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NSCLC Drug Development Updates | Lung cancer news


The Phase 3 MARIPOSA-2 study has achieved significant breakthroughs in treating EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC), particularly in patients who have experienced disease progression on osimertinib. The drug met the primary endpoint of progression-free survival.


MARIPOSA-2 is a Phase 3 trial for Rybrevant (amivantamab), a bispecific antibody aimed at improving outcomes for patients with EGFR-mutated NSCLC. The study investigated Rybrevant given in combination with chemotherapy (carboplatin and pemetrexed), with and without lazertinib, an oral third-generation EGFR tyrosine kinase inhibitor (TKI), compared to chemotherapy alone. The trial included patients with locally advanced or metastatic EGFR exon 19 deletions (ex19del) or L858R substitution NSCLC who had previously progressed on or after osimertinib treatment.


Importantly, MARIPOSA-2 successfully met its dual primary endpoint, demonstrating statistically significant improvement in PFS when Rybrevant was combined with chemotherapy, with or without lazertinib, compared to chemotherapy alone. Notably, no new safety concerns were identified with the addition of Rybrevant to chemotherapy.


Janssen intends to present these significant findings at upcoming scientific congresses, including detailed results on secondary endpoints such as overall survival (OS), objective response, duration of response (DoR), and intracranial PFS.




Roche's Alecensa has delivered groundbreaking Phase III results for individuals diagnosed with ALK-positive early-stage lung cancer. The ALINA study data demonstrates Alecensa's ability to reduce disease recurrence in the early stages of ALK-positive non-small cell lung cancer.


Despite the use of adjuvant chemotherapy following surgery, roughly half of NSCLC patients still face the recurrence of their disease, emphasizing the urgent need for new and effective treatments. These results from the ALINA study will be submitted to health authorities worldwide and presented at an upcoming medical conference.


Roche recently announced that the Phase III ALINA study, comparing Alecensa (alectinib) to platinum-based chemotherapy, achieved its primary endpoint of disease-free survival (DFS) during a predetermined interim analysis. In the trial, Alecensa exhibited both statistically significant and clinically meaningful improvements in DFS as an add-on therapy for patients with completely resected stage IB (tumor size ≥4cm) to IIIA ALK-positive NSCLC. Notably, as proven in a Phase III trial, Alecensa is the first and only ALK inhibitor to demonstrate a reduction in the risk of disease recurrence or death in early-stage ALK-positive NSCLC patients.

Although overall survival (OS) data were still preliminary at the time of this analysis, no unexpected safety concerns emerged from the study. Further insights from the ALINA study will be unveiled at an upcoming medical conference, and comprehensive submissions will be made to health authorities worldwide, including the FDA and the EMA.


Despite the utilization of adjuvant chemotherapy, nearly half of all early lung cancer patients (45-76%, depending on the disease stage) experience cancer recurrence after surgery. Recent advancements in treatment, such as immunotherapies, have provided hope for some early-stage NSCLC patients. However, there remains a lack of approved ALK inhibitors for those with early-stage ALK-positive disease. Approximately five percent of NSCLC patients are ALK-positive, and this subtype is more prevalent among younger individuals, typically 55 or younger, who have a history of light or non-smoking.


The ALINA study [NCT03456076] is a Phase III, randomized, active-controlled, multicenter, open-label research initiative evaluating the efficacy and safety of adjuvant Alecensa (alectinib) in comparison to platinum-based chemotherapy in individuals with completely resected stage IB (tumor size ≥4cm) to IIIA ALK-positive NSCLC. The study involved 257 randomly assigned to the investigational or control treatment group. The primary endpoint of the trial was disease-free survival (DFS), and overall survival was included as a secondary endpoint.

Alecensa is an orally administered, highly selective, central nervous system-active medication developed at Chugai, a Roche Group. It is designed for individuals diagnosed with non-small cell lung cancer (NSCLC) whose tumors have tested positive for anaplastic lymphoma kinase (ALK). Alecensa has received approval in over 100 countries as an initial (first-line) treatment for ALK-positive, metastatic NSCLC, including regulatory approvals in the United States, Europe, Japan, and China.



The latest data update from the TRIDENT-1 trial has unveiled the sustained efficacy advantages of repotrectinib for patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). This next-generation inhibitor has consistently displayed strong response rates and lasting treatment effects, including notable responses within the brain, for patients with ROS1-positive NSCLC who were either new to tyrosine kinase inhibitor (TKI) treatment or had previously received one TKI without chemotherapy.

The outcomes encompassing median duration of response and progression-free survival have been made available for the first time in the combined Phase 1 and Phase 2 population of patients diagnosed with ROS1-positive NSCLC. Bristol Myers Squibb (BMS) has announced these updates as part of the ongoing TRIDENT-1 study, a registrational endeavour that has showcased repotrectinib—a next-generation ROS1/TRK tyrosine kinase inhibitor—as a promising therapeutic option for ROS1-positive locally advanced or metastatic NSCLC. Based on the findings from the TRIDENT-1 trial, the Food and Drug Administration in the US has granted Priority Review and accepted the New Drug Application for repotrectinib's usage in treating ROS1-positive locally advanced or metastatic NSCLC.


This updated analysis underscores the continued and robust effectiveness of repotrectinib in treating ROS1-positive NSCLC patients, including those with brain involvement, either as a treatment-naïve subjects or individuals previously treated with a single TKI and no chemotherapy. Key findings from this updated analysis are as follows:

  1. For TKI-naïve patients (n=71) who were monitored for a median duration of 24.0 months, the confirmed objective response rate (cORR) assessed by Blinded Independent Central Review (BICR) was 79%. The median duration of response (DOR) and progression-free survival (PFS) reached 34.1 months and 35.7 months, respectively. Notably, in patients with baseline measurable brain metastases (n=9), there was an impressive intracranial ORR of 89%, with prolonged responses.

  2. Among patients previously treated with one TKI and no chemotherapy (n=56) who were followed for a median duration of 21.5 months, the cORR via BICR stood at 38%. Median DOR and PFS were observed to be 14.8 months and 9.0 months, respectively. For the subset of patients with measurable brain metastases at baseline (n=13), the intracranial ORR per BICR was 38%.

The safety profile of repotrectinib at the recommended Phase 2 dosage remained manageable and consistent with previous assessments. The study is ongoing, seeking to evaluate long-term outcomes and additional endpoints across various patient groups dealing with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors. Bristol Myers Squibb extends its gratitude to the participants and investigators contributing to the TRIDENT-1 clinical trial.



The Phase III trial, known as TROPION-Lung01, evaluating the efficacy of datopotamab deruxtecan (Dato-DXd) in advanced non-small cell lung cancer (NSCLC) patients, has achieved positive results in its primary endpoint of progression-free survival (PFS). AstraZeneca and Daiichi Sankyo jointly developed this TROP2-directed antibody-drug conjugate.


The trial included locally advanced or metastatic NSCLC patients previously treated with one therapy. The trial showed that there was a statistically significant improvement in PFS with datopotamab deruxtecan treatment compared to the standard chemotherapy, docetaxel. However, the data on the other primary endpoint, overall survival (OS), still needed to be mature at the time of this analysis. Although an early trend favouring datopotamab deruxtecan was observed, it did not reach the predetermined threshold for statistical significance.


AstraZeneca stated that the trial would continue to evaluate OS as planned, allowing for more comprehensive data analysis. Both the investigators and participants will remain blinded to the results.


The safety profile of datopotamab deruxtecan was in line with previous clinical trials, with no new safety concerns identified.



Merck announced the results of its Phase 3 KEYNOTE-671 trial, which aimed to investigate the effectiveness of Keytruda (pembrolizumab) in patients with resectable stage II, IIIA, or IIIB non-small cell lung cancer (NSCLC). The trial is continuing to evaluate the other key endpoint, overall survival.


The trial found that Keytruda, when given alongside chemotherapy before and after surgery, improved event-free survival (EFS) in these patients. EFS is defined as the time from randomization to disease recurrence, a new cancer diagnosis, or death from any cause.

Merck has submitted a new supplemental Biologics License Application (sBLA) based on the KEYNOTE-671 trial. The new indication extension in combination with chemotherapy is for patients with resectable stage II, IIIA, or IIIB NSCLC as neoadjuvant treatment.


 

Oct 05, 2022

GSK announced positive results from PERLA, a head-to-head trial of Jemperli versus Keytruda

GSK announced that in the PERLA Phase 2 trial, Jemperli (dostarlimab) met the primary endpoint of objective response rate. The trial is evaluating the dostarilab plus chemotherapy combination versus pembrolizumab plus chemotherapy in first-line patients with metastatic non-small cell lung cancer (NSCLC).


PERLA trial included 243 patients, the largest head-to-head trial of programmed death receptor-1 (PD-1) inhibitors in NSCLC. GSK announced that it was not designed to demonstrate superiority over Keytruda. The safety profile was consistent with the previous studies.

GSK also announced that it is advancing both the arms of the COSTAR trial into Phase 3. The COSTAR is an open-label trial comparing cobolimab, dostarlimab, and docetaxel combination versus dostarlimab plus docetaxel versus docetaxel alone in patients with NSCLC who have disease progression after PD-L1 therapy and chemotherapy.





 

Aug 15, 2022

Canakinumab failed to meet the primary endpoint in NSCLC patients.

Novartis gave an update on the Phase III CANOPY-A trial stating that canakinumab did not meet the primary endpoint in stages II-IIIA and IIIB completely resected non-small cell lung cancer patients. There was no improvement in the disease-free progression survival compared to placebo.

CANOPY-A trial recruited 1,382 patients and was randomized in 1:1 for canakinumab and placebo.




 

Jan 10, 2022

Merck's Keytruda showed improvement in disease-free survival versus placebo in stage IB-IIIA NSCLC regardless of PD-L1 expression

Merck has announced that the European Organisation for Research and Treatment of Cancer (EORTC) and the European Thoracic Oncology Platform (ETOP) stated that Keytruda had met the primary endpoint in Phase 3 KEYNOTE-091 trial.

Merck's anti-PD-1 therapy, Keytruda (pembrolizumab), met one of its dual primary endpoints of disease-free survival (DFS) in patients stage IB-IIIA non-small cell lung cancer (NSCLC) following surgery, irrespective of the PD-L1 expression. Based on the independent Data Monitoring Committee results, Keytruda has met the primary endpoint in the interim analysis in patients with stage IB-IIIA NSCLC.

In the interim analysis, there was an improvement in the DFS in patients whose disease expressed PD-L1; however, it has not met the statistical significance. The company announced that the trial would evaluate DFS in patients whose tumors express a high level of PD-L1 and overall survival, a key secondary endpoint.

The safety profile is consistent with the existing safety profile of Keytruda.



AbbVie's telisotuzumab vedotin received breakthrough therapy designation from the US FDA

AbbVie has announced that it has received the breakthrough therapy designation from the US FDA for telisotuzumab vedotin to treat non-small cell lung cancer patients in the second line.

Telisotuzumab vedotin is an antibody-drug conjugate and is in development for advanced/metastatic epidermal growth factor receptor (EGFR) wild type, NSLCLC with c-Met overexpression. It is being evaluated in patients who were previously treated with platinum-based therapy.


Currently, there are no drugs for NSCLC with c-Met overexpression. AbbVie is currently conducting a Phase II trial, and a Phase III trial is being planned to start in the first half of 2022.

The breakthrough therapy designation was based on Phase II LUMINOSITY (Study M14-239) trial, in which the efficacy of telisotuzumab is being evaluated in NSCLC patients who overexpressed c-Met. The primary endpoint is the overall response rate in patients with ≥ 12 weeks follow-up.


In patients with EGFR WT nonsquamous NSCLC, the overall response rate was 53.8% in patients with high expression of c-Met and 25% in the c-Met intermediate group.

The drug is still under evaluation for efficacy and safety and has not received approval anywhere in the world.


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