Top 10 Successful Clinical Studies of August 2023 Highlight Promising Advances in Oncology Therapeutics

PharmaCube DeepMed Database"Evidence-based Data"Section, tracking the latest progress in global oncology literature, international conference data, and corporate news announcements, screens out clinical studies with positive results each month for reference.

1. BP1001-201-AML Study

On August 1, Bio-Path Holdings announced interim data from the second phase of its Phase II trial evaluating prexigebersen, an investigational antisense oligodeoxynucleotide therapy, in combination with decitabine and venetoclax for the treatment of acute myeloid leukemia (AML). Analysis indicates that the therapy was well-tolerated and demonstrated superior efficacy compared to current first-line treatments across two cohorts.

Phase II, Stage 2 is a multicenter, open-label study designed with three patient cohorts, providing Bio-Path Holdings with three registration pathways:

Cohort 1Prexigbersen in combination with decitabine and venetoclax for the treatment of newly diagnosed AML patients.

Cohort 2：Prexigbersen in combination with decitabine and venetoclax for the treatment of refractory/relapsed AML patients.

Cohort 3: For refractory/relapsed AML patients with venetoclax resistance or intolerance, treatment with prexigebersen in combination with decitabine is administered.

The primary purpose of this study is to evaluate whether the response rate of prexigebersen in combination with decitabine + venetoclax in AML patients is higher than that of decitabine + venetoclax alone, and whether the response rate of prexigebersen in combination with decitabine in AML patients is higher than that of decitabine alone.

In Cohort 1, 14 newly diagnosed AML patients were evaluable and received at least one cycle of prexigbersen in combination with decitabine + venetoclax. Prexigbersen was well-tolerated, with adverse events (AEs) showing no significant differences compared to decitabine ± venetoclax. Among the 14 evaluable patients, 12 (86%) achieved complete remission (CR/CRi), and 2 (14%) achieved partial remission (PR). Numerically, this exceeded the 62% CR/CRi rate observed with frontline treatment using decitabine + venetoclax in newly diagnosed patients. Cohort 1 of Bio-Path Holdings included high-risk and secondary AML patients (29%), with results consistent with the overall outcomes; both categories represent particularly difficult-to-treat diseases.

In Cohort 2, 14 patients with refractory/relapsed AML received at least one cycle of prexigbersen in combination with decitabine and venetoclax. Among the 14 evaluable patients, 8 (57%) achieved CR/CRi, 2 (14%) achieved PR, and 3 (22%) achieved SD. Overall, these figures are numerically higher than the CR/CRi rate (21%) observed with decitabine and venetoclax in refractory/relapsed patients.

2. LIBRETTO-431 Study

On August 4, Eli Lilly announced the results of the LIBRETTO-431 study, which evaluated the efficacy of selpercatinib (Retsevmo) versus pemetrexed plus platinum-based chemotherapy (with or without pembrolizumab) as a first-line treatment for patients with RET fusion-positive advanced or metastatic NSCLC. The study met its primary endpoint, showing a statistically significant and clinically meaningful improvement in PFS for selpercatinib compared to the control group. LIBRETTO-431 is the first randomized study to compare the safety and efficacy of targeted therapy versus a PD-1 inhibitor plus chemotherapy in a specific genomic biomarker patient population.

3. TRIDENT-1 Study

The results of the TRIDENT-1 study were announced during the 2023 WCLC conference. The incidence of ROS1 fusion, a driver gene in NSCLC, is approximately 2%. Currently, standard treatments for these patients include ROS1 inhibitors such as crizotinib and entrectinib, but the duration of response is limited, and there is still room for improvement in intracranial control rates.

Repotrectinib is a new generation ROS1 and TRK inhibitor. The updated data from the TRIDENT-1 report shows that in ROS1-positive NSCLC patients, the follow-up time ranged from 21.5 to 24 months.

The study design is shown in the figure below. In the Phase II dose-expansion cohort, patients were divided into four groups: 1) Patients who had not previously received ROS1-TKI treatment; 2) Patients who had previously received one ROS1-TKI and one platinum-based chemotherapy; 3) Patients who had previously received two ROS1-TKIs and had not received chemotherapy; 4) Patients who had previously received one ROS1-TKI and had not received chemotherapy.

The primary endpoint is the ORR assessed by BICR (Blinded Independent Central Review), and secondary endpoints include DOR, CBR (Clinical Benefit Rate), TTR (Time to Response), PFS, OS, and safety, among others. The data reported this time are for Cohort 1 (n=71) and Cohort 4 (n=56).

The results showed that in patients who had not previously received TKI treatment, the ORR was 79%, the median DOR was 34.1 months, the median PFS was 35.7 months, and the median OS was NE.

In patients previously treated with one ROS1-TKI and without prior chemotherapy, the ORR was 38%, the median DOR was 14.8 months, the median PFS was 9.0 months, and the median OS was 25.1 months.

In patients with brain metastases at baseline, the intracranial ORR was 89% in those who had not previously received TKI and 38% in those who had received TKI. In patients without brain metastases at baseline, the 12-month intracranial PFS rates were 91% in those who had not previously received TKI and 82% in those who had received TKI.

In terms of drug resistance, no patients who had not previously received TKI treatment developed on-target resistance mutations after treatment with Repotrectinib. In patients who had previously received TKI treatment and had baseline G2032R mutations, the ORR was 59%, the median DOR was 7.6 months, and the median PFS was 9.2 months.

4. CHRYSALIS-2 Study

During the 2023 WCLC conference, the results of the CHRYSALIS-2 study were announced. Amivantamab is an EGFR-MET bispecific antibody, and Lazertinib is a third-generation EGFR-TKI with CNS penetration, demonstrating anti-tumor activity against EGFR-sensitive mutations, T790M mutations, and brain metastases. The combination of targeted drugs inhibiting the EGFR/MET signaling pathway with platinum-based chemotherapy may address resistance issues following progression on Osimertinib.

CHRYSALIS-2 is a Phase I clinical trial that enrolled 20 patients with EGFR-mutant advanced NSCLC who had previously received EGFR-TKI treatment (up to three lines of therapy). As of November 15, 2022, the median follow-up time was 13.1 months. The results showed that 18/20 (90%) patients developed neutropenia, including 14 cases of ≥Grade 3 AE, most commonly occurring during the first treatment cycle; no patients experienced febrile neutropenia. Additionally, 8/20 (40%) patients developed thrombocytopenia, including 5 cases of ≥Grade 3 AE.

ORR was 50%, median DOR not evaluable; as of the cutoff date, 8 of 10 patients remained in response, with 8 having DOR ≥6 months, and CBR was 80%.

The median PFS was 14.0 months, with a 6-month PFS rate of 70% and a 1-year PFS rate of 59%. The median OS was not reached, and the 1-year OS rate was 80%. The safety and efficacy of this treatment regimen will be further evaluated in the Phase III randomized MARIPOSA-2 study (NCT04988295).

5. HERTHENA-Lung01 Study

HERTHENA-Lung01 data were presented at the 2023 WCLC conference and simultaneously published in the JCO journal.

Patritumab deruxtecan (HER3-DXd) is an ADC drug composed of a HER3 monoclonal antibody, a cleavable linker, and a topoisomerase I inhibitor payload. HERTHENA-Lung01 is a Phase II study (NCT04619004) designed to evaluate the efficacy and safety of HER3-ADC in patients with advanced EGFR-mutated NSCLC who have progressed after prior treatment with EGFR-TKI and platinum-based chemotherapy (PBC). Patients received HER3-DXd at 5.6 mg/kg intravenously every 3 weeks or an escalating dosing regimen (3.2 → 4.8 → 6.4 mg/kg). The primary endpoint was BICR ORR.

The results showed that 225 patients received HER3-DXd 5.6 mg/kg treatment. As of May 18, 2023, the median study duration was 18.9 months, with a BICR ORR of 29.8%, a median DOR of 6.4 months, a median PFS of 5.5 months, and a median OS of 11.9 months.

In subgroup of patients previously treated with osimertinib and PBC, the results were similar. Efficacy was observed in patients who had received multiple prior treatments, across different levels of HER3 expression, and with various EGFR-TKI resistance mechanisms. In brain metastasis patients who had not received radiotherapy at baseline (n=30), the CNS ORR was 33.3%. Safety was consistent with previous observations.

Overall, treatment with HER3-DXd demonstrated clinically meaningful efficacy, including in patients with CNS metastases. A phase III trial in EGFR-mutated NSCLC progressing after EGFR-TKI therapy is currently ongoing.

6. FLAURA2 Study

The FLAURA2 study was also presented at the 2023 WCLC conference. This is an international, multicenter, Phase III randomized controlled clinical trial designed to evaluate the efficacy and safety of osimertinib combined with pemetrexed and platinum-based chemotherapy versus osimertinib monotherapy as first-line treatment for patients with EGFR sensitizing mutations (19del, 21 L858R mutations) in advanced NSCLC. Patients were randomized in a 1:1 ratio to receive either osimertinib plus chemotherapy or osimertinib alone. The primary endpoint was PFS assessed by BICR. Secondary endpoints included OS, PFS2, ORR, health-related quality of life, CNS PFS, and safety, among others. Data cut-off date was April 3, 2023.

A total of 557 patients were enrolled and randomly assigned to the osimertinib plus chemotherapy group (n=279) or the osimertinib monotherapy group (n=278). The median PFS assessed by investigators was 25.5 months vs. 16.7 months (HR=0.62, P<0.0001) for the combination therapy group and the monotherapy group, respectively. The median PFS assessed by BICR was 29.4 months vs. 19.9 months (HR=0.62, P=0.0002), respectively.

Subgroup analysis showed that in the ex19del subgroup, the median PFS for the combination chemotherapy group and the monotherapy group were 27.9 months vs. 19.4 months (HR=0.60), respectively; in the L858R mutation subgroup, the median PFS for the two groups were 24.7 months vs. 13.9 months (HR=0.63), respectively. In patients with baseline brain metastases, the median PFS for the two groups were 24.9 months vs. 13.8 months (HR=0.47), respectively, while in the subgroup without baseline brain metastases, the median PFS was longer in the combination chemotherapy group, reaching 27.6 months (vs. 21.0 months, HR=0.75).

The ORR for the combination chemotherapy group and the single-agent group were 83% and 76%, respectively, and the DOR were 24.0 months and 15.3 months, respectively. At the time of this data release, PFS2 and OS were not yet mature.

In terms of safety, the incidence of ≥3 grade adverse events (AEs) caused by any reason in the combination chemotherapy group and the single-agent group were 64% and 27%, respectively, and the incidence of any AEs leading to discontinuation were 48% and 6%, respectively.

7, LOTIS-5, LOTIS-7 Studies

On August 30, ADC Therapeutics SA announced that two abstracts (LOTIS-5 and LOTIS-7) on loncastuximab tesirine-lpyl (product name: ZYNLONTA, anti-CD19-ADC) were presented at the 11th Annual Meeting of the Society of Hematologic Oncology from September 6 to 9, 2023.

LOTIS-5，It is a Phase III, randomized, open-label, two-stage, two-arm, multicenter study investigating loncastuximab tesirine in combination with rituximab (Lonca-R) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). This is the confirmatory trial for accelerated approval as a third-line treatment and will also support a potential indication expansion to second-line use in combination with rituximab. In the first part of the trial, 20 patients will undergo a non-randomized safety evaluation. In the second part, approximately 330 patients will be randomized in a 1:1 ratio to receive either a fixed dose of Lonca-R or rituximab-gemcitabine-oxaliplatin (R-GemOx).

Among the 20 patients in the safety trial, the median age was 74.5 years, having received 5 cycles of Lonca-R and one prior treatment. Data cutoff date was April 10, 2023. Seven patients completed the treatment, and 5 patients continued follow-up. The central evaluation showed an overall response rate of 16/20 (80%). A total of 10/20 (50%) and 6/20 (30%) patients achieved CR and PR, respectively. The median DOR was 8.0 months, and the median PFS was 8.3 months. Eleven (55%) patients experienced ≥ Grade 3 treatment-emergent adverse events (TEAEs). The most common ≥ Grade 3 TEAEs were increased gamma-glutamyl transferase (5 cases [25%]) and neutropenia (3 cases [15%]).

LOTIS-7, is a Phase Ib open-label study of Loncastuximab Tesirine in combination with other anti-cancer drugs for the treatment of relapsed or refractory B-cell non-Hodgkin lymphoma. Approximately 200 patients with relapsed or refractory B-cell non-Hodgkin lymphoma are planned to be enrolled, with the first part (approximately 60 patients, dose escalation) and the second part (approximately 120 patients, dose expansion). The dosing regimens include ZYNLONTA (loncastuximab tesirine-lpyl) + polatuzumab vedotin, as well as ZYNLONTA (loncastuximab tesirine-lpyl) + glofitamab and mosunetuzumab (anti-CD3/CD20 bispecific antibodies). The study is currently actively recruiting patients.

8. LITESPARK-005 Study

On August 18, MSD announced that the Phase III LITESPARK-005 study of Belzutifan (brand name: Welireg) for the treatment of advanced renal cell carcinoma (RCC) met the primary endpoint of significant PFS prolongation. The other primary endpoint, OS, showed a trend of extension but has not yet demonstrated statistical significance, and OS will continue to be evaluated subsequently. In addition, this study also achieved the secondary endpoint of a significant improvement in ORR.

LITESPARK-005 Study is a randomized, open-label clinical trial that enrolled 746 patients with advanced RCC whose disease progressed after prior treatment with PD-(L)1 inhibitors and anti-VEGF therapies. The study aims to compare the efficacy and safety of Belzutifan versus Everolimus. Detailed study data will be presented at an upcoming medical conference.

Belzutifan is a small-molecule hypoxia-inducible factor 2α (HIF-2α) inhibitor that reduces the transcription and expression of HIF-2α target genes associated with cell proliferation, angiogenesis, and tumor growth. In August 2021, Belzutifan received accelerated FDA approval based on Phase II clinical data for the treatment of patients with von Hippel-Lindau disease (VHL)-associated renal cell carcinoma, central nervous system hemangioblastoma, or pancreatic neuroendocrine tumors who do not require immediate surgery. It became the world’s first and currently only approved HIF-2α inhibitor. Globally, there are only seven HIF-2α inhibitors currently in clinical development, one of which comes from the Chinese pharmaceutical company, Betta Pharmaceuticals.

9, CONTACT-02 Study

On August 21, Exelixis and Ipsen jointly announced that the Phase III CONTACT-02 study evaluating cabozantinib in combination with atezolizumab for the treatment of metastatic castration-resistant prostate cancer (mCRPC) met the primary endpoint of PFS in an interim analysis. The CONTACT-02 study is a randomized, open-label clinical trial that enrolled 575 patients with mCRPC who had previously received only one hormonal therapy (e.g., abiraterone, apalutamide, darolutamide, or enzalutamide). The study aims to evaluate the efficacy and safety of cabozantinib plus atezolizumab compared to new hormonal therapies (abiraterone + prednisone or enzalutamide). The primary endpoints of the study include PFS and OS. According to the press release, PFS was significantly prolonged in the cabozantinib plus atezolizumab group. However, no statistically significant improvement in OS has been observed yet, though a trend toward prolongation has emerged. Exelixis and Ipsen will continue to assess OS data. We look forward to the release of further detailed data.

10. HER2CLIMB-02 Study

On August 16, Seagen announced that the Phase III HER2CLIMB-02 clinical trial of TUKYSA (tucatinib) in combination with the ADC trastuzumab emtansine had met its primary endpoint of PFS. The trial enrolled patients with unresectable locally advanced or metastatic HER2-positive breast cancer who had previously received taxane and trastuzumab treatment. The OS data, a secondary endpoint, remain immature. Discontinuation due to adverse events was more common in the combination therapy group, but no new safety signals emerged with the combination.

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