Yu Fujiwara, MD, from Mount Sinai Beth Israel in New York City, and colleagues conducted a systematic review and meta-analysis to examine how adding an immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. Data were included from 28 randomized controlled trials with 16,976 cancer patients.

The researchers found no significant association for addition of an immune checkpoint blockade with increased treatment-related deaths, and this finding was consistent across immune checkpoint blockade subtypes. Across 9864 patients treated with an immune checkpoint blockade, 40 fatal toxicities were identified, with pneumonitis the most common (15.0%); among 7112 patients who were not treated with an immune checkpoint blockade, 13 fatal toxicities were identified. The incidence rates of grade 3 to 4 treatment-related adverse events, adverse events leading to treatment discontinuation, and treatment-related adverse events of any grade were increased with the addition of an immune checkpoint blockade (odds ratios, 2.73, 3.67, and 2.60, respectively). Increased incidence rates of treatment-related deaths and grade 3 to 4 adverse events were seen in association with an immune checkpoint blockade vs placebo design primarily used as adjuvant therapy (odds ratios, 4.02 and 5.31, respectively), while incidence was not increased with the addition of an immune checkpoint blockade in the neoadjuvant setting.

“Our analysis points to a need for further research into risk factors and identification of appropriate biomarkers to predict both efficacy and toxicity associated with cancer immunotherapy,” Fujiwara said in a statement.

Several authors disclosed ties to the biopharmaceutical industry.

Abstract/Full Text (subscription or payment may be required)

Editorial (subscription or payment may be required)

Avzivi is a vascular endothelial growth factor inhibitor indicated for the treatment of:

• Metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment.
• Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen.
• Unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment.
• Recurrent glioblastoma in adults.
• Metastatic renal cell carcinoma in combination with interferon alfa.
• Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.
• Epithelial ovarian, fallopian tube, or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens.

The approval was based on a comprehensive data package that included a pharmacokinetic study (ClinicalTrials.gov Identifier: NCT05865574) in healthy individuals, as well as a phase 3 comparative study (ClinicalTrials.gov Identifier: NCT03329911) in patients with advanced nonsquamous non-small cell lung cancer.

“The global phase 3 clinical trial has confirmed that Avzivi is highly similar to Avastin in terms of efficacy, safety and immunogenicity,” said professor Li Zhang, leading investigator for global phase 3 study of Avzivi. “The approval of Avzivi by the FDA will provide lung and colorectal cancer patients a new cost-effective treatment option.”

Cancer patients were more likely to die from the BA.1 and BA.2 omicron variants of SARS-CoV-2 than from wild-type SARS-CoV-2, according to research published in JAMA Oncology.^1,2

The study showed that, among US cancer patients, COVID-19 deaths were more likely during the initial omicron wave when the BA.1 and BA.2 variants were in circulation (December 2021 to February 2022) than when wild-type SARS-CoV-2 was circulating (December 2020 to February 2021).

According to data from the US Centers for Disease Control and Prevention, there were 54,692 COVID-19 deaths among patients with cancer and 1,008,510 COVID-19 deaths in the general population from March 1, 2020, through May 31, 2022.

This study included 34,350 patients with cancer and 628,156 individuals from the general population who died from COVID-19 when wild-type SARS-CoV-2 was in circulation (December 2020-February 2021), the delta variant was in circulation (July 2021-November 2021), or the BA.1 and BA.2 omicron variants were in circulation (December 2021-February 2022).

The highest number of COVID-19-related deaths among patients with cancer occurred during the 2021-2022 omicron wave. At the peak of this wave, in January 2022, there were 18% more deaths than during the peak of the wild-type period, which occurred during January 2021.

This trend was maintained when patients were stratified by age group. The number of deaths per month among patients with cancer younger than 50 years of age was 64% higher during the 2021 to 2022 omicron wave than during the wild-type wave. The number was 62% higher among patients aged 50 to 59 years, 31% higher for those aged 60 to 69 years, and 16% higher for those aged 70 to 79 years.

When the researchers looked at individual cancer types, they found that COVID-19 deaths were more likely during the 2021-2022 omicron wave for most cancer types. The exceptions were brain cancer (mortality ratio [MR], 0.77; 95% CI, 0.65-0.90), thyroid cancer (MR, 0.76; 95% CI, 0.54-0.99), and bladder cancer (MR, 0.58; 95% CI, 0.52-0.65).

Patients with lymphoma had the greatest increase in deaths from the wild-type wave to the 2021 to 2022 omicron wave, at 38% (mortality ratio [MR], 1.38; 95% CI, 1.31-1.45).

In the general population, the highest number of COVID-19 deaths per month occurred when wild-type SARS-CoV-2 was prevalent. At the peak of the initial omicron wave in January 2022, there were 21% fewer deaths in the general US population than at the peak of the wild-type period in January 2021 (MR, 0.69; 95% CI, 0.69-0.70).

“[W]hile the general US population experienced a large reduction in COVID-19 mortality during the winter Omicron period, patients with cancer experienced the highest COVID-19 mortality during the winter Omicron period, likely due to increased SARS-CoV-2 exposure during this period combined with the reduced effectiveness of COVID-19 vaccines and increased risk of COVID-19 mortality in this population,” the researchers wrote. “With future COVID-19 waves imminent, strategies to protect those at highest risk should remain a high priority, even during future pandemic waves with less virulent SARS-CoV-2 variants.”

Disclosures: One of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

References

1. Potter AL, Vaddaraju V, Venkateswaran S, et al. Deaths due to COVID-19 in patients with cancer during different waves of the pandemic in the US. JAMA Oncol. Published online August 31, 2023. doi: 10.1001/jamaoncol.2023.3066

2. SARS-CoV-2 sequences by variant, United States, Jan 3, 2022. Our World in Data. Updated August 22, 2023. Accessed September 1, 2023.

Chemotherapy-Induced Nausea and Vomiting Prophylaxis

The cisplatin shortage that has affected cancer centers and patients across the US is nearly resolved, according to a statement from the Biden Administration.¹

The White House reported last week that the cisplatin supply has been restored to almost 100% of pre-shortage levels.

According to the US Food and Drug Administration’s (FDA) drug shortage database, 3 companies had cisplatin available on allocation as of September 18.² Additional supplies of cisplatin are expected to be released this month and next month.

The shortage of cisplatin has occurred alongside prolonged shortages of several other cancer drugs, including methotrexate and carboplatin.³ In June, the National Comprehensive Cancer Network (NCCN) published survey results reporting that cisplatin was in short supply at 70% of included cancer centers, and carboplatin was in short supply at 93%.⁴

The FDA has worked to alleviate these shortages over the past several months.¹ In June, the FDA announced that it would work with Chinese drugmaker Qilu Pharmaceutical and Canadian pharmaceutical company Apotex to temporarily import cisplatin.⁵ According to the FDA, distribution of this product has been completed.²

The FDA also worked with various drug manufacturers to increase production of cisplatin, carboplatin, and methotrexate.¹ According to the FDA database, several companies have methotrexate and carboplatin available now, and additional supplies of both drugs are expected this month and next month.²

“The Administration will continue to work through the FDA, the Department of Health and Human Services, and other agencies to address and prevent drug shortages and mitigate impacts to people facing a cancer diagnosis,” the White House said in its statement.¹

This is despite the fact that cancer survivors are more likely to be vaccinated against COVID-19 and just as likely as the general population to be infected with SARS-CoV-2. These findings were published in the Journal of the National Cancer Institute.

For this study, researchers evaluated data from the National Health Interview Survey in 2021 and 2022. The cohort from 2021 included 3428 cancer survivors and 26,023 control individuals without a cancer history. The cohort from 2022 included 3218 cancer survivors and 24,393 control individuals.

The cancer survivors were more likely than control individuals to have received 2 or more COVID-19 vaccines in 2021 (66.6% and 62.3%, respectively; P =.003) and 2022 (77.0% and 72.4%, respectively; P <.001).

However, cancer survivors were just as likely as control individuals to report having COVID-19 in 2021 (14.1% and 14.2%, respectively; P =.93) and 2022 (39.9% and 39.3%, respectively; P =.55).

Cancer survivors were more likely than control individuals to report moderate to severe COVID-19 symptoms in 2021 (62.5% and 54.2%, respectively; P =.02). In 2022, there was a trend toward more moderate and severe COVID-19 among cancer survivors, but the difference between cancer survivors and control individuals was not statistically significant (54.5% and 51.3%, respectively; P =.13).

However, the data from 2022 showed that cancer survivors were more likely than control individuals to have symptoms of long COVID (20.6% and 17.3%, respectively; P =.04). There were no data on long COVID from 2021.

“With the continuing high infectious rate and seasonal resurgences of COVID-19 infections and ongoing recommendations for vaccination, especially for vulnerable populations, monitoring the impact of COVID-19 infection and the effectiveness of prevention and control strategies continue to be a public health priority,” the researchers wrote. “Our findings suggest the need for tailored efforts to prevent and control COVID-19 infection for cancer survivors.”

Drug-Induced Photosensitivity

The Food and Drug Administration (FDA) has accepted for Priority Review the New Drug Application (NDA) for ADX-2191 (methotrexate injection) for the treatment of primary vitreoretinal lymphoma, a rare, aggressive retinal cancer.

ADX-2191 is a preservative-free, intravitreal formulation of methotrexate designed to be vitreous-compatible. The application is supported by safety data from the phase 3 GUARD trial (ClinicalTrials.gov Identifier: NCT04136366), which compared treatment with repeated intravitreal injections of ADX-2191 to standard of care in patients with proliferative vitreoretinopathy.

Findings showed that ADX-2191 was well tolerated; no safety signals or treatment-emergent serious adverse events were observed in the trial. The most common adverse event reported was punctate keratitis, which was mild in severity. 

A Prescription Drug User Fee Act (PDUFA) target date of June 21, 2023 has been set for the application.

“The FDA’s decision to grant Priority Review with a PDUFA date 4 months from NDA acceptance underscores the significant need for an FDA-approved treatment of primary vitreoretinal lymphoma, a rare but potentially fatal cancer,” stated Todd C. Brady, MD, PhD, Aldeyra’s President and CEO. “We are working closely with the FDA during the review process to bring ADX‑2191 to patients as quickly as possible, and plan to launch ADX-2191 in the United States in the second half of this year, pending approval by the FDA.”

Reference

FDA accepts for Priority Review ADX-2191 New Drug Application for the treatment of primary vitreoretinal lymphoma. News release. Aldeyra Therapeutics, Inc. Accessed March 2, 2023. https://www.businesswire.com/news/home/20230301005873/en/FDA-Accepts-for-Priority-Review-ADX-2191-New-Drug-Application-for-the-Treatment-of-Primary-Vitreoretinal-Lymphoma.

Coverage determination for oncology drugs can be delayed for months after regulatory approval, according to research published in JAMA Oncology.

Researchers found that coverage determination by pharmacy and therapeutics committees (PTCs) is “frequently delayed for months” after a cancer drug is approved by the US Food and Drug Administration (FDA). However, lag times vary, and the determination delay has improved over time, “suggesting that PTC determinations are becoming more efficient,” the researchers wrote.

For this study, the researchers evaluated the time from FDA approval to PTC determination between 2010 and 2019 for 127 payers. There were a total of 89 oncology drugs with 974 PTC determination dates.

The median coverage lag was 4.2 months, and the median lag range was 32.2 months. The median lag between oncology drug approval and PTC determination was 10.9 months in 2010, and this decreased to 3.4 months in 2018. The median lag range decreased from 39.8 months in 2010 to 14.4 months in 2018.

A more recent year of FDA approval was significantly associated with lower odds of a long lag between approval and determination (odds ratio [OR], 0.20; 95% CI, 0.07-0.59) and of a large lag range (OR, 0.54; 95% CI, 0.34-0.85).

There was no association between determination lag and drug class, orphan drug status, or FDA expedited review pathways, including fast track designation, priority review, and accelerated approval.

“These results indicate that PTC determinations are frequently delayed for months after initial FDA approval and that lag periods are highly variable among payers,” the researchers concluded. “Coupled with drug coverage being frequently subject to formulary exclusions and restrictions across many coverage plans, our results indicate that the existing payer system for oncology care may severely hamper patient access to effective drugs.”

Ranitidine does not pose an increased risk of cancer when compared to other histamine-2 receptor antagonists (H₂RAs), according to a study published in JAMA Network Open.

For this study, researchers analyzed data from health claims and electronic health record databases in the US, UK, Germany, Spain, France, South Korea, and Taiwan.

The study included more than 1.1 million individuals who were at least 20 years of age, had no history of cancer, and who used H₂RAs for more than 30 days between January 1986 and December 2020. The cohort included 909,168 new users of ranitidine and 274,831 new users of other H₂RAs.

The crude incidence rate of cancer was 14.30 events per 1000 person-years among ranitidine users and 15.03 events per 1000 person-years for users of other H₂RAs.

After propensity score matching (n=217,406 in each group), the risk of all cancers was similar with ranitidine and other H₂RAs; 18.11 and 17.82 per 1000 person-years, respectively (hazard ratio [HR], 1.04; 95% CI, 0.97-1.13; P =.24). For all cancers excluding nonmelanoma skin cancer, the primary outcome, the risk was similar with ranitidine and other H₂RAs; 15.92 and 15.65 per 1000 person-years, respectively (HR, 1.04; 95% CI, 0.97-1.12).

When the researchers looked at individual cancers, they found no association between ranitidine and an increased risk of leukemia or breast, prostate, lung, colorectal, bladder, liver, pancreatic, stomach, thyroid, uterine, ovarian, esophageal, gallbladder and biliary tract, cervical, or lip/oral cavity/pharynx cancers.

The researchers also looked at the primary outcome, all cancers excluding nonmelanoma skin cancer, across databases and regions. They found no significant differences in risk between the ranitidine and H₂RA groups in the AmbEMR (HR, 1.00; 95%CI: 0.97-1.03) and CUIMC (HR, 0.97; 95%CI, 0.87-1.08) databases. However, ranitidine use was associated with a higher risk of the primary outcome in the SIDIAP (HR, 1.16; 95% CI, 1.01-1.34) and NHIS-NSC (HR, 1.11; 95% CI, 1.02-1.20) databases.

The risk of all cancers excluding nonmelanoma skin cancer was not significantly higher with ranitidine in the primary meta-analysis of results from 4 databases (HR, 1.04; 95% CI, 0.97-1.12) or in the meta-analysis of results across 11 databases (HR, 1.03; 95% CI, 0.99-1.08).  

In addition, a subgroup meta-analysis showed no significant difference in the risk of the primary outcome between ranitidine users and other H₂RA users in the US (HR, 1.00; 95% CI, 0.97-1.03) or Europe (HR, 1.09; 95% CI, 0.99-1.19). However, the risk of the primary outcome was higher among ranitidine users in Asia (HR, 1.09; 95% CI, 1.02-1.18).

“These findings suggest that a history of ranitidine use is not associated with an increased risk of cancer compared with use of other H2 receptor antagonists, but further research is needed on the long-term effects of ranitidine on cancer development,” the researchers concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Redispensing unused oral cancer drugs is associated with waste reduction and cost savings, according to research published in JAMA Oncology.

The findings suggest that redispensing unused therapies may improve the affordability and sustainability of cancer treatment, researchers reported. The researchers evaluated the impact of redispensing unused cancer drugs in the multicenter ROAD trial.

The study included 1071 cancer patients in the Netherlands who had a prescription for an oral cancer drug that could be stored at room temperature. Treatments included targeted therapies (56.8%), cytotoxic agents (22.1%), endocrine therapy (13.2%), and immunosuppressants (7.9%).

The drugs were dispensed in sealed packaging with a time-temperature indicator. Patients were instructed to return unused drugs to the pharmacy during planned hospital visits.

Drugs that met quality requirements were redispensed to other patients. Quality requirements included unopened and undamaged packaging, a shelf life of 6 months or more, and drug storage per the summary of product characteristics, measured by a time-temperature indicator.

A total of 13,069 drug packages containing an average of 27 daily doses were dispensed during the study period. Ultimately, 171 patients returned 335 unused drug packages, and 228 of the packages were redispensed. This resulted in a 68.1% reduction in waste when compared to drug disposal. In other words, for every 8 patients receiving oral anticancer drug treatment, redispensing unused drugs enabled waste avoidance for 1 patient.

The quality requirements were met for 73.4% of returned packages. Reasons for returned drugs not meeting the quality standard included opened packaging (77.5%), damaged outer packaging (60.7%), lack of a time-temperature indicator (31.5%), short shelf life (21.3%), and/or temperature breach (10.1%).

Eighteen packages were not redispensed due to reasons other than quality, such as no need for that particular drug or change in stock.

Of the returned drugs, 68.0% were targeted therapies, 18.0% were endocrine therapies, 7.5% were immunosuppressants, and 6.6% were cytotoxic agents. Reasons for the return of drugs included disease progression (47.4%), drug switch (44.8%), discontinuation (34.0%), toxicity (29.4%), and dose adjustments (18.0%).

Redispensing of unused drugs resulted in a mean net annual cost savings of $680 to $1591 USD per patient. Waste reduction through redispensing drugs comprised 2.4% of total drug costs.

The cost savings could be increased by minimizing quality assurance and focusing on subgroups of patients, the researchers noted. “Nevertheless, these findings indicate that redispensing unused drugs has the potential to improve sustainability and affordability in cancer treatment,” they concluded.