Summarizaiton Article Test 11

Although the severity of the shortage of chemotherapy agents, particularly with the platinum-based therapies cisplatin and carboplatin, has receded from the heights seen earlier in 2023, clinicians are still dealing with its ramifications and having to strategically manage how they employ certain chemotherapies, according to Alan Tan, MD.

“Currently, I would say that we are OK,” Tan, director of genitourinary medical oncology and an assistant professor in the Department of Internal Medicine at Rush University in Chicago, Illinois, said in an interview with OncologyLive®. “[However], earlier in the spring, when we got notice that there was a shortage of cisplatin and that we would have to start conserving our usage, we decided as an institution to reserve cisplatin for patients that we deem highly curable. If the intent is not curability and it’s more palliative, we would probably substitute cisplatin with something else such as carboplatin, but weeks [after the announcement of the cisplatin shortage], we got notification that there was a severe shortage in [carboplatin] as well.”

“[Importantly], when we’re talking about curative intent, there are some cancers we treat that we can’t substitute [another agent for platinum therapy],” Tan added. “Testicular cancer, for example, is a highly curable cancer where we were quoting 85% to 90% cure rates for seminoma and nonseminoma. When you have a shortage in such a crucial ingredient that hasn’t changed in several decades, it’s really a big problem. If you can’t cure young men with advanced testicular cancer, that’s a huge issue.”

On June 7, 2023, the National Comprehensive Cancer Network (NCCN) Best Practices Committee shared findings from a survey of 27 NCCN member institutions across the United States gathered from May 23 to 31, 2023. The data showed that 93% of centers were experiencing a shortage of carboplatin and 70% had a shortage of cisplatin. Sixteen percent of centers noted that they had to delay treatment due to needing to reobtain prior authorization for modified treatment plans; centers also reported shortages of methotrexate (67%), 5-FU (26%), fludarabine (11%), paclitaxel (4%), and hydrocortisone (4%).1

Although all centers surveyed were still able to treat patients requiring cisplatin without delays or claim denials, only 64% were able to do so for all patients needing carboplatin. Additionally, 20% of centers reported that they were able to continue carboplatin- containing regimens for some current patients, but not all.1

In conjunction with the survey results, the NCCN also released a statement in June 2023 on mitigating the impacts of anticancer drug shortages. The statement called upon the federal government, pharmaceutical industry, providers, and payers to contribute to preventing and addressing the impacts of anticancer drug shortages.2

The NCCN recommended that the federal government and its agencies place emphasis on fostering a regulatory environment that produces a steady supply of safe, effective anticancer agents. They also noted that the pharmaceutical industry has an obligation to act ethically and morally to ensure the steady supply of anticancer drugs. For providers, the NCCN said use of anticancer agents must be carefully prioritized by efficacy, safety, and cost to achieve pragmatic drug use and maximize societal impact. Finally, they implored payers to put patients first and provide coverage for treatment alternatives to the therapies that are in shortage.2 More recently, on October 5, 2023, the NCCN announced the findings from a follow-up to the June 2023 survey concerning the ongoing chemotherapy shortages, with survey data being collected from September 6 to 27, 2023. Among member institutions surveyed (n = 29), 72% responded that they were still experiencing a carboplatin shortage and 59% were still experiencing a cisplatin shortage.3

Although 95% of centers were still able to treat all patients needing a carboplatin-containing regimen according to the intended dosing schedule, the remaining 5% were able to do so with some current patients, but not all. In terms of cisplatin-containing regimens, these rates were 88% and 12%, respectively. Overall, 62% and 71% of centers said they had not received indications from manufacturers or suppliers when carboplatin and cisplatin, respectively, would be readily available. However, all centers indicated that no instances of modified treatment plans due to shortages were denied by payers and no treatment delays occurred because centers reobtained prior authorizations due to shortage- induced treatment plan modifications.3

The follow-up also included an expanded survey portion that gauged the rate of shortage regarding other anticancer agents. Outside of cisplatin and carboplatin, centers reported shortages of methotrexate (66%), 5-FU (55%), fludarabine (45%), hydrocortisone (41%), dacarbazine (28%), liposomal doxorubicin (24%), vinblastine (21%), capecitabine (14%), decitabine (14%), docetaxel (10%), paclitaxel (10%), amifostine (7%), and azacitidine (7%).3

“Unfortunately, the practices and the patients that suffer the most from the shortage are going to be the ones that don’t have access to referral or academic centers,” Tan commented. “I recently gave a talk at a community practice, and they let me know that they have had to change their practices. Some patients who needed cisplatin could not get it and they had to be referred to higher-volume centers.”

In September 2023, the White House issued a statement acknowledging the issue of the ongoing shortage and attributing it to manufacturing and supply chain issues, giving special mention to cisplatin, carboplatin, and methotrexate, and noting that the shortages were having an adverse effect on the administration’s Cancer Moonshot Initiative. They explained that the FDA has taken steps to address the problem, including working with the manufacturers of generic carboplatin, cisplatin, and methotrexate to increase supplies during the shortages by identifying opportunities to increase manufacturing capacity and lure companies that had stopped making the agents back to the US market—including an instance where 14 lots of cisplatin were imported from an FDA-registered facility outside the United States.4

The statement also highlighted a meeting in July 2023 at which the White House Office of Science and Technology Policy gathered leaders involved in the generic oncology drug supply chain, patient advocates, caregivers, and health care providers to get feedback on the effects of the shortages. The White House concluded its statement by affirming that the administration would “continue to work through the FDA, the [US] Department of Health and Human Services, and other agencies to address and prevent drug shortages and mitigate impacts to people facing a cancer diagnosis.”4

To combat the ongoing shortage of carboplatin and cisplatin, the most practical approach is using alternative agents and regimens whenever possible, as long as safety and efficacy are not greatly compromised, Tan said. For example, with the April 2023 FDA accelerated approval of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda), patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy gained another effective option. Findings from the phase 1/2 EV-103/KEYNOTE-869 (NCT03288545) trial showed that patients who received the combination (n = 121) achieved an objective response rate of 68% (95% CI, 59%-76%), including a 12% complete response rate.5

“Of course, this shortage is not limited to cisplatin and carboplatin; there are other shortages in the field, whether it’s BCG or 5-FU shortages,” Tan added. “Earlier in the year, we had a shortage in a different type of treatment for prostate cancer. What differentiates this from the generic drug [shortages] is that this is a brand-name drug that has a high dollar tag, lutetium 177Lu vipivotide tetraxetan (Pluvicto; 177Lu-PSMA-617). There was a problem with quality manufacturing, [as] it was only supplied out of Italy at one point. When they tried to validate sites in the United States, it didn’t meet the optimal standards, so there were delays in getting it to patients. It’s not a curative drug, but it does prolong survival. Patients who were without other options and failed chemotherapies unfortunately died early because they did not have this option.”

The lutetium 177Lu vipivotide tetraxetan shortage, which began in March 2023, was classified as resolved by the FDA in October 2023 following efforts to significantly scale up production that led to a doubled weekly production capacity of the agent.6 In contrast, as of November 2023, the FDA drug shortages webpage lists the status of both cisplatin and carboplatin injection as “currently still in shortage.”7,8

“This is one of those issues where we need to come together as a community,” Tan said in conclusion. “The bottom line is there’s not a lot of profits being made in generics. We need to change how we think of incentivizing care in this country.”