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)

Artificial intelligence (AI) chatbots can sometimes provide accurate information about cancers, but these tools have limitations, according to a pair of studies published in JAMA Oncology.^1,2

In the first study, researchers assessed chatbots’ responses to the top Internet searches related to 5 cancers.¹ The chatbots provided information that was generally of high quality but not always actionable, and it was written at a college reading level.

In the second study, researchers found that a chatbot’s responses to queries about cancer treatments did not always align with recommendations in National Comprehensive Cancer Network (NCCN) guidelines.²

Most-Searched Queries About Cancers

Alexander Pan, of SUNY Downstate Health Sciences University in Brooklyn, New York, and colleagues evaluated chatbots’ responses to the top 5 search queries for skin, colorectal, prostate, lung, and breast cancers.¹ All queries contained the terms “cancer symptoms” and “what is [specific cancer].”

The researchers tested 4 chatbots, ChatGPT, Perplexity, Chatsonic, and Bing AI. The team used the DISCERN validation tool to assess the quality of information the chatbots provided and the Patient Education Materials Assessment Tool (PEMAT) to analyze the understandability and actionability of responses. On a scale of 1-5 (DISCERN) or 0%-100% (PEMAT), higher scores on the validation tools indicated higher-quality responses.

The quality of the cancer information provided by the chatbots was high, with a median DISCERN score of 5 (range, 2-5). However, the information was of moderate understandability. The median PEMAT score was 66.7% (range, 33.3%-90.1%), which the researchers deemed “college reading level.” Furthermore, the chatbots often failed to provide actionable responses, with a median PEMAT score of 20.0% (range, 0%-40.0%).

“These limitations suggest that AI chatbots should be used supplementarily and not as a primary source for medical information,” the researchers concluded.

ChatGPT and Cancer Treatment Recommendations

Shan Chen, of Mass General Brigham in Boston, and colleagues evaluated whether ChatGPT responded to queries about cancer treatments with recommendations that were in line with NCCN guidelines.²

Because ChatGPT’s knowledge cutoff was September 2021, the researchers measured responses against the 2021 NCCN guidelines. Responses were assessed by board-certified oncologists. The researchers used 104 queries for breast, prostate, and lung cancer. The chatbot provided at least 1 treatment recommendation for 102 of the queries (98%). All of these responses included at least 1 NCCN-concordant recommendation, but 35 (34.3%) also included at least 1 non-concordant recommendation. Additionally, 13 of 104 chatbot responses (12.5%) were “hallucinated”, that is, they were not part of any recommended treatment for the specified cancer.

“The chatbot did not purport to be a medical device and need not be held to such standards,” the researchers noted. “However, patients will likely use such technologies in their self-education, which may affect shared decision-making and the patient-clinician relationship. Developers should have some responsibility to distribute technologies that do not cause harm, and patients and clinicians need to be aware of these technologies’ limitations.”

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

The Food and Drug Administration (FDA) has accepted for Priority Review the New Drug Application (NDA) for avasopasem manganese (GC4419) for radiotherapy (RT)-induced severe oral mucositis (SOM) in patients with head and neck cancer undergoing standard of care treatment.

Avasopasem is a selective dismutase mimetic designed to convert superoxide to hydrogen peroxide, thereby stopping the cascade that results in radiation damage to normal tissue. The NDA is supported by the randomized, double-blind, placebo-controlled phase 3 ROMAN trial (ClinicalTrials.gov Identifier: NCT03689712) and the phase 2b GT-201 (ClinicalTrials.gov Identifier: NCT02508389) trial. These studies enrolled a total of 678 patients with locally advanced, nonmetastatic squamous cell carcinoma of the head and neck. 

In the ROMAN trial (N=455), results showed that treatment with avasopasem met the primary endpoint demonstrating a statistically significant 16% relative reduction in the incidence of SOM (54% vs 64%; P =.045) and a 56% relative reduction in the duration of SOM (median, 8 vs 18 days; P =.002) compared with placebo. There were also improvements observed across multiple secondary and exploratory endpoints, including the incidence and duration of grade 4 incidence of SOM.

An analysis at 1 year showed that avasopasem did not affect the treatment benefit of standard of care chemoradiotherapy. Tumor outcomes and overall survival were observed to be similar in the avasopasem and placebo arms.

In the GT-201 trial, treatment with avasopasem statistically significantly reduced the duration of SOM compared with placebo (median, 1.5 days vs 19 days; P =.024). Avasopasem was also associated with a lower incidence of SOM (43% vs 65%; P =.009) and grade 4 SOM (16% vs 30%; P =.045) compared with placebo.

“The impact of SOM, the most burdensome toxicity of standard-of-care RT, on a patient’s physical and psychological wellbeing is substantial, particularly when hospitalization and surgical placement of feeding tubes to maintain nutrition and hydration are required,” said Mel Sorensen, MD, President and Chief Executive Officer of Galera Therapeutics. “In some patients, SOM is so debilitating that they may delay and/or discontinue potentially curative RT, undermining their care. Avasopasem, if approved, has the potential to reduce pain and suffering for these patients, as well as reduce the costs associated with hospitalizations, surgical placement of feeding tubes, and other treatment burdens.”

A Prescription Drug User Fee Act target date of August 9, 2023 has been set for the application. 

References

1. Galera announces FDA acceptance and Priority Review of avasopasem NDA for radiotherapy-induced severe oral mucositis. News release. Galera Therapeutics, Inc. Accessed February 15, 2023. https://www.globenewswire.com/news-release/2023/02/15/2608650/0/en/Galera-Announces-FDA-Acceptance-and-Priority-Review-of-Avasopasem-NDA-for-Radiotherapy-Induced-Severe-Oral-Mucositis.html.
2. Anderson CM, Lee CM, Saunders DP, et al. Phase IIb, randomized, double-blind trial of GC4419 versus placebo to reduce severe oral mucositis due to concurrent radiotherapy and cisplatin for head and neck cancer. J Clin Oncol. 2019;37(34):3256-3265. Published online October 16, 2019. doi:10.1200/JCO.19.01507
3. Anderson CM, Lee CM, Kelley Jr, et al. ROMAN: phase 3 trial of avasopasem manganese (GC4419) for severe oral mucositis (SOM) in patients receiving chemoradiotherapy (CRT) for locally advanced, nonmetastatic head and neck cancer (LAHNC). J Clin Oncol. 2022;40 (suppl 16):abstr 6005. Published online June 2, 2022. doi:10.1200/JCO.2022.40.16_suppl.6005

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.”

Jubbonti is approved to treat postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with osteoporosis at high risk for fracture, to treat glucocorticoid-induced osteoporosis in men and women at high risk for fracture, to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. The Jubbonti approval also includes a Risk Evaluation and Mitigation Strategy program designed to inform prescribers of the risk of severe hypocalcemia in patients with advanced kidney disease. 

Wyost is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors, to treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity, and to treat hypercalcemia of malignancy refractory to bisphosphonate therapy.

For this approval, the FDA reviewed a comprehensive clinical data package, which included data from the phase 3 ROSALIA trial (ClinicalTrials.gov Identifier: NCT03974100). The study compared denosumab-bbdz to the reference product (Prolia) in 527 postmenopausal women with osteoporosis. Study participants were randomly assigned to receive the biosimilar or the reference product for up to 78 weeks of treatment. Findings showed the biosimilar denosumab was comparable to the reference product with regard to pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity.

The availability of Jubbonti and Wyost is still unclear as ongoing patent litigation precludes Sandoz from launching the products at this time.

(HealthDay News) — For patients with acute myeloid leukemia (AML), supplementation with vitamins C and D during chemotherapy may improve outcomes but may not improve overall survival (OS), according to a study published online Sept. 6 in Blood Advances.

Pierre Luc Mouchel, MD, from the Centre Hospitalier Universitaire de Toulouse in France, and colleagues compared the outcomes of patients treated before and after the practice change of adding vitamins C and D to the supportive care of AML patients in 2018. A total of 431 patients were included from 2015 to 2020: 262 and 169 received no supplementation and supplementation, respectively. Vitamins C and D were administered from day 10 of chemotherapy until hematologic recovery from induction and consolidation.

The researchers found that in the supplementation group, vitamin D levels increased significantly upon recovery from induction compared with diagnosis, and pretransplant levels were significantly higher in the supplementation group vs the control group (median, 33 vs 19 ng/mL). The rates of bacterial or fungal infection, hemorrhage, or macrophage activation syndrome were lower in the supplementation group during induction, while no difference was seen in response rate, relapse incidence, or OS.

There was a significant interaction between vitamin C/D and NPM1 mutation in a multivariate analysis for OS, indicating better OS with supplementation among patients with NPM1 mutations (hazard ratio [HR], 0.52; 95% CI, 0.30-0.90) vs wild-type NPM1 patients (HR, 1.01; 95% CI, 0.68-1.51).

“We have shown that supplementation is feasible and safe and may help reduce some significant adverse events associated with intensive chemotherapy, which is a clear benefit for patients,” coauthor Christian Récher, M.D., of the University Cancer Institute of Toulouse, said in a statement.

Several authors disclosed ties to the pharmaceutical industry.

Abstract/Full Text

Lorazepam use may impact survival outcomes in patients with a range of cancers, according to a study published in Clinical Cancer Research.

Lorazepam use was associated with significantly worse outcomes in patients with pancreatic, prostate, ovarian, head and neck, colon, uterine, and breast cancer as well as melanoma, researchers found.

In this retrospective study, researchers examined benzodiazepine use in patients treated at Roswell Park Comprehensive Cancer Center in Buffalo, New York, during 2004 to 2020.

The researchers assessed use of 2 benzodiazepines, lorazepam and alprazolam, in this cohort and looked for associations with progression-free survival (PFS) and overall survival (OS). The researchers first looked at 1450 patients with pancreatic cancer. In an adjusted analysis, patients who were prescribed lorazepam had significantly worse PFS than those who were not prescribed lorazepam (hazard ratio [HR], 3.83; 95% CI, 1.53-9.57; P =.004).

In contrast, pancreatic cancer patients who were prescribed alprazolam had significantly improved PFS when compared to patients who were not prescribed alprazolam (HR, 0.38; 95% CI, 0.16-0.92; P =.032). There was no association between alprazolam or lorazepam and OS in patients with pancreatic cancer.

However, lorazepam and alprazolam were associated with OS and PFS for patients with other cancers. The researchers evaluated patients with brain (n=664), breast (n=2332), uterine (n=630), head and neck (n=803), renal (n=588), ovarian (n=570), colon (n=780), and prostate (n=821) cancer as well as melanoma/invasive nevi (n=700).

In adjusted analyses, lorazepam use was associated with significantly worse PFS in patients with:

• Prostate cancer (HR, 1.899; 95% CI, 1.433-2.517; P <.0001 )
• Ovarian cancer (HR, 1.464; 95% CI, 1.174-1.826; P =.0007)
• Melanoma/invasive nevi (HR, 2.195; 95% CI, 1.699-2.835; P <.0001)
• Head and neck cancer (HR, 1.635; 95% CI, 1.313-2.036; P <.0001)
• Colon cancer (HR, 1.782; 95% CI, 1.457-2.179; P <.0001)
• Uterine cancer (HR, 1.433; 95% CI, 1.069-1.921; P =.0160)
• Breast cancer (HR, 1.345; 95% CI, 1.138-1.591; P =.0005).

Lorazepam use was also associated with significantly worse OS in patients with:

• Prostate cancer (HR, 2.160; 95% CI, 1.589-2.936; P <.0001)
• Ovarian cancer (HR, 1.521; 95% CI, 1.212-1.907; P =.0003)
• Melanoma/invasive nevi (HR, 1.978; 95% CI, 1.519-2.576; P <.0001)
• Head and neck cancer (HR, 1.629; 95% CI, 1.304-2.035; P <.0001)
• Colon cancer (HR, 1.620; 95% CI, 1.317-1.993; P <.0001)
• Uterine cancer (HR, 1.376; 95% CI, 1.021-1.854; P =.0362)
• Breast cancer (HR, 1.248; 95% CI, 1.050, 1.484; P =.0119).

However, lorazepam was associated with improved OS in patients with brain cancer (HR, 0.779; 95% CI, 0.616-0.986 P =.0381). For most cancers, alprazolam was not associated with significant differences in outcomes. However, patients with breast cancer had significantly worse OS (HR, 1.867; 95% CI, 1.528-2.281; P <.0001) and PFS (HR, 1.850; 95% CI, 1.523-2.248; P <.0001) if they were prescribed alprazolam.

Patients with uterine cancer had worse PFS if they were prescribed alprazolam (HR, 1.668; 95% CI, 1.051-2.646; P =.0298), and patients with prostate cancer had worse OS if they were prescribed alprazolam (HR, 1.464; 95% CI, 1.038-2.064; P =.0298).

“Due to the frequency that BZDs [benzodiazepines] are prescribed, this is an issue that could affect a large percentage of cancer patients,” the researchers concluded. “Performing prospective clinical trials and additional experimental studies to determine whether BZDs affect therapeutic efficacy is vital.”

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