Fendler.

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Jonathan W. Goldman, MD, health sciences clinical instructor, Department of Medicine, and Hematology/Oncology member, Jonsson Comprehensive Cancer Center Signal Transduction and Therapeutics Program, UCLA, discusses the use of immunotherapy in patients with oncogene-driven non—small cell lung cancer (NSCLC).

Immunotherapy, either alone or in combination with chemotherapy, plays an important role in the treatment of patients with advanced nonsquamous and squamous NSCLC. However, the role of immunotherapy in oncogene-driven cancers, such as 

, is less apparent. While the benefit of immunotherapy alone in these subsets is limited, there may be benefit to chemoimmunotherapy for patients whose tumors harbor 

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Alexandra Drakaki, MD, oncologist/hematologist at the University of California, Los Angeles, discusses the design of the MORPHEUS-mUC trial in advanced/metastatic urothelial carcinoma.

With the use of immunotherapy, investigators are trying to enable preexisting immunity to create an effective response to cancer, says Drakaki. The phase Ib/II MORPHEUS-mUC trial will evaluate 6 immunotherapy combinations compared with a single immunotherapy control in patients with locally advanced/metastatic urothelial carcinoma who progressed during or after a platinum-containing regimen.

The PD-L1 inhibitor atezolizumab (Tecentriq) will be combined with agents that target different mechanisms via CD47, CD38, DPP-4, nectin-4, interleukin-6 receptor, and PARP, adds Drakaki.

Patients enrolled in the study will start in stage I of the trial, in which they will be randomized to either the control arm of atezolizumab monotherapy or 1 of the following experimental arms: atezolizumab plus either enfortumab vedotin-ejfv (Padcev), niraparib (Zejula), magrolimab (Hu5F9-G4), isatuximab-irfc (Sarclisa), linagliptin (Tradjenta), or tocilizumab (Actemra).

At the time of progression, if they have a good performance status, no safety concerns, and available tissue, they will undergo biopsy. Then, they will be moved into the stage II portion of the trial, says Drakaki. In stage II, patients will be randomized to receive either atezolizumab plus either enfortumab vedotin-ejfv or linagliptin, concludes Drakaki.

Alexandra Drakaki, MD, discusses the design of the MORPHEUS-mUC trial in advanced/metastatic urothelial carcinoma.

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