ASCO 2021

ASCO 2021: Systemic Therapy Considerations After Immunotherapy Combination or Monotherapy in Advanced Renal Cell Carcinoma

(UroToday.com) In this talk, Dr. Rana McKay reviewed the evidence for systemic therapy after immunotherapy combination or monotherapy in advanced renal cell carcinoma as well as highlight current clinical trials in progress.

First-line treatment options for renal cell carcinoma typically consists of immune checkpoint blockade (ICB) combination therapy either with two ICB agent (nivolumab and ipilimumab) or ICB blockade in combination with a VEGF tyrosine kinase inhibitor (TKI). Second-line therapies can include VEGF TKI, immunotherapy, or combinations.

The data to support single-agent VEGF TKI as second-line therapy are summarized below. These are largely retrospective studies, with the exception of the last three rows, with response rates in the 30-40% range. Some of these studies suggest that cabozantinib may be the preferred TKI in the second-line setting based on the retrospective observational cohort study from Marteau et al, which showed improved response rates and longer time to treatment discontinuation relative to other TKIs, although no overall survival advantage for cabozantinib was observed in this dataset.

The phase 3 TIVO-3 trial demonstrated a statistically significant improvement in progression-free survival for tivozanib relative to sorafenib in pre-treated RCC patients as third- or fourth-line therapy. This trial led to the FDA approval of tivozanib for relapsed or refractory advanced renal cell carcinoma.

Dr. McKay then covered the evidence for immunotherapy after first-line immunotherapy in advanced RCC. She first highlighted a retrospective multicenter cohort study (https://doi.org/10.1001/jamaoncol.2020.2169) of 69 patients who were re-challenged with ICB after receiving at least two separate lines of immunotherapy. Though no complete responses were observed, the overall response rate was 23%. The best responses to re-challenge immunotherapy were seen in patients who had the best response to initial immunotherapy.

Two other studies were then highlighted looking at combination nivolumab and ipilimumab after immunotherapy, with a 15-20% response rate, including the phase 2 FRACTION study (last row). In FRACTION, no complete responses were observed, but the disease control rate was 52%.

Adaptive trials have been conducted with the addition of ipilimumab to nivolumab in patients not responding to ICB monotherapy. Though each trial was slightly different, there was a low rate of conversion from non-response to objective response and low rates of complete response.

Finally, Dr. McKay focused on VEGF TKI combination therapies post-immunotherapy. One retrospective study suggested a response rate of 51%- and 11.6-month progression-free survival in 48 patients treated with any IO + TKI after immunotherapy. The combination of pembrolizumab and Lenvatinib was studied in a recently presented phase 2 trial. The schema for this was shown below.

There were no complete responses, but the overall response rate was 55%.

Several novel combinations are being tested post-immunotherapy. Belzutifan is a selective and potent inhibitor of HIF2-alpha which has shown an objective response rate of 25% of heavily pre-treated advanced RCC patients. Based on this data, a phase 3 randomized controlled trial testing belzutifan as subsequent line therapy is ongoing.

Other trials highlighted by Dr. McKay include the CONTACT-3 study of cabozantinib +/- atezolizumab in multiple histologies of advanced RCC

as well as the TiNivo-2 study of tivozanib +/- nivolumab.

Dr. McKay concluded her talk by summarizing the evidence behind multiple treatment options post-immunotherapy in advanced renal cell carcinoma. Treatment options in this context are evolving, but novel targets are needed to continue to improve outcomes for patients.

Presented by: Rana R. McKay, MD, Associate professor of medicine and urology at the University of California, San Diego in San Diego, CA

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Sequencing Therapies in Advanced Kidney Cancer in the Contemporary Era – Integration of Multimodality Treatment in Advanced Kidney Cancer: The Roles of Surgery and Radiation Therapy

(UroToday.com) Dr. Singer presented a talk on the role of surgery and radiation in advanced kidney cancer.

He first began with a discussion of cytoreductive nephrectomy, the underlying rationale for which has been supported in other cancers such as breast and ovarian cancers. There has been much debate in the field about the role of cytoreductive nephrectomy in advanced renal cell carcinoma (aRCC). Dr. Singer showed data from a systematic review published in 2019 (https://doi.org/10.1016/j.eururo.2018.09.016) highlighting that multiple observational studies suggest a benefit for cytoreductive nephrectomy, but the CARMENA randomized clinical trial did not show a similar benefit.

This holds true for non-clear cell RCC observational studies, where there are no randomized prospective studies,

As well as in the immunotherapy era (https://doi.org/10.1016/j.urolonc.2020.02.029) based on studies where patients first received cytoreductive nephrectomy then systemic immunotherapy.

Several randomized trials that are ongoing will help clarify the role of cytoreductive nephrectomy in aRCC, including PROBE, NORDIC-SUN, and Cyto-KIK.

Dr. Singer then shifted to discussing the potential advantage of metastasectomy. Multiple considerations must be taken into account when deciding about metastasectomy. From a patient perspective, risk stratification, performance status, nutritional status, and frailty are factors to consider. From a tumor perspective, histology, grade, ability to achieve complete surgical resection, and the absence of hepatic, brain, or bone metastases should be considered. Patients who are able to have a complete metastasectomy have been shown to have significantly improved overall survival relative to matched controls in multiple retrospective datasets (https://doi.org/10.1016/j.urolonc.2020.07.021). Regarding surgical risk, this study showed that age greater than 65 or brain metastasis was associated with increased risk of mortality with metastasectomy. The benefit from complete resection of metastases holds true regardless of whether this was done in the targeted therapy era or more modern immunotherapy era.

Next, Dr. Singer transitioned to talking about the role of radiation therapy in aRCC. Lower volume metastatic disease can be treated successfully with stereotactic ablative radiation therapy (SABR), and patients with just 1 metastatic site are able to remain free of systemic therapy longer than patients with 2-4 metastatic sites. Other factors associated with longer freedom from systemic therapy in aRCC include clear cell histology, favorable risk stratification, and absence of bony metastases.

There is data examining the combination of radiotherapy with immunotherapy in aRCC. For example, one paper (https://doi.org/10.1111/bju.15284) evaluated the safety of stereotactic radiotherapy in aRCC patients receiving either immunotherapy or targeted therapy. In this small study, overall and progression-free survival was improved with this approach in patients with less than 5 metastatic sites and better ECOG performance status. Many trials are ongoing to understand the role of radiotherapy in aRCC, including helping define a definition of oligometastatic disease.

Dr. Singer concluded that surgery and radiotherapy have a role in aRCC, typically for patients with good performance status, limited metastatic disease burden in certain states, but the optimal timing along with systemic therapy continues to require further investigation.

Presented by: Eric A. Singer, MD, FASCO, FACS, MA, MS, Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Jersey

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Sequencing Therapies in Advanced Kidney Cancer in the Contemporary Era – Integration of Multimodality Treatment in Advanced Kidney Cancer: Novel Therapeutics on the Horizon in Advanced Kidney Cancer

(UroToday.com) In this talk, Dr. Albiges focused on novel therapeutics on the horizon in advanced renal cell carcinoma (aRCC). She focused first on how a deeper understanding of this disease has nominated targets for novel therapeutics.

Dr. Albiges first discussed the inhibitor of the hypoxia-inducible factors (HIFs). These are a target of treatment based on their accumulation related to loss of the Von Hippel Lindau gene on chromosome 3 and their multifaceted control of cell survival. A second-generation HIF-2alpha inhibitor, MK-6482 or belzutifan, has been tested in heavily pre-treated aRCC and resulted in an ORR of 25%, disease control rate of 80%, and a median PFS of 14.5 months. This PFS is quite long for pre-treated aRCC and is being further explored in a phase 3 study of belzutifan versus everolimus. Belzutifan is also being tested in combination with other therapies in clear cell aRCC as well as against tumors related to the hereditary von-Hippel-Lindau disease due to germline alterations in VHL. Tumors such as hemangioblastomas and pancreatic neuroendocrine tumors respond to this agent as well. The safety profile of this agent is different from VEGF TKIs in that it mostly causes anemia and hypoxia as on-target effects of the molecule.

Dr. Albiges then discussed metabolic targeting in aRCC. Preclinical evidence suggested that aRCC is dependent on glutamine metabolism to generate glutamate for entry into the Krebs cycle, leading to the randomized phase 2 CANTATA study. At this conference, the PFS results were presented, showing no difference in PFS with the addition of the glutaminase inhibitor telaglenastat to cabozantinib. It is possible that additional metabolic targeting agents will be tested in the future.

She then focused on therapeutic strategies to augment the immune response against aRCC. Dr. Albiges highlighted many immunomodulatory molecules that could potentially be targeted therapeutically.

She specifically mentioned an ongoing trial of NKTR-214 (bempegaldesleukin) in combination with nivolumab in previously untreated aRCC versus sunitinib. Additionally, Dr. Albiges mentioned two immune checkpoints of interest to her. These are HHLA2, which is over-expressed in aRCC, and TIGIT which has shown promising responses in lung cancer. Allogeneic chimeric antigen receptor T-cells are being developed against CD-70 in aRCC. Finally, there is some thought that epigenetic modulatory drugs may augment immune responses, but data from this is still early.

Beyond novel therapeutic targets, Dr. Albiges discussed different therapeutic approaches including triplet therapy in COSMIC-313 (nivolumab and ipilimumab +/- cabozantinib) and NCT04736706 (pembrolizumab and Lenvatinib +/- belzutifan +/- the anti-CTLA4 antibody quavonlimab). The opposite approach to escalating with triplet therapy is de-escalation trials, including TITAN RCC and PDIGREE.

Dr. Albiges stressed that biomarker-driven trials will be essential moving forward for how to choose between IO-only treatment, combination IO/TKI, and other emerging treatment strategies.

Presented by: Laurence Albiges, MD, PhD, Medical Oncologist at the Gustave Roussey Intitute in France.

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: The Variability in Prostate Cancer Treatments and Outcomes Based on Geographic Location and Race

(UroToday.com) In this educational session, Dr. Heath discussed the variability in prostate cancer treatments and outcomes based on geographic location and race.

Within localized disease, Dr. Heath highlighted data published in 2020 from the National Cancer Database, which includes over 214,000 men diagnosed with high-risk prostate cancer between 2004 and 2016. This disease is typically managed with either prostatectomy or radiotherapy. Black men are less likely to undergo prostatectomy from historical data, but this gap is narrowing with time. For patients treated with prostatectomy, Black men have a 20% higher mortality than white men, whereas Asian men have a 35% lower mortality than white men. From SEER data, there is a suggestion that in low-risk prostate cancer, Black men are more likely to die than white men, though it is important to note that information on causes of death is lacking in this cohort. With regards to radiotherapy, SEER data suggests that Black and Hispanic men are less likely to receive therapy. Black men have slightly higher rates of not completing radiotherapy, but when examining treatment strategies with lower numbers of total fractions (SBRT), no disparity in completion rates between Blacks and Whites has been noted.

Dr. Heath also noted that ethnicity is a complex construct. For example, cancer incidence rates differ between Hispanic patients (those from Spanish-speaking countries) and Latino patients (those from Latin American countries like Brazil). She showed a figure looking at incidence rates of different cancers with Hispanic males, illustrating that the rates vary based on country of origin.

Place of residence (rural vs urban) also matters. Patients living in rural areas, even when controlling for urologist density, are less likely to receive treatment for prostate cancer. Patients in rural areas need as much supportive interventions as other patients, but data suggests the quality of life is lower for prostate cancer survivors living in rural areas. This may be due to delays in treatment resulting in more advanced disease, local cultural taboos about talking about the effects of treatment, or limited access to supportive care like mental health services. However, place of treatment (academic vs community center) research suggests that both academic and community centers have equal amounts of disparities in the treatment of minorities and uninsured patients with high-risk localized prostate cancer. This includes access to imaging studies with prostate-cancer-specific advanced imaging techniques.

Data from Switzerland suggests that patients with higher socioeconomic status have a lower risk of death than patients with low socioeconomic status. Patients with lower socioeconomic status also tended to be older at the age of diagnosis with more advanced disease/higher tumor grade.

Dr. Heath then focused on available surrounding how different racial groups respond to treatments for advanced prostate cancers. African American patients with minimally symptomatic castration-resistant prostate cancer treated with sipuleucel-T were found to have improved overall survival relative to Caucasian patients in the PROCEED registry (https://doi.org/10.1038/s41391-020-0213-7). In a meta-analysis of ten phase 3 trials of patients treated with docetaxel chemotherapy for metastatic castration-resistant prostate cancer (https:doi.org/10.1200/JCO.18.01279), researchers found equivalent median overall survival (21 months) for both Black and White men, though the pooled hazard ratio suggested a superior overall survival for Black men (HR 0.81, 95% CI 0.72-0.91). Patients treated within the Veterans Affairs system with radium-223 were found to have a decreased risk of mortality and numerically longer overall survival relative to non-Black patients (https://doi.org/ 10.1097/JU.0000000000000524). Comparisons by race for PSA responses with abiraterone acetate as front-line therapy for metastatic castration-resistant prostate cancer suggest superior median PSA progression-free survival for Black patients (16.6 months vs 11.5 months). Analysis of the 7-month PSA response rate for enzalutamide therapy as first-line treatment for metastatic castration-sensitive prostate cancer suggests equivalent rates in Black and White patients (93% vs 94%), but much lower rates for Black patients with bicalutamide (42% vs 86%). In total, these studies suggest that Black patients have equivalent or improved outcomes with therapies administered for advanced prostate cancer when administered especially in the monitored and supported setting of a clinical trial.

Finally, Dr. Heath talked about disparities in clinical trial accrual and data collection across different racial groups. She showed the following summary slide. Globally, disparities in enrollment in trial exist, with 96% of patients enrolled in the global phase 3 or 4 trials in prostate cancer identifying as White.

Efforts are underway to improve data collection and greater inclusivity in prostate cancer. One example is the IRONMAN registry, a global effort to include all men with advanced prostate cancer to provide information on care. A multilevel intervention to increase the participation of African Americans in Prostate Cancer (PAACT) initiative is also underway to help enroll African American patients into trials.

Finally, Dr. Heath provided the following suggestion slide for what providers can do to be more mindful of disparities and attempt to address them.

Presented by: Elisabeth I. Heath, MD, FACP, Hartmann Endowed Chair for Prostate Cancer Research and Professor of Oncology at the Karmanos Cancer Center, Detroit, MI

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Optimizing Urothelial Cancer Management From Organ-Confined to Metastatic Disease: A Multidisciplinary Approach – Urologic Oncologist Perspective

(UroToday.com) This session was a multidisciplinary case discussion focusing on multiple topics including (1) treatment of BCG unresponsive non-muscle invasive bladder cancer, (2) treatment of muscle-invasive urothelial carcinoma in cisplatin eligible and ineligible patients, (3) the implications of pathologic response to neoadjuvant chemotherapy, (4) the role of adjuvant therapy, (5) the management of metastatic urothelial carcinoma and the role of chemotherapy, immune therapies, FGFR inhibition, and antibody-drug conjugates, and finally (5) palliative therapy.

Case: 62F presents with gross hematuria and undergoes cystoscopy.

Dr. Lee discussed the cystoscopy findings as a couple of areas of erythema that appear released. In this patient, she would be initially concerned for carcinoma in situ. In the pathology slide, we have labeled carcinoma in situ (CIS). This is an important diagnosis to make earlier because we think it is a precursor to invasive disease, and so I would be interested in talking with her about intravesicular therapy. We still look to intravesical BCG for our first-line treatment, roughly 2/3 of patients will respond initially, and about ½ of patients will have a long-term benefit. After induction BCG, we know that maintenance therapy reduces the risk of recurrence and disease progression. Most urologists follow the SWOG schedule for high-risk patients (such as patients with carcinoma in situ), which provides a course of induction BCG with six doses and then maintenance therapy at 3, 6, 12, 18, 24, 30, and 36 months post-induction so long as the patient tolerates therapy and has no recurrence.

Case continued: She is diagnosed with carcinoma in situ and receives intravesicular BCG for six treatments followed by maintenance therapy. After six months of maintenance therapy, her surveillance cystoscopy reveals recurrence carcinoma and situ and a new invasive T1 urothelial carcinoma.

Dr. Lee commented that this appears to be a more concerning tumor based on size with neovascularity around the edges and erythema at the 6 o’clock position. Based on the appearance with some suggestion of papillation, she would worry about an invasive component, and so would suggest transurethral resection of the bladder tumor (TURBT), examination under anesthesia, and upper tract imaging. The degree of invasion seen on the pathology slide (more extensive, not focal) is concerning for an even higher risk of future prediction.

The first question posed was “What treatment option would you proceed with?”. (A) Intravesical chemotherapy, (B) Intravenous pembrolizumab, (C) Radical Cystectomy, or (D) Other.

Dr. Lee discussed that based on her early timing of relapse, if the patient has reasonable performance status, then she would be talking about radical cystectomy. Not everyone will agree with this and many will remain committed to bladder preservation at this point. If she does not agree to cystectomy then I think about second-line therapies including pembrolizumab or intravesical chemotherapy. More and more provocative data is emerging from studies looking at gemcitabine and docetaxel sequentially with intravesical chemotherapy, which in recent data is well-tolerated and showing 50% recurrence-free survival at two years. Though this is retrospective data, it is provocative and likely warrants a clinical trial.

I would pursue re-resection here if the patient does not opt for cystectomy to take a deeper resection.

The patient is not interested in radical cystectomy or intravenous pembrolizumab due to travel requirements. She is willing to receive intravesical chemotherapy with gemcitabine and docetaxel.

Dr. Lee commented that for a long time valrubicin was the only FDA-approved option for intravesical chemotherapy in BCG-unresponsive patients. Unfortunately, this was not durable, as less than 10% of patients were free of disease after two years. Also, for this patient who has travel concerns, it is possible to think of every 6-week infusion schedule for pembrolizumab. However, it is important to monitor these patients on pembrolizumab with labs, so in her practice, she typically throws in a telehealth visit. She also discussed the potential role of nadofaragene firadenovec, which is a non-replicating adenoviral vector that induced interferon alfa-2B destruction of tumors. It’s delivered every three months and not yet approved but appears promising. She also discussed the potential emerging role of oportuzumab monatox (single-chain monoclonal antibody fragment against EpCAM conjugated to a truncated form of Pseudomonas exotoxin that inhibits protein synthesis in target cells), and FGFR inhibitors in BCG-unresponsive disease.

After intravesical chemotherapy, surveillance cystoscopy performed 6 months later reveals invasive disease obscuring the bilateral ureteral orifices, resulting in kidney injury. CT imaging reveals bilateral hydronephrosis but no significant lymphadenopathy.

Dr. Lee discussed that this bladder view, which appears to be in the operating room, is very concerning for recurrence which encompasses most of the visual field and appears more nodular than papillary. The presence of bilateral hydronephrosis and is suggestive of extravesicular disease and potentially vaginal invasion. An exam under anesthesia will be important to fully stage the patient. Given the likelihood that the disease is obstructing both ureteral orifices, it would likely be difficult to place internalized stents, so she would probably opt for percutaneous nephrostomy tubes in this patient to improve her renal function. It is important to remember that patients are never excited about external tubes and drains that they have to manage as it impacts their quality of life.

Bilateral percutaneous nephrostomy tubes are recommended, and the patient wants to start treatment as soon as possible. Her ECOG PS is 1 and she has no other major comorbidities. What options do you consider? (A) Radical cystectomy, (B) Split-dose cisplatin-combination chemotherapy followed by cystectomy, (C) carboplatin-combination chemotherapy followed by cystectomy, (D) pembrolizumab followed by cystectomy, (E) Bladder preservation with cisplatin-based chemoradiation, (F) Bladder preservation with 5FU based chemoradiation.

Dr. Lee discussed the promising data from RTOG 0712 exploring the role of trimodality therapy for bladder preservation. However, patients were not recruited to this trial if they had prognostic factors that suggest they might fail, and so it is important to consider what the most efficacious therapy might be in the context of whatever prognostic factors are present.

Although primary cystectomy is possible, we have level 1 evidence to show improved survival outcomes with neoadjuvant cisplatin-based chemotherapy as well as provocative early data showing reasonable pT0 rates in neoadjuvant pembrolizumab. Her preference would be to avoid primary cystectomy unless no neoadjuvant therapy can be administered.

With bilateral nephrostomy tubes, the creatinine clearance improves to 61 ml/min and becomes cisplatin eligible. She prefers surgery but would be willing to receive neoadjuvant chemotherapy if recommended. The patient undergoes accelerated MVAC and then radical cystectomy with an ileal conduit. Pathology reveals ypT2N0 disease.

The goal of neoadjuvant therapy, dating back to the SWOG-8710 trial, is pathologic complete response (pCR). Patients who had pCR had overall survival improvement, with 85% of patients surviving at 5 years, which was very impressive. We know survival outcomes for patients who do not achieve pCR are worse, and also retrospective data showing that patients with the residual muscle-invasive disease do worse than those with residual non-muscle invasive disease.

What course of action would you recommend next? (A) Adjuvant carboplatin with gemcitabine, (B) Adjuvant taxane-combination chemotherapy regimen, (C) Adjuvant checkpoint inhibitor, (D) Observation

The most effective context for adjuvant therapy appears to be in patients with an extravesical component of residual disease. With an organ-confined state after neoadjuvant chemotherapy and surgery, I might favor observation.

The patient undergoes observation. Six months later, surveillance CT imaging reveals the following image. Creatinine clearance is now 48 ml/min and ECOG performance status is 1. Would you perform PD-L1 IHC on archival tissue to aid in treatment decision-making?

The remainder of the session involved input from medical oncology as the patient developed the systemic disease. The take-home points below were provided at the end.

Presented by: Cheryl T. Lee, MD, Urologic Oncologist and Chair of the Department of Urology at the Ohio State University, Colombus, OH

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Optimizing Urothelial Cancer Management From Organ-Confined to Metastatic Disease: A Multidisciplinary Approach – Radiation Oncologist Perspective

She is diagnosed with carcinoma in situ (CIS) and receives intravesicular BCG for six treatments followed by maintenance therapy. After six months of maintenance therapy, her surveillance cystoscopy reveals recurrence carcinoma and situ and a new invasive T1 urothelial carcinoma.

Dr. Vapiwala then commented on the pathology from the TURBT, which reveals invasion of the muscularis mucosa of the lamina propria. Muscle invasion is defined as invasion of the muscularis propria, and so to accurately assess this there needs to be muscularis propria present in your resection/biopsy specimen. This is a high-grade disease due to the presence of dense nuclei and invasion of muscularis mucosa but not muscularis propria, so we would call this pathologic T1 high-grade disease.

The first question posed was “What treatment option would you proceed with?”. (A) Intravesical chemotherapy, (B) Intravenous pembrolizumab, (C) Radical Cystectomy, or (D) Other.

Expert consensus in this discussion was that radical cystectomy is the best option for long-term disease control.

The patient is not interested in radical cystectomy or intravenous pembrolizumab due to travel requirements. She is willing to receive intravesical chemotherapy with gemcitabine and docetaxel. After intravesical chemotherapy, surveillance cystoscopy performed 6 months later reveals invasive disease obscuring the bilateral ureteral orifices, resulting in kidney injury. CT imaging reveals bilateral hydronephrosis but no significant lymphadenopathy. Bilateral percutaneous nephrostomy tubes are recommended, and the patient wants to start treatment as soon as possible. Her ECOG PS is 1 and she has no other major comorbidities. What options do you consider? (A) Radical cystectomy, (B) Split-dose cisplatin-combination chemotherapy followed by cystectomy, (C) carboplatin-combination chemotherapy followed by cystectomy, (D) pembrolizumab followed by cystectomy, (E) Bladder preservation with cisplatin-based chemoradiation, (F) Bladder preservation with 5FU based chemoradiation.

Dr. Vapiwala discussed that weighing patient wishes and goals of care in each context is really important, especially because there is an interest in bladder preservation trimodality therapy. This refers to maximal transurethral resection of bladder tumor followed by radiation and concurrent radiosensitizing chemotherapy. This has historically been chosen for patients who are deemed unfit for radical cystectomy or who refuse. Many clinical trials exclude patients with specific conditions that are typically related to poor prognosis (tumor greater than 6 cm, hydronephrosis, etc) and so these would need to be incorporated into the counseling of every patient’s specific context. The importance of multi-disciplinary discussion cannot be overstated. We also have more promising initial trial data that other chemotherapies other than cisplatin can be used for concurrent chemoradiation along with more sophisticated radiotherapy techniques. For this patient, I would want to know how her kidney function trends, and what her motivations with treatment are, and whether she might be interested in bladder preservation understanding that salvage cystectomy may be possible down the line. This would involve chemoradiation and then seeing if there is a good response, and if not, proceeding with radical cystectomy.

With bilateral nephrostomy tubes, the creatinine clearance improves to 61 ml/min and becomes cisplatin eligible. She prefers surgery but would be willing to receive neoadjuvant chemotherapy is recommended. The patient undergoes neoadjuvant dd MVAC and then radical cystectomy with an ileal conduit. Pathology reveals ypT2N0 disease. What course of action would you recommend next? (A) Adjuvant carboplatin with gemcitabine, (B) Adjuvant taxane-combination chemotherapy regimen, (C) Adjuvant checkpoint inhibitor, (D) Observation

The largest data set regarding adjuvant radiation therapy is a National Cancer Database study published in 2018. This study suggested while there was no overall survival benefit with adjuvant radiation in all patients, patients with positive surgical margins did have an overall survival benefit. One risk stratification criteria for trying to avoid locoregional recurrence is the Penn risk stratification method, which incorporates pathological T stage, margin status, and the number of lymph nodes identified during surgery. With regards to margin status, the location of the positive margin appeared to be important, with the highest risk of locoregional recurrence associated with a positive margin at the external/internal iliac region. While there are definitely toxicity concerns, intensity-modulated radiotherapy with image guidance can drastically reduce the risk to adjacent organs such as the bowel. For this patient, if a margin was positive, I would discuss the implication of the margin location, assess her overall function, and see how she felt about it as well.

The patient undergoes observation. Six months later, surveillance CT imaging reveals the following image. Creatinine clearance is now 48 ml/min and ECOG performance status is 1. Would you perform PD-L1 IHC on archival tissue to aid in treatment decision-making?

Much of the intervening discussion focused on medical oncology options for systemic therapy.

The patient responds to enfortumab vedotin for 9 months before developing increasing back pain. ECOG PS is now 3. After obtaining a spine MRI, what will be your next course of action? (A) Hospice, (B) Radiation therapy, (C) Surgical decompression, (D) Palliative chemotherapy and bisphosphonates.

Emerging data suggest that SBRT is superior for providing pain relief compared to conventional therapy and may improve clinical outcomes beyond pain control. Dr. Vapiwala would favor aggressive palliation with pain medication as well as SBRT to the lesion causing pain.

The session ended with key take-home points, which are shown below.

Presented by: Neha Vapiwala, MD, Radiation Oncologist at the University of Pennsylvania, Philadelphia, PA

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Optimizing Urothelial Cancer Management From Organ-Confined to Metastatic Disease: A Multidisciplinary Approach – Medical Oncologist Perspective

Dr. Hahn discussed that this would be termed BCG-unresponsive non-muscle-invasive bladder cancer. The term BCG-unresponsive, which has evolved over time through workshops and FDA consultations, is defined as recurrence of carcinoma in situ within 12 months of adequate BCG, or in a patient without CIS, if they had high-grade papillary disease recurrence within six months of adequate BCG. Adequate BCG is defined by the 5+2 rule, meaning they needed to have received at least 5 of the 6 planned induction treatments, then at least 2 of 3 maintenance therapies. We do not typically recommend additional BCG treatments for BCG-unresponsive patients.

The first question posed was “What treatment option would you proceed with?”. (A) Intravesical chemotherapy, (B) Intravenous pembrolizumab, (C) Radical Cystectomy, or (D) Other.

Dr. Hahn discussed some of the data behind intravenous pembrolizumab if the patient is not interested in cystectomy. This is an FDA-approved therapy for BCG-unresponsive patients with a component of CIS. Though this particular patient would have been eligible for KEYNOTE-57, which established this treatment as standard of care, it is important to note that in that trial the majority of patients were flat CIS alone, and only 1/3 had an associated high-grade papillary component. Based on data with advanced disease, where 15-20% of patients have disease durable control, we expect some patients to get long-term disease control in the non-muscle invasive patient as well. There are no clear biomarkers such as PD-L1 status that help identify patients more likely to respond. It is important to understand more deeply how the patient thinks about cystectomy because for pT1 disease it is the therapy that gives them the best chance for long-term durable disease control.

The patient is not interested in radical cystectomy or intravenous pembrolizumab due to travel requirements. She is willing to receive intravesical chemotherapy with gemcitabine and docetaxel. After intravesical chemotherapy, surveillance cystoscopy performed 6 months later reveals invasive disease obscuring the bilateral ureteral orifices, resulting in kidney injury. CT imaging reveals bilateral hydronephrosis but no significant lymphadenopathy.

From a medical oncology perspective, relieving ureteral obstruction with bilateral nephrostomy tubes helps us understand quickly if the patient can recover enough renal function to receive cisplatin-based chemotherapy. Second, it helps avoid start/stops with cisplatin, because if the renal function is worsening on the therapy you don’t have to consider ureteral obstruction as a potential reason. However, we must also be sympathetic to the quality-of-life decrease associated with these external drains and managing them. I try to emphasize especially in the pre-operative setting, that the goal is to facilitate the best chance of cure and hopefully the tubes will be only in for 2-3 months.

Bilateral percutaneous nephrostomy tubes are recommended, and the patient wants to start treatment as soon as possible. Her ECOG PS is 1 and she has no other major comorbidities. What options do you consider? (A) Radical cystectomy, (B) Split-dose cisplatin-combination chemotherapy followed by cystectomy, (C) carboplatin-combination chemotherapy followed by cystectomy, (D) pembrolizumab followed by cystectomy, (E) Bladder preservation with cisplatin-based chemoradiation, (F) Bladder preservation with 5FU based chemoradiation.

Based on the patient’s kidney injury, she would be likely ineligible for cisplatin, and at 38 mL/min, split dose chemotherapy is also concerning. We now have published data from Matt Galsky in JCO that set some uniform definitions of cisplatin eligibility, including performance status (0 or 1) and creatinine clearance of around 60. Other factors are also important such as baseline neuropathy, ototoxicity, or heart failure. However, in a patient that could receive curative therapy, many practitioners would lower the creatinine clearance threshold for cisplatin eligibility. Many people are comfortable going down to 50 if using split-dose cisplatin regimens, and this can be pushed a little further if nephrostomy tubes are in place and we can do adequate hydration, but 38 is a bit too low. Carboplatin can certainly be given, but I am not as comfortable with this in a patient who is cystectomy eligible. The role of immunotherapy is interesting given data from PURE-01 (pembrolizumab single agent) and ABACUS (single-agent atezolizumab). Even with brief exposure of three cycles relative to three months with chemotherapy, there is a complete response rate of 20-30%, but this still lives really in the clinical trial realm given that we do not know the long-term implications of complete response to immunotherapy. Multiple trials are ongoing, such as KEYNOTE-905 looking at pembrolizumab versus enfortumab vedotin (anti-nectin4 antibody-drug conjugate) versus cystectomy in cisplatin-ineligible patients.

With bilateral nephrostomy tubes, the creatinine clearance improves to 61 ml/min and becomes cisplatin eligible. She prefers surgery but would be willing to receive neoadjuvant chemotherapy if recommended. Do you agree or disagree?

Dr. Hahn agreed with neoadjuvant chemotherapy, and as a general statement does not have a clear preference between regimens. Both dose-dense MVAC and cisplatin/gemcitabine are accepted regimens, and in retrospective studies, there was no difference in pathologic complete responses or overall survival. Furthermore, in SWOG-1314 (COXEN), there was no difference in pathologic complete response in a randomized phase 2 trial between these two regimens, with an approximate 30% complete response rate.

The patient undergoes neoadjuvant dd MVAC and then radical cystectomy with an ileal conduit. Pathology reveals ypT2N0 disease. What course of action would you recommend next? (A) Adjuvant carboplatin with gemcitabine, (B) Adjuvant taxane-combination chemotherapy regimen, (C) Adjuvant checkpoint inhibitor, (D) Observation

Current guidelines recommend observation as there are no prospective data proving an advantage for any adjuvant chemotherapy, just retrospective and potentially flawed data. There have been two trials that have read out in this context. The IMvigor010 study of 800 patients looking at the impact of adjuvant atezolizumab in high-risk patients. No disease-free survival benefit was seen with the atezo treated group, and there was no clear subgroup that benefitted from therapy. CheckMate-274 looking at a similar population of over 700 patients showed a significant disease-free survival advantage for adjuvant nivolumab (21 months with nivolumab versus 10.9 months with placebo), but no overall survival data is available yet. Finally, we have the AMBASSADOR trial of adjuvant pembrolizumab that has not read out yet. As of today, I am not offering adjuvant checkpoint inhibitor therapy, but based on regulatory agency approvals and further clinical trial data, this may change.

The patient undergoes observation. Six months later, surveillance CT imaging reveals the following image. Creatinine clearance is now 48 ml/min and ECOG performance status is 1. Would you perform PD-L1 IHC on archival tissue to aid in treatment decision-making?

For a patient with visceral liver metastases, I am not reaching towards immunotherapy first, and so PD-L1 IHC would not impact my treatment choice. If the patient is frail and not enthusiastic about carboplatin-based chemotherapy, then PD-L1 testing is useful especially if the label indication for immunotherapy requires it. At this point, given the quick relapse, this could be considered second-line therapy. While the responses to immunotherapy are not as good in liver metastases, patients with low-volume liver disease burden will have a chance of durable long-term disease control with immunotherapy.

PD-L1 testing is performed with the 22C3 antibody, and the CPS score returns at < 1. What course of action would you take next? (A) Gemcitabine with cisplatin, (B) Gemcitabine with carboplatin, (C) pembrolizumab, (D) gemcitabine with carboplatin plus atezolizumab

This is a tough question because the patient has relapse so soon after cisplatin-based chemotherapy, so would still be considering pembrolizumab therapy given the chance of durable response. Patients with a CPS score of less than 1 do have responses to immunotherapy. This is not a thrilling choice, but Dr. Hahn would favor pembrolizumab here.

Agree or Disagree: If the patient relapsed after 15 months instead of 6 months after neoadjuvant chemotherapy, that would change my systemic treatment selection.

Dr. Hahn would think more favorably about giving chemotherapy in this context, especially with the CPS score of less than 1. The chance of durable response in this patient is not high, but the presence of liver metastases is concerning for impending rapid expansion of systemic disease and so chemotherapy gives a better shot at a response. Dr. Hahn does not think it would be wrong to give immunotherapy given the chance of durability. Given that it is 12 months post neoadjuvant chemotherapy, there is an FDA label for immunotherapy if PD-L1 expression is high. However, he would favor chemotherapy more.

Agree or Disagree: I would obtain next-generation sequencing of the tumor at this time

Yes, given that an FDA-approved therapy for certain FGFR alteration-positive urothelial cancers, Dr. Hahn would sequence the tumor.

Foundation Medicine sequencing reveals a microsatellite stable tumor without hypermutation. There is no FGFR alteration or other actionable genomic alteration. The patient has a response to pembrolizumab for one year before liver metastases begin to grow and new lung and bone metastases are found on restaging imaging. What therapy would you proceed with next? (A) Taxane chemotherapy, (B) enfortumab vedotin, (C) Erdafitinib, (D) Sacituzumab govitecan

Dr. Hahn would favor enfortumab vedotin for two reasons: (1) presence of liver metastases where other therapies like taxanes have response rates of 10% but enfortumab has response rates in the 30-40% range, and (2) enfortumab has an overall survival advantage demonstrated compared to additional non-platinum-based chemotherapy in the randomized phase 3 trials. Because there is no proven overall survival advantage yet with Sacituzumab, though a promising strategy, he would go with enfortumab first.

The patient responds to enfortumab vedotin for 9 months before developing increasing back pain. ECOG PS is now 3. After obtaining a spine MRI, what will be your next course of action? (A) Hospice, (B) Radiation therapy, (C) Surgical decompression, (D) Palliative chemotherapy and bisphosphonates

The session ended with key take-home points, which are shown below.

Presented by: Noah M. Hahn, MD, Medical Oncologist at the Johns Hopkins University School of Medicine, Baltimore, MD

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Clinical Activity of Durvalumab and Savolitinib in Met-Driven, Metastatic Papillary Renal Cancer

(UroToday.com) While there have been transformational changes in first-line therapy for patients with advanced renal cell carcinoma (RCC) in the past three years, these studies have focused on patients with clear cell histology. As a result, there have been little direct data to guide care for patients with non-clear cell histologies and we have had to rely primarily on extrapolation from data derived among patients with clear cell disease.

ASCO 2021: Randomized Phase Ib Study To Evaluate Safety, Pharmacokinetics and Therapeutic Activity of Simlukafusp α in Combination With Atezolizumab ± Bevacizumab in Patients With Unresectable Advanced/ Metastatic Renal Cell Carcinoma (Rcc) (NCT03063762)

(UroToday.com) There have been transformational changes in systemic treatment for patients with advanced renal cell carcinoma (RCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches.

ASCO 2021: Making Strides in the Treatment of Non-Clear Cell Carcinoma: Are We Ready for Adaptive and Biomarker-Driven Strategies?

(UroToday.com) Following three presentations regarding novel treatment approaches for patients with advanced non-clear cell renal cell carcinoma (nccRCC) in the Kidney and Bladder Poster Discussion session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Deepak Kilari provided a discussant overview of these data and the rapidly moving disease space of non-clear cell renal cell carcinoma.

ASCO 2021: Pembrolizumab (Pembro) plus Axitinib (Axi) Versus Sunitinib as First-Line Therapy for Advanced Clear Cell Renal Cell Carcinoma (ccRCC): Results from 42-Month Follow-up of KEYNOTE-426

(UroToday.com) In this presentation, Dr. Brian Rini presented 42-month follow-up data from the KEYNOTE-426 trial of pembrolizumab in combination with axitinib as first-line therapy for clear cell renal cell carcinoma (ccRCC). The first interim analysis of this combination, published in 2019¹ showed a statistically significant improvement in overall survival and progression-free survival relative to sunitinib. Subsequent follow-up at a median of 30.6 months confirmed these findings. For this presentation, Dr. Rini presented data from a median follow-up of 42.8 months, with a minimum follow-up of 35.6 months.

ASCO 2021: Complementary Detection of Genomic Alterations in Metastatic Castration Resistant Prostate Cancer From CheckMate 9KD Through Analyses of Tumor Tissue and Plasma DNA

(UroToday.com) There has been a proliferation in treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) in the last 10 years. While there are many available treatment options, to date, we have been unable to widely operationalize rationale treatment selection in this disease space.

ASCO 2021: Real-World Outcomes in Patients with Metastatic Clear Cell Renal Cell Carcinoma Receiving Front-Line Axitinib plus Pembrolizumab Versus Ipilimumab plus Nivolumab

(UroToday.com) There have been transformational changes in first-line therapy for patients with metastatic renal cell carcinoma (mRCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches. While CheckMate 214 first brought combination therapy with dual checkpoint inhibition (nivolumab and ipilimumab) to the forefront, subsequent studies have examined combinations of immune checkpoint inhibitors and tyrosine-kinase inhibitors in the first-line setting including pembrolizumab and axitinib. In the Kidney and Bladder Poster session at the 2021 American Society of Clinical Oncology Annual Meeting, Dr. Kevin Zarrabi presented real-world outcomes in patients treated with either axitinib and pembrolizumab or ipilimumab and nivolumab, stratified according to International Metastatic RCC Database Consortium (IMDC) score.

ASCO 2021: Vorolanib, Everolimus, and the Combination in Patients with Pretreated Metastatic Renal Cell Carcinoma (CONCEPT Study): A Randomized, Phase 3, Double-Blind, Multicenter Trial

(UroToday.com) There have been transformational changes in first-line therapy for patients with advanced renal cell carcinoma (RCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches. While CheckMate 214 first brought combination therapy with dual checkpoint inhibition to the forefront, subsequent studies have examined combinations of immune checkpoint inhibitors in the first-line setting. In the Kidney and Bladder Poster Discussion session at the 2021 American Society of Clinical Oncology Annual Meeting, Dr. Xinan Sheng presented results from the phase III CONCEPT randomized controlled trial of vorolanib, everolimus, and the combination in patients with pretreated metastatic renal cell carcinoma.

ASCO 2021: An Open-Label, Pharmacokinetic Study to Determine the Bioavailability, Safety and Tolerability of Single Dose Oral Docetaxel in Metastatic Prostate Cancer Patients Treated with IV Docetaxel

(UroToday.com) Following androgen deprivation therapy (ADT) which was introduced decades prior, the TAX-327 trial of docetaxel for patients with metastatic castration-resistant prostate cancer was the first to demonstrate a survival advantage for systemic treatment in prostate cancer. Since then, docetaxel has proven survival benefit for men with metastatic castration-sensitive disease. However, docetaxel requires the non-ionic surfactant polysorbate 80 which is associated with hypersensitivity to allow for IV solubility, necessitating steroid pre-medication. While oral treatment may improve tolerability and improve convenience, docetaxel has poor oral bioavailability due to extrusion by intestinal p-glycoprotein. In the Prostate, Testicular, Penile Poster session at the 2021 American Society of Clinical Oncology Annual Meeting, Dr. Christopher Jackson presented an assessment of Oradoxel, a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). This agent has already been used in combination with oral paclitaxel.

ASCO 2021: Differences in Toxicity and Outcomes: A Race-based Case Study

(UroToday.com) As part of the 2021 American Society of Clinical Oncology Annual Meeting, a session entitled “Minority Enrollment in Cancer Clinical Trials”. Within this session, Dr. Daniel George presented on Differences in Toxicity and Outcomes utilizing a Race-based Case Study.

ASCO 2021: CANTATA: Primary Analysis of a Global, Randomized, Placebo-Controlled, Double-Blind Trial of Telaglenastat (CB-839) + Cabozantinib Versus Placebo + Cabozantinib in Advanced/Metastatic Renal Cell Carcinoma Patients on Immune Checkpoint Inhibitor

(UroToday.com) In this presentation, Dr. Tannir presented data of a randomized placebo-controlled trial of cabozantinib without the glutaminase inhibitor telaglenastat in patients with advanced renal cell carcinoma (RCC) who have previously progressed on immune checkpoint blockade or anti-angiogenic therapies.

The potential benefit of glutaminase inhibitors in cancer is predicated on data suggesting that tumor cells have an increased dependence on glutamine due to their altered glucose metabolism via the Warburg effect. The conversion of glutamine to glutamate via the enzyme glutaminase thus serves to fuel cancer cell proliferation and survival. Blocking glutaminase with small molecule inhibitors such as telaglenastat has been shown to deprive cancer cells of glutamine as a fuel source, inhibiting their growth. RCCs are highly metabolic tumors that express high levels of glutaminase. Preclinical data demonstrated synergy in RCC models with the addition of telaglenastat to cabozantinib. Clinically, the phase 2 ENTRATA study of telaglenastat in combination with everolimus showed a tolerable safety profile and a longer median progression-free survival of 3.8 months relative to 1.9 months on everolimus alone. A phase 1 dose-expansion study of telaglenastat with cabozantinib in heavily pretreated RCC showed a 50% overall response rate and a 100% disease control rate.

These data together prompted the randomized CANTATA trial, the schema of which is shown below. A total of 444 patients, stratified by prior immune checkpoint blockade and IMDC risk stratification were randomized in a 1:1 fashion to the treatment arms shown below. The primary endpoint was progression-free survival as assessed by an independent review committee.

The study was designed to have 85% power to detect a hazard ratio for the primary outcome of 0.69 for combination therapy versus cabozantinib alone, with a 2-sided alpha of 0.05. The primary analysis data cut-off date was August 31, 2020.

As shown below, patient characteristics were balanced between arms.

Unfortunately, the primary endpoint of this study was not met, with similar median progression-free survival between the two treatment arms of approximately 9.2 months. There were no clear differences between response rates as well.

Subgroup analysis was suggestive of a numerical trend towards an improved outcome in patients with IMDC-poor-risk disease, as well as in patients who received prior immune checkpoint blockade.

A majority of patients in both treatment arms had received prior immune checkpoint blockade (62%). The median PFS of patients who had received prior ICI was 11.1 months in the telaglenastat/cabozantinib arm, and 9.2 months in the cabozantinib alone arm.

ASCO2021_CANTATA_PFSsubgroups_of_patients_withprior_ICI.png

ASCO2021_CANTATA_PFSsubgroups_of_patients_withprior_ICI.png

Overall survival data is not currently mature.

Treatment-related adverse events are shown below and are notable for similar rates in all presented events including diarrhea and hypertension between the two arms.

Dr. Tannir concluded that telaglenastat did not improve the median progression-free survival of metastatic RCC patients treated with cabozantinib in this study. Telaglenastat was well tolerated. Future work may focus on patients who previously received immune checkpoint blockade or tumor contexts that are especially dependent on glutaminase, though the mechanism whereby immunotherapy-treated patients would uniquely benefit from glutaminase inhibition is unclear.

Presented by: Nizar Tannir, MD, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Genomic Disparities Across Gleason Scores

(UroToday.com) As part of the 2021 American Society of Clinical Oncology Annual Meeting, a session entitled “Evolution of Disparities in Prostate Cancer Treatment: Is This a New Normal?”. Within this session, Dr. Brandon Mahal discussed genomic disparities in prostate cancer.

ASCO 2021: Safety and Efficacy of AMG 160, a Half-Life Extended BiTE Immune Therapy Targeting PSMA, and Other Therapies for Metastatic Castration-Resistant Prostate Cancer

(UroToday.com) There has been a proliferation in treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) in the last 10 years. While the most commonly utilized approaches in prostate cancer are cytotoxic chemotherapy or target the androgen-axis (including abiraterone acetate and enzalutamide), there is an ongoing interest to explore and develop a novel therapeutic approach that may have more durable responses.

ASCO 2021: Expanding VEGF Blockade Combination Therapeutic Options in Advanced Renal Cell Carcinoma

(UroToday.com) In this session, Dr. Andrea Apolo reviewed the rationale behind combination therapies for management in advanced renal cell carcinoma (RCC). Over the past 15 years, treatment for advanced RCC has focused on anti-VEGF molecules based on knowledge of the complex signaling interplay between VHL, hypoxia-inducible factors, and VEGF. More recently, it has become clear that tyrosine kinase inhibitors (TKI) used to target VEGF signaling can also modulate tumor immunity, leading to several phase 3 clinical trials proving the efficacy of combined TKI and immunotherapy for first-line therapy in advanced disease.

ASCO 2021

ASCO 2021

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