Janssen and AbbVie are voluntarily withdrawing the accelerated approvals of Imbruvica^® (ibrutinib) for mantle cell lymphoma (MCL) in patients who have received at least 1 prior therapy, and for marginal zone lymphoma (MZL) in patients who require systemic therapy and have received at least 1 prior anti-CD20-based therapy, due to requirements related to accelerated approval status granted by the Food and Drug Administration (FDA).

Under the accelerated approval pathway, continued approval of both of these indications was contingent upon verification and description of clinical benefit in confirmatory trials. The phase 3 SHINE study (ClinicalTrials.gov Identifier: NCT01776840) and the phase 3 SELENE study (ClinicalTrials.gov Identifier: NCT01974440) served as confirmatory studies for the MCL and MZL indications, respectively.

In the SHINE study, patients 65 years and older with untreated MCL were randomly assigned to receive ibrutinib or placebo, in combination with bendamustine and rituximab. Results showed that treatment with ibrutinib significantly prolonged progression-free survival (PFS) compared with placebo (80.6 months vs 52.9 months; hazard ratio, 0.75; 95% CI, 0.59-0.96; P =.01); however, overall survival was found to be similar between the groups. The addition of ibrutinib to chemoimmunotherapy was associated with increased adverse reactions.

The randomized, double-blind, placebo-controlled SELENE study compared ibrutinib to placebo in combination with bendamustine and rituximab (BR) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated MZL. According to the Companies, the study did not meet its primary endpoint of PFS. Additional information from the SELENE trial will be presented at a future medical meeting.

Following a review of the data, the FDA concluded that the primary outcomes from these confirmatory studies were considered insufficient to support conversion to full approval.

“We pursued accelerated approvals for MCL and MZL indications for Imbruvica in the US to offer a treatment to patients who at the time had limited therapeutic options,” said Roopal Thakkar, senior vice president, chief medical officer, AbbVie. “While we are disappointed in the outcome of the confirmatory trials for these indications, we remain confident in the benefit/risk profile of Imbruvica for patients living with multiple forms of blood cancer around the world.”

The withdrawal of the MCL and MZL indications does not affect the other approved indications for Imbruvica.

The Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Citius Pharmaceuticals regarding the Biologics License Application (BLA) for denileukin diftitox for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy.

Denileukin diftitox is an engineered interleukin-2 (IL-2)-diphtheria toxin fusion protein. By binding to the IL-2 receptor on the cell surface, the drug is internalized and causes diphtheria toxin fragments to inhibit protein synthesis resulting in cell death.

Denileukin diftitox was previously approved under the brand name Ontak, which was withdrawn from the market in 2014. The product being developed by Citius under the proposed brand name Lymphir is a reformulation of Ontak.

The BLA submission included data from a phase 3 trial (ClinicalTrials.gov Identifier: NCT01871727) that assessed the safety and efficacy of the reformulated product in patients with recurrent or persistent CTCL. Sixty-nine patients were included in the primary efficacy analysis set. Findings showed the treatment was considered efficacious with an objective response rate (primary endpoint) of 36.2% (95% CI, 25.0-48.7%; 25 patients out of 69). Adverse events were consistent with those previously seen in studies with Ontak.

While no efficacy or safety issues were raised in the CRL, the FDA is requiring the Company to “incorporate enhanced product testing, and additional controls.”

“We intend to provide additional data and remain fully engaged with the FDA as we continue to work toward approval,” said Leonard Mazur, Chairman and CEO of Citius. “We remain confident in the potential of Lymphir to become an important addition to the treatment landscape for patients with relapsed or refractory CTCL and make a meaningful difference in their lives.”

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 table below is a review of notable updates that occurred in April 2023 for investigational products in development (not an inclusive list). Click on the status to view our full coverage.

Lumoxiti (moxetumomab pasudotox-tdfk) for injection is expected to be permanently discontinued by August 31, 2023, according to a recent communication from the Food and Drug Administration (FDA).

Lumoxiti, a CD22-directed cytotoxin, was approved by the FDA in September 2018 for the treatment of adults with relapsed or refractory hairy cell leukemia who received at least 2 prior systemic therapies, including treatment with a purine nucleoside analog.

According to AstraZeneca’s letter to health care providers, the decision to remove Lumoxiti from the US market was related to its very low clinical uptake due to the availability of other treatment options. Complex administration and the need for toxicity prophylaxis and safety monitoring may also have contributed to its low uptake. The removal is not related to the safety or efficacy of the drug.

Physicians are advised not to initiate new treatment with Lumoxiti. Other options should be considered, including vemurafenib with or without rituximab as a preferred option and ibrutinib as other recommended regimens.

The postmarketing study evaluating the safety of Lumoxiti (ClinicalTrial.gov Identifier: NCT04125290) will also be terminated.

References

1. US Food and Drug Administration. FDA Drug Shortages. Accessed January 11, 2023. https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Moxetumomab+pasudotox-tdfk+%28Lumoxiti%29+Injection&st=d&tab=tabs-4&panels=0.
2. Important information for Lumoxiti (moxetumomab pasudotox-tdfk) for injection, for intravenous use – permanent withdrawal for Lumoxiti from the US Market. Dear Healthcare Provider Letter. AstraZeneca. November 18, 2022. Accessed January 11, 2023. https://www.fda.gov/media/164425/download.

Aliqopa, a kinase inhibitor, received accelerated approval for this indication in 2017. The accelerated approval was based on overall response rate from the single-arm, multicenter, phase 2 CHRONOS-1 trial (ClinicalTrials.gov Identifier: NCT01660451).

The conversion to full approval was contingent upon demonstration of clinical benefit in the phase 3 CHRONOS-4 trial (ClinicalTrials.gov Identifier: NCT02626455), which compared Aliqopa plus standard immunochemotherapy to standard immunochemotherapy regimens in patients with relapsed follicular lymphoma. The decision to withdraw Alipoa was made after the confirmatory trial failed to meet the primary endpoint of progression free survival. 

According to the Company, Aliqopa should not be prescribed to new patients at this time. Bayer is looking for ways to continue to provide access to the treatment for those who have experienced a favorable response and who may not have a suitable alternative available. Individuals with questions related to ongoing access can contact Bayer Medical Communications at 1-888-84-Bayer.

Besponsa is a CD22-directed antibody and cytotoxic drug conjugate. The expanded approval was based on data from a single-arm, open-label study in 53 pediatric patients 1 to less than 18 years of age with relapsed or refractory CD22-positive B-cell precursor ALL. Study participants received either 1.4mg/m²/cycle (n=12) or 1.8mg/m²/cycle (n=41) for a median of 2 cycles (range, 1 to 4 cycles).

The primary outcomes of the trial were complete remission rate (CR; defined as fewer than 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts [platelets ≥100 × 10⁹/L and ANC ≥1 × 10⁹/L] and resolution of any extramedullary disease), duration of CR, and the proportion of patients with minimal residual disease (MRD) negative CR (defined by leukemic cells comprising <1 × 10^-4 (< 0.01%) of bone marrow nucleated cells by flow cytometry or by polymerase chain reaction (PCR)].

Findings showed 42% (95% CI, 28.1-55.9) of patients (22/53) achieved CR. Median duration of CR was 8.2 months (95% CI, 2.6, not estimable). Among patients with CR, the MRD negativity rate was 95.5% (95% CI, 77.2-99.9) based on flow cytometry and 86.4% (95% CI, 65.1-97.1) based on real-time PCR. 

The most common adverse reactions reported were thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.

Besponsa is supplied as a 0.9mg lyophilized powder in a single-dose vial for reconstitution and further dilution. It is administered as an intravenous infusion following premedication with a corticosteroid, antipyretic, and antihistamine.

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.”

The Food and Drug Administration (FDA) has granted Orphan Drug designation to bexmarilimab for the treatment of acute myeloid leukemia (AML).

Bexmarilimab is an investigational first-in-class, humanized monoclonal antibody designed to target the Clever-1 immunosuppressive receptor on macrophages. The Company believes bexmarilimab can potentially alter the tumor microenvironment, reprogram macrophages from an immunosuppressive state to an immunostimulatory one, upregulate interferon production and prime the immune system to attack tumor cells and sensitize cancer cells to standard of care.

The Company is currently evaluating bexmarilimab in combination with standard of care in patients with hematological malignancies (eg, AML and myelodysplastic syndromes) in the phase 1/2 BEXMAB study (ClinicalTrials.gov Identifier: NCT05428969).

“Receiving Orphan Drug Designation from the FDA signifies our continued progress and commitment to develop bexmarilimab as a potential treatment for AML,” said Chief Medical Officer Dr. Marie-Louise Fjällskog. “The designation represents a milestone in our development journey, one that we believe when combined with standard of care, will lead to better patient outcomes and improved quality of life.”

Tecvayli, a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, is indicated for the treatment of adult patients with RRMM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

The approval of the new regimen was based on data from the phase 1/2 MajesTEC-1 study (ClinicalTrials.gov Identifier: Phase 1 [NCT03145181], Phase 2 [NCT04557098]). Patients who had achieved a confirmed CR or better for 6 months or longer were eligible to transition to the biweekly regimen. Findings showed transitioning to less frequent dosing was associated with sustained remission; median duration of response was 20.5 months from the date of switch.  

“Today’s approval of biweekly dosing for eligible patients will further enable clinicians to meet the individual needs of patients who may want flexibility in their dosing schedules,” said Rachel Kobos, MD, Vice President, Oncology Research & Development, Johnson & Johnson Innovative Medicine.