Novartis is still running the phase II CANOPY-N study of neoadjuvant (pre-surgery) canakinumab in NSCLC, with a readout due in the coming days, but hopes for a positive outcome are now slim, and it is not expected to produce a result that would support a regulatory filing on its own. Novartis is also developing several cancer medications that target the PTI pathway, including gevokizumab, an IL-1 beta-targeting antibody in phase 1 testing with a lead indication of first-line colorectal cancer therapy.
Novartis Confirms Deaths of 2 Patients Treated with Zolgensma
The news that two patients treated with Novartis’ spinal muscular atrophy (SMA) therapy Zolgensma died as a result of severe liver failure has renewed concerns about the safety of gene treatments. According to the pharma group, the two fatalities occurred in children with the genetic neuromuscular wasting disease, and the incidents do not indicate a new safety signal with Zolgensma (onasemnogene abeparvovec). Novartis said it was changing the treatment’s labelling to indicate that it has been linked to cases of acute liver failure.
The two deaths happened in children in Russia and Kazakhstan, with the liver failure occurring 5 to 6 weeks after the adeno-associated virus-based therapy was administered. Both children died after tapering off corticosteroid medications designed to lessen the likelihood of negative effects once therapy began. There is ample evidence that systemic injection of AAV vectors can result in liver cell damage and inflammation, which is why medicines are used to try to prevent these side effects. More than 2,300 people have been treated with Zolgensma so far, with use increasing as more nations where it is approved — 43 in total – agree to cover therapy.
Zolgensma is now administered intravenously; hence it is only an option for smaller children under a particular weight. Novartis is investigating intrathecal dosing of gene therapy, which involves administering an injection straight into the cerebrospinal fluid via the lower back. The FDA placed that version on clinical hold last year when inflammation was observed in the dorsal root ganglia of spinal nerves, which was occasionally followed by neurodegeneration, though that was lifted in August. The new delivery method is being tested in a phase III trial in individuals aged 2 to 18 with SMA type 2, who have never walked and have never received prior SMA treatment, and if the results are positive, a regulatory application might be made in 2025.
Survival Data Firms up Trodelvy Prospects in New Breast Cancer Use
Gilead Sciences announced statistically significant and clinically meaningful results from the second interim analysis of the key secondary endpoint of overall survival in Phase III TROPiCS-02 study evaluating Trodelvy in patients suffering from HR+/HER2- metastatic breast cancer who received prior endocrine therapy, CDK4/6 inhibitors and 2 to 4 lines of chemotherapy. Detailed overall survival results will be presented at an upcoming medical conference. The safety profile for Trodelvy was persistent with prior studies, and no new safety signals emerged in this patient population.
Gilead has recommended a supplemental Biologics License Application to the U.S. Food & Drug Administration. These data will also be shared with health authorities outside the United States.
In June 2022, established on the positive primary results from the TROPiCS-02 study presented at the American Society of Clinical Oncology Annual Meeting 2022, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology included a category 2A preferred recommendation for sacituzumab govitecan-hziy for the investigational use in patients suffering with HR+/HER2- advanced breast cancer after prior treatment including the endocrine therapy, a CDK4/6 inhibitor and at least 2 lines of chemotherapy. The TROPiCS-02 study enrolled patients with HR+/HER2- metastatic breast cancer, which included patients with HER2-low and IHC 0 status.
TROPiCS-02 is an event-driven study with planned analyses based on a pre-specified number of events. This interim analysis was accomplished based on the pre-specified criteria.
Any regulatory agency has not approved Trodelvy for treating HR+/HER2- metastatic breast cancer, and its safety and efficiency have not been established for HR+/HER2- metastatic breast cancer.
Novartis Secures First European Approval For Prostate Cancer Radioligand Therapy Pluvicto
Novartis announced today that the U.S. Food and Drug Administration approved Pluvicto to treat adult patients with a specific type of advanced cancer called prostate-specific membrane antigen–positive metastatic castration-resistant prostate cancer that has spread to other body parts. These patients have already been treated with other anti-cancer treatments, i.e., androgen receptor pathway inhibition and taxane-based chemotherapy.
Pluvicto is the first FDA-approved targeted radio-ligand therapy for eligible patients with mCRPC that combines a targeting compound with a therapeutic radioisotope. Pluvicto is predicted to be available to physicians and patients within weeks.
The FDA has also approved Locametz, a kit for preparing gallium Ga 68 gozetotide injection. After radiolabeling, this imaging agent may identify PSMA-positive lesions in adult patients with mCRPC through a positron emission tomography scan. Gallium-68 labelled Locametz can analyze tumour lesions expressing the PSMA biomarker and locate where tumors may have spread in the body, helping in determining patients eligible for targeted treatment with Pluvicto. PSMA is highly expressed in more than 80 per cent of patients suffering from prostate cancer, making it an essential phenotypic biomarker for assessing the progression of metastatic prostate cancer. Locametz is predicted to be available to physicians and patients within weeks.
FDA approval of Pluvicto is established on the Phase III VISION trial results, which showed that PSMA-positive mCRPC patients previously treated with androgen receptor pathway inhibition and taxane-based chemotherapy who received Pluvicto plus standard of care had improved overall survival compared to standard of care alone. Participants treated with Pluvicto plus standard of care had a 38 per cent decrease in chance of death and a statistically significant decrease in the risk of radiographic disease progression or death compared to standard of care alone. The interpretation of the magnitude of the rPFS effect was limited due to a high degree of censoring from early dropout in the control arm.
In addition, about 30 per cent of patients with evaluable disease at baseline demonstrated an overall response with Pluvicto plus standard of care, compared to 2% in the standard of care alone arm. The common adverse events in the Pluvicto arm of the study were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.
Bristol-Myers Squibb’s Abecma Meets its Objectives in Phase III Trials
Bristol Myers Squibb has announced positive results from its open-label study evaluating Abecma (idecabtagene vicleucel) in adults with multiple myeloma. Abecma is the first-in-class B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell immunotherapy approved in the U.S. for the treatment of adult patients with R/R multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Both the companies are now planning to submit the trial data to regulators and are expected to make the therapy available to earlier-stage myeloma patients.
Abecma is studied under the KarMMa-3 trial, a Phase 3, global, randomized, multicenter study compared to standard combination regimens. Abecma recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. KarMMa-3 met its primary endpoint and showed a statistically significant advancement in progression-free survival. Treatment with Abecma also improved the key secondary endpoint of overall response rate compared to standard regimens. Follow-up for overall survival, a key secondary endpoint, remains ongoing.
Abecma is being jointly developed and commercialized in the U.S. by Bristol Myers Squibb and 2seventy bio under Co-Development, Co-Promotion, and Profit Share Agreement. Both the companies are yet to share the specific data on Abecma’s efficacy or rates of side effects. However, the result is expected to be presented at an upcoming medical conferences.
FDA Approves Trastuzumab Deruxtecan for HER2-Mutant NSCLC
In the major regulatory update, FDA has approved AstraZeneca and Daiichi Sankyo’s ENHERTU® (fam-trastuzumab deruxtecan-nxki) for the treatment of unresectable or metastatic non-small cell lung cancer (NSCLC) in adult patients whose tumors have activating human epidermal growth factor receptor 2 HER2 (ERBB2) mutations, and who have received prior systemic therapy. ENHERTU® is the first drug approved for HER2-mutant NSCLC.
The indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DoR). The results from the DESTINY-Lung02, a multicenter, multi-cohort, randomized, blinded, dose-optimization, Phase II trial, have paved the way for the accelerated approval of the therapy by the FDA. An interim efficacy analysis in a pre-specified patient cohort showed that ENHERTU had demonstrated a confirmed ORR of 57.7% in patients with previously treated unresectable or metastatic non-squamous HER2-mutant (HER2m) NSCLC.
ENHERTU is a specifically engineered HER2-directed antibody-drug conjugate (ADC) being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. Results from the DESTINY-Lung02 trial will be presented at an upcoming medical meeting.
Before ENHERTU®, there were no approved agents for HER2-mutant lung cancers, and in patients with advanced HER2-mutant NSCLC, the NCCN guidelines advise trastuzumab and afatinib as the targeted therapeutic options. Currently, several other studies are investigating the efficacy of other irreversible pan-HER receptor family inhibitors combined with mTOR inhibitors in advanced NSCLC patients harbouring HER2 mutations.
