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In the field of solid tumors, the FDA received key approval in September
Finishing | Su Xuhan
In September 2024, based on the results of related studies, the United States Food and Drug Administration (FDA) approved a number of drugs (new drugs/indications), including 6 in the field of solid tumors.
Quick Facts
September 12: Atezolizumab SC dosage form was approved for marketing;
September 17: Rebociclib and AI were approved for HR+/HER2- early breast cancer;
September 17: Pembrolizumab in combination with chemotherapy was approved for the treatment of malignant pleural mesothelioma;
Sep 19: Amivantamab in combination with chemotherapy approved for EGFR+ advanced NSCLC;
September 25: Osimertinib was approved for the treatment of locally advanced, unresectable EGFR+ NSCLC after chemoradiotherapy;
September 27: Selpercatinib was approved for the treatment of RET+ medullary thyroid cancer.
01
The SC dosage form of atezolizumab was approved for marketing
Atezolizumab is a monoclonal antibody targeting PD-L1 that blocks the interaction of PD-L1 expressed by tumor cells with PD-1 and B7.1 receptors on immune cells and activates T cells, and its intravenous infusion (IV) dosage form was approved for marketing in the United States in May 2016.
On September 12, 2024, atezolizumab was approved by the FDA for the treatment of all adult indications for which its IV dosage form has been approved by the FDA, including non-small cell lung cancer (NSCLC), liver cancer, melanoma, and alveolar soft tissue sarcoma. It is reported that this is the first and only PD-1/PD-L1 inhibitor approved for subcutaneous injection.
The dosage form was approved based on key data from the Phase IB/III IMscin001 study (NCT03735121). The study is a global, multicenter, randomized trial evaluating the pharmacokinetics, safety, and efficacy of atezolizumab SC versus atezolizumab IV in 371 patients with locally advanced/metastatic NSCLC. The co-primary endpoints of the study were the observed serum trough concentration in Cycle 1 and the area under the curve predicted by the model (AUC0-21d). Secondary endpoints include safety, immunogenicity, patient-reported outcomes, and efficacy.
The results showed that the geometric mean ratio (GMR) of trough concentrations observed in the SC and IV groups of atezolizumab in cycle 1 was 1.05 (90% CI 0.88-1.24); The model predicted an AUC0-21d GMR of 0.87 (90% CI 0.83-0.92). See Figure 1.
Fig.1 GMR of the common primary pharmacokinetic endpoint
The progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) benefits were similar for both dosage forms. Atezolizumab had PFS of 2.8 versus 2.9 months in the SC and IV arms (HR 1.08; 95% CI: 0.82-1.41), and ORRs were 12% (n=29, 95% CI: 8.07-16.56) and 10% (n=12, 95% CI: 5.10-16.29), respectively, with partial response in both arms (Δ 2.16, 95% CI: 4.86-9.18). See Figure 2.
Fig.2 PFS and ORR of IMscin001 study
The data for Part 2 of IMscin001 was updated in October this year, and the median dosing time was 7.1 minutes (95% CI: 6.6-7.4) in the SC group compared with 40.0 minutes (95% CI: 37.5-45.0) in the IV group, and the median survival follow-up time was 9.5 months, with a similar median OS in both groups (10.7 versus 10.1 months (HR 0.88; 95% CI: 0.67–1.16), See Figure 3.
Fig.3 OS of IMscin001 study
The study group further conducted a study on the preference of patients and healthcare workers to use atezolizumab SC or IV for the treatment of NSCLC (IMscin002), the results of which were presented at the 2024 European Conference on Lung Cancer (ELCC), indicating that atezolizumab SC is more popular among patients and has significant advantages due to its greater flexibility of use, shorter treatment time, and higher comfort during treatment.
02
Rebociclib in combination with AI was approved for HR+/HER2- early breast cancer
On September 17, 2024, the FDA officially approved rebociclib in combination with an aromatase inhibitor (Al) for the adjuvant treatment of adult patients with stage II and III stage II and stage III breast cancer with a high risk of recurrence who are hormone receptor positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-). Rebociclib is a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) approved in March 2017 for the first-line treatment of HR+/HER2- advanced breast cancer in postmenopausal women.
The approval of this new indication is based on the results of the global Phase III multicenter, randomized, open-label NATALEE study (NCT03701334). The study included 5101 adults with early-stage breast cancer with HR+/HER2- who were randomized in a 1:1 ratio to receive rebociclib in combination with a nonsteroidal aromatase inhibitor (NSAI) or NSAI alone, with the primary efficacy outcome being invasive disease-free survival (iDFS).
Data presented at the 2023 San Dantonio Breast Cancer Symposium (SABCS) showed a significant therapeutic benefit in the reboxiclib + NSAI combination group compared with the NSAI monotherapy group, with a three-year iDFS rate of 90.7% versus 87.6% (HR 0.749; 95% CI: 0.628-0.892; P=0.0006), respectively, as shown in Figure 4. Data updated at the European Society of Medical Oncology (ESMO) in 2024 showed that the benefit of the combination rebociclib + NSAI in the intention-to-treat (ITT) population was further expanded, with an absolute benefit of 4.9% (88.5% versus 83.6%; p＜0.0001）。
Fig. 4 Results of the 3-year iDFS study in NATALEE
03
Pembrolizumab in combination with chemotherapy was approved for the treatment of malignant pleural mesothelioma
On September 17, 2024, pembrolizumab was approved by the FDA for the first-line treatment of unresectable advanced or metastatic pleural mesothelioma in combination with pemetrexed and platinum-based chemotherapy, which is the first FDA-approved "immunoleast+chemotherapy" therapy for malignant pleural mesothelioma.
The approval is based on the results of the KEYNOTE-483 study (NCT02784171). The study is an open-label, randomized phase III clinical trial that enrolled patients with unresectable advanced or metastatic malignant pleural mesothelioma randomized in a 1:1 ratio to receive pembrolizumab + pemetrexed + platinum-based chemotherapy or pemetrexed + platinum-based chemotherapy alone. The primary endpoint was OS, and the secondary endpoints were PFS, ORR, and duration of response (DoR).
The results of the study were published in November 2023 in the top international journal The Lancet. The data showed a statistically significant improvement in OS and a 21 percent reduction in mortality risk with pembrolizumab plus chemotherapy compared with chemotherapy alone (17.3 versus 16.1 months) (HR 0.79; 95% CI: 14.4-21.3 months; p=0.0162); PFS was improved (HR 0.80; 95% CI 0.65-0.99; p=0.0194). In addition, patients in the combination group had a higher confirmed ORR (52 versus 29 percent) and a longer median DoR (6.9 versus 6.8 months).
Figure 5 Screenshot of KEYNOTE-483 research presentation
04
Amivantamab in combination with chemotherapy was approved for EGFR+ advanced NSCLC
On August 19, 2024, the FDA just approved amivantamab + Lazertinib for the first-line treatment of locally advanced or metastatic NSCLC harboring epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation. One month later, on September 19, amivantamab was approved for a new indication in combination with carboplatin/pemetrexed in adult patients with advanced NSCLC who had EGFR+ and whose disease had progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.
THE APPROVAL OF THE NEW INDICATION WAS BASED PRIMARILY ON THE RESULTS OF THE MARIPOSA-2 STUDY (NCT04988295). The study evaluated the efficacy and safety of amivantamab in combination with chemotherapy versus chemotherapy alone as a second-line treatment for EGFR+ advanced NSLCLC that has failed osimertinib. The primary endpoint of the study was PFS as assessed by a blinded independent review centre (BICR).
According to data presented at the 2024 ESMO Congress, amivantamab plus chemotherapy significantly improved PFS compared with chemotherapy alone (6.3 versus 4.2 months), reduced the risk of disease progression by 52% (HR 0.48; 95% CI: 0.36-0.64; P<0.001), and significantly improved both intracranial PFS and ORR. See Figure 6.
FIGURE 6 PFS FROM MARIPOSA-2 STUDY
05
Osimertinib was approved for the treatment of locally advanced, unresectable EGFR+ NSCLC following chemoradiotherapy
On September 25, 2024, osimertinib was approved by the FDA for the treatment of adult patients with locally advanced, unresectable stage III EGFR+ (exon 19 deletion or exon 21 L858R mutation) who have not progressed on or after concurrent or sequential platinum-based chemoradiotherapy.
The FDA's approval of osimertinib for a new indication is based on the strong results of the Phase III LAURA study (NCT03521154). LAURA is a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of osimertinib consolidation therapy in patients with EGFR-mutated stage III unresectable NSCLC.
According to data published at the 2024 Society of Clinical Oncology of United States (ASCO), osimertinib significantly longer PFS compared with placebo control (39.1 versus 5.6 months; HR 0.16；p<0.001）； PFS rates at 12 and 24 months were 74 and 65 percent in the osimertinib group, compared with 22 and 13 percent in the placebo group.
Figure 7 PFS of the LAURA study
The results were simultaneously published in the international authoritative journal NEJM. The excellent results of the LAURA study mark the success of the targeted therapy model for phase III unresectable EGFR-mutant NSCLC and fill this part of the treatment gap.
06
塞普替尼获批治疗RET+甲状腺髓样癌
On September 27, 2024, the FDA officially approved selpercatinib for adult and pediatric patients ≥ 2 years of age with advanced or metastatic medullary thyroid cancer with RET+ who require systemic therapy.
Selpercatinib is a potent, oral, highly selective RET kinase inhibitor. As early as May 2020, the FDA granted accelerated approval for selpercatinib for multiple indications, including adult and pediatric patients ≥ 12 years of age with advanced or metastatic RET+ medullary thyroid cancer requiring systemic therapy.
The approval is based on the results of the LIBRETTO-531 trial (NCT04211337). The study is a randomized, multicenter, open-label clinical trial in which patients are randomized in a 2:1 ratio to receive selpercatinib versus physician's choice of cabozantinib or vandetanib. The primary endpoint of the study was PFS as assessed by BICR according to RECIST v1.1.
In this analysis, median PFS was not achieved (NR) and the risk of disease progression or death was significantly reduced with selpercatinib compared with cabozantinib or vandetanib (16.8 months; 95% CI: 12.2-25.1) and significantly reduced risk of disease progression or death (HR 0.28; 95% CI: 0.16-0.48; p<0.001).
图8 LIBRETTO-531研究的PFS
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