Sara Karlovitch

Standard treatment for muscle-invasive bladder cancer (MIBC) involves trimodal therapy with maximal TURBT followed by chemoradiation. In a recent interview with 

, Parminder Singh, MD, discussed efforts to build on this standard with the addition of immunotherapy.

Singh, a medical oncologist at the Mayo Clinic, specifically highlights the phase 3 INTACT trial (NCT03775265), which is comparing the safety and efficacy of standard chemoradiation alone versus chemoradiation plus atezolizumab in patients who received TURBT.

What kind of safety have we seen with trimodality therapy in MIBC in the past?

 With concurrent chemoradiation, the primary toxicity, or concerns have always been radiation and chemotherapy-induced diarrhea, gastrointestinal (GI) toxicity, and also toxicity of the bladder itself causing cystitis. Close to 25% will have severe GI toxicity during the treatment, which is considered acceptable. When we were planning this trial, we anticipated that the toxicity may be higher. We had a built-in safety check after we had enrolled 80 patients and this abstract talks about those toxicities.

Can you give rationale for the addition of atezolizumab to the standard of care?

When patients are receiving chemoradiation, some of the toxicity also depends on the type of chemotherapy regimen being used by the oncologist for combining the radiation. Each physician has their own choice of regimen and some physicians use cisplatin as the accommodation agent. Others use gemcitabine and some of them will use mitomycin with 5-FU.

Each of the drugs has their own specific toxicities. For example, cisplatin can cause nephrotoxicity or may cause nausea more than the other agents. Gemcitabine combined with radiation has been known to cause more cytopenia, and mitomycin with 5-FU can cause more GI toxicity since diarrhea is a common adverse event of 5-FU. So, the oncologists using this modality of treatment for their patients with bladder cancer are used to handling these toxicities which come with the chemotherapy. The bladder toxicity which is the inflammation of the bladder caused by radiation is something that will be seen across all chemotherapy regimens and is managed with pain medication or by improving hydration. Some patients may even have so much frequency that we may have to offer them catheterization so that it will alleviate the need of getting up in the night to go to the bathroom. But these are more decisions taken at the clinic based on the experience of the patient. Some patients may also have hematuria, and it may require cystoscopy, or cloud evacuation during radiation. But more or less, most of the patients will tolerate this regimen and finish the treatment without any severe toxicities, and their bladder function will recover.

There are certain long-term toxicities that community oncologists need to be aware of, that the patients may notice a decrease in function of the bladder, the capacity of the bladder may go down post-radiation, so a proper selection of the patient for this type of intervention may help reduce the risk for long-term complications. In my practice, I've seen some patients having long-term radiation cystitis that causes disabling symptoms, but this is very uncommon. However, it's possible that since I see more patients with this modality that I've seen those AEs. In general, most of the patients do okay and require a 3-month follow-up visit with their urologist to make sure there's no recurrence of the disease.

What was the rationale for adding atezolizumab to trimodality therapy for this safety run-in analysis?

Close to half the patients will eventually recur with MIBC, despite adequate treatment effort. There's a need to improve bladder preservation strategies, so that we can give an option to our patients, that they can get rid of their cancer without losing their bladder. With that intention, we decided on what could lead to an incremental benefit in controlling this disease without adding significant toxicity, and in that time span, immunotherapy was approved for bladder cancer. There were data emerging from other tumor types that adding immunotherapy to chemotherapy or radiation seems to automate the activity of radiation or chemotherapy, especially in lung cancer. So, we decided to investigate this strategy in bladder cancer in order to improve upon the EFS, which is the ability of a patient to keep their bladder intact.

This trial was designed as a randomized study. In one arm, patients receive atezolizumab combined with concurrent chemoradiation added to standard of care versus concurrent chemoradiation, which is the standard of care for MIBC. And the safety run-in was built into this trial because this trial was designed without a proceeding phase 1 or phase 2 safety clinical trial. It was designed as a phase 3 trial to begin with. There was conversation between the FDA and the National Cancer Institute, and the investigators, that we still have to make sure that this combination is safe for our patients. So, we built in a safety check-in at the time point of enrollment at 80 patients that we are going to look back into the data and see if we are noticing any excessive toxicity, attributed to the addition of atezolizumab to the combination. Then, we'll present that data for review. If it is decided that the data are significant then the trial will be stopped. If the safety or toxicity evaluation suggests that there is no excessive toxicity, the trial will continue to enroll.

We presented the safety data which we had accumulated of 73 patients, 36 patients had received concurrent chemoradiation, and 37 patients had received immunotherapy combined with concurrent chemoradiation. We were happy to report that there were no grade 3 GI toxicities or colitis that was reported with the immunotherapy, which was one of our biggest concerns.

Seven patients had severe urinary tract infection (UTI), or grade 3 UTI in the immunotherapy arm with no patients having UTI in the standard therapy arm. One patient had grade 3 radiation cystitis, which was diagnosed after finishing 6 months of atezolizumab. The patient did not receive any steroids, suggesting that this was an outcome of radiation to the bladder, which we see rarely in our patients and is not related to immunotherapy. Overall, 23 patients had grade 3 or higher toxicity in the investigational arm versus 11 patients in the non-immunotherapy arm. The most common toxicity was cytopenias including anemia, lymphopenia, or decreased white blood cell count. Now, we have to keep in mind that the patient population is predominantly a senior population, with the median age in the range of 70 to 80 years old. These patients’ bone marrow gets affected with radiation going to the pelvis, causing more cyclopedia. We'll find out more as we enroll more patients if these differences are statistically significant and clinically meaningful. However, we did not see extra toxicity with the addition of immunotherapy. So, in conclusion, what we said was that atezolizumab and concurrent chemoradiation did not show any excessive GI toxicity and the clinical trial continues to enroll.

1. Singh P, Efstathiou J, Tangen C, et al. INTACT (S/N1806) phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle-invasive bladder cancer: Safety update on first 73 patients. 

. 39; (6): 428-428. doi: 10.1200/JCO.2021.39.6

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Singh highlights the phase 3 INTACT trial, which is comparing the safety and efficacy of standard chemoradiation alone versus chemoradiation plus atezolizumab in patients who received TURBT.

Sara Karlovitch

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