Legislation Needed to Overcome Chemo Shortage; Expert Discusses Impact in GU

Kirollos Hanna, PharmD, BCPS, BCOP, FCCC

Mayo Clinic College of Medicine and Science

Although the ongoing cisplatin shortage hasn’t largely impacted the genitourinary cancer space,¹ bladder cancer has proven to be an area of ‘critical need,’ especially for those with muscle-invasive bladder cancer where the agents are used with curative intent, according to Kirollos Hanna, PharmD, BCPS, BCOP, FCCC.

In an interview with CancerNetwork^®, Hanna, director of pharmacy at Minnesota Oncology and assistant professor of pharmacy at the Mayo Clinic College of Medicine and Science, emphasized that there are few alternative treatment options for the population. However, he explained that several strategies may help to lessen the impact of the shortage in the bladder cancer space, including reducing doses where appropriate to preserve cisplatin, as well importing platinum-based chemotherapy agents from China through the help of the FDA.² Although it is early, Hanna discussed the differences these strategies have made.

“We have already seen with this importation of supply that our allocations from our wholesale distributor have increased,” Hanna said. “They haven’t increased to a comfortable level where we’re just opening prescribing backup. During the most intense parts of the shortage around cisplatin, we were conserving utility in 2 patient populations: curative intent for bladder cancer and curative intent for testicular cancer because of the limited opportunity. Now, with what we’ve been able to get in, we have further expanded additional indications like head and neck cancers and some cervical cancers where you still have curative intent with cisplatin and limited opportunities outside of that.”

Can you discuss the impact of the chemotherapy shortage in the bladder cancer space?

When you’re talking about bladder cancer, specifically in terms of GU [genitourinary] cancers, [drugs] like cisplatin and carboplatin play a critical role at different stages for these patients. When you talk about something like kidney cancer, platinum agents, and some of the drugs we’ve seen shortages [for] haven’t played a significant role in the GU space, but bladder [cancer] has certainly been our number 1 [space in need]. Most critically and recently have been these platinum agents that have been in shortage.

To understand bladder cancer, there are 3 key stages of the disease. There are patients who have non-muscle invasive disease where we try to resect the tumors. Once these patients move into the muscle-invasive space, something like a cisplatin-containing regimen is the gold standard. It’s recommended across guidelines, and across most of the literature in the data that we are still trying to cure patients with muscle-invasive disease. Moving away from cisplatin-containing regimens is a significant disservice to these patients, as carboplatin has inferior data.

Oftentimes, for these patients with muscle-invasive disease, we have 2 modalities that we can treat them with: there’s dose-dense MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin], and then there’s gemcitabine with cisplatin. You’ll find many GU experts tried to push the envelope with dose-dense MVAC. It’s a more intensive regimen but does lead to better surgical outcomes. We generally administer neoadjuvant treatment for these patients and take them to surgery. Oftentimes, a good portion of these patients do well; I would say 70% to 75% of these patients are considered cured of their disease.

When you talk about metastatic disease, even though we can get away from cisplatin in the metastatic setting, carboplatin has still played a significant role for these patients with metastatic disease. We’re still utilizing similar regimens, but we can substitute carboplatin. What we’re finding in the oncology space is that the shortage of cisplatin has now led to a shortage of carboplatin due to some therapeutic interchanges across many tumor types, which has even trickled into the GU space.

For our system, when we were going through phases—we’re still going through the shortage phase—[and] were in critical supply, we had patients with bladder cancer as one of the diagnoses where we were conserving cisplatin just because of the importance of curing [the disease]. Those were some of the strategies that we've been utilizing.

[Regarding] therapeutic alternative, if you look at [patients with] muscle invasive [disease], there aren't really many alternatives that you're going to provide this population that have as good of data around outside of platinum agents, especially cisplatin containing regimens. In the metastatic setting, though, bladder cancer has really had a lot of exciting updates. Even if you do have to move away from maybe a carboplatin, or a cisplatin based regimen in the frontline setting, a study just recently reported out, EV-103, looking at the combination of pembrolizumab with enfortumab vedotin, which is an antibody-drug conjugate with really exciting outcomes for this patient population.

Now, the intent of the cohort that reported out was in patients who were platinum ineligible but regardless of that, we still saw some really great responses. And again, this was an early study with early data, but within the metastatic setting among immunotherapy, among antibody-drug conjugates, as well as a targeted therapeutic. We have a few more options, but it's really a curative intent patient where it's very hard for us right now.

How can the importation of cisplatin from China help to alleviate the shortage in the United States?

It’s exciting to see the FDA thinking of unique strategies to bring in drug supply to alleviate some of the things we’re seeing here in the United States. It makes you think, ‘Why haven’t we been doing this over time to try to improve supply chain in any type of drug shortages? How long have drug shortages been impacting us here in the United States?’ This is an exciting opportunity for patients.

The FDA has also partnered with Apotek Pharmaceuticals. They are one of the biotech companies here in the United States that is responsible for the distribution of this inventory. They’re working with our wholesale distributors like McKesson and Cardinal to get this [product] out. For patients, I think that this is an exciting opportunity where this has helped alleviate the shortage to some extent, as well as some small supply that has also been released by many of our generic manufacturers here in the United States. I don’t think in terms of manufacturing and quality assurance that there are any major concerns greater than the state of the shortage. Although [the treatments are] coming and not vetted through the normal channels we have here in the United States with our manufacturing, certainly the shortage in terms of patient impact is much greater. I am happy that we're able to bring this in.

The drug is the same concentration; what we have in the United States is a 50 mg vial. There will be a temporary NDC [national drug code] number generated for this product as well to help in terms of billing and processing insurance claims.

How has your institution responded to the shortage?

Early in March, when we started to hear about the shortage of cisplatin, you oftentimes have to think of what’s going to happen next, or what are the implications that are going to come of this. We put ourselves [at Minnesota Oncology] in a comfortable situation around carboplatin at that time. We kept what we call in the pharmacy world par levels or minimum levels; we kept them at a much higher level than what we would generally be accustomed to on a day-in/day-out basis. We then started to implement strategies to help utilize a little bit less of the drug where it didn’t clinically impact our patients. This was both for carboplatin and cisplatin. Strategies like dose rounding [were utilized]. If we can dose round down to a vial size or a billing unit, we did that. We informed providers if there's a clinically appropriate situation where instead of giving a patient a 21-day cycle to go to a 28-day cycle, to do that, around carboplatin.

In many situations, it’s very hard for a patient to tolerate an AUC of 6, so we as providers, instead of an AUC of 6 went down to an AUC of 5. We implemented all these strategies to try to alleviate and conserve some supply. We also have clinical pharmacists who evaluate all our new start regimens. One of the initiatives that we also implemented with our clinical pharmacists is that if there was a therapeutic alternative that was deemed to be as clinically equivalent where it’s not taking away from the impact for that patient. Our clinical pharmacists worked with our providers to determine if a patient is on a cisplatin-containing regimen or carboplatin-containing regimen, [and asked for their] opinion on the potential opportunity to conserve what we have. We’ve been doing well and we’re still sitting on a very good supply of carboplatin.

Our planning strategies and efforts have really put us in a good spot for our patients.

Moving forward, what can be potential solutions for avoiding a shortage of this magnitude in the future?

This cisplatin shortage stemmed from [a quality control issue with] a manufacturer, one of the largest manufacturers that make about 70% to 80% of the cisplatin in the country. The FDA had to shut down that plant, and they're working with them. All of a sudden, other generic manufacturers that were generally responsible for making about 20% of allocations for the country, the ask is much higher, but they can’t produce accordingly. We have seen numerous things that have led to shortages, sometimes pandemic related, sometimes pre-pandemic. We’ve been dealing with shortages for years now.

What I find interesting is if you look at a Keytruda [pembrolizumab], if you look at an Opdivo [nivolumab], or Darzalex [daratumumab], if you look at these branded therapeutics, these monoclonal antibodies where so much money is invested from these larger pharmaceutical companies, we will never find a shortage of these drugs. We have never seen a shortage of these drugs. Why is it that these critical therapeutics that in many areas are tied to curative intent regimens [have shortages]? Why do we not invest in those plants or organizations [that produce generic drugs] to alleviate the situation from ever happening.

Why don’t we partner with different manufacturers outside of the United States, similar to what we did with China ,to alleviate the cisplatin shortage to alleviate what’s going on? Why do we wait until it gets so critical? For something of this magnitude, for there to be a true resolution, there needs to be something that comes down from legislation that is national and governs all. I'm working with the FDA wand the government to really invest and fund some type of manufacturers and plants to address all of this.

Sometimes because of the cheap cost of generic therapeutics, a lot of time, money, and effort aren’t invested in that because your ROI [return on investment], isn’t there, as you see with your big branded products. That’s what I think needs to happen at a national level for this situation to resolve. As practices and healthcare providers, the number of times we’ve seen this should have people think a little bit differently about shortages.

References

1. FDA. FDA drug shortages. Accessed Jun 28, 2023. https://bit.ly/44rjKBn
2. Temporary importation of cisplatin injection with non-U.S. labeling to address drug shortage. News release. Qilu Pharmaceutical. May 24, 2023. Accessed August 8, 2023. https://bit.ly/431J7Zh American Society of Clinical Oncology. Clinical Guidance. Accessed August 8, 2023. https://bit.ly/3pzph9Y