NVL-330 for Advanced Lung Cancer

Recruiting at 15 trial locations

Overseen By Lisa Morelli

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Nuvalent Inc.

Disqualifiers: Other oncogenic drivers, Allergy, Recent surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

120 Participants Needed

Trial Summary

What is the purpose of this trial?

Phase 1a/1b dose escalation and expansion study designed to evaluate the safety and tolerability of NVL-330, determine the recommended Phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced or metastatic HER2-altered NSCLC. Phase 1a dose escalation is designed to assess the safety and tolerability of NVL-330 and to select the candidate RP2D(s) and, if applicable, the MTD. Phase 1b expansion is designed to further evaluate the overall safety and tolerability of the candidate RP2D(s) of NVL-330 and to determine the RP2D of NVL 330 in patients with advanced or metastatic HER2 mutant NSCLC.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are currently receiving ongoing or recent anticancer therapy, you may not be eligible to participate.

What safety data exists for nivolumab in treating advanced lung cancer?

Nivolumab has been shown to increase the risk of immune-related side effects, such as pneumonitis (lung inflammation), in patients with advanced lung cancer. While it does not increase the risk of common side effects like fatigue or liver issues, the potential for serious immune-related side effects is a concern. ^{1 2 3 4 5}

How is the drug NVL-330 different from other treatments for advanced lung cancer?

The drug NVL-330 is unique because it may offer a novel approach compared to existing treatments like nivolumab, which targets the PD-1 pathway to help the immune system fight cancer. While standard treatments often involve chemotherapy or other immune checkpoint inhibitors, NVL-330 could provide a new mechanism of action or administration method that distinguishes it from these options. ^{6 7 8 9 10}

Research Team

Steve Margossian, MD PhD

Principal Investigator

Nuvalent Inc.

Eligibility Criteria

This trial is for patients with advanced or metastatic non-small cell lung cancer (NSCLC) that has a specific change in their DNA called HER2 alteration. The study is open to those who have not responded well to standard treatments.

Inclusion Criteria

My cancer has a specific HER2 mutation or amplification.

My lung cancer is advanced or has spread to other areas.

Identification of lesions as follows: Phase 1a - Must have evaluable disease (target or nontarget) according to RECIST 1.1. Phase 1b - Must have measurable disease, defined as ≥ 1 radiologically measurable target lesion according to RECIST 1.1.

Exclusion Criteria

I am allergic to ingredients in NVL-330.

My cancer is driven by a genetic change not related to HER2.

I am currently receiving or have recently finished cancer treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Dose Escalation

Participants receive NVL-330 to assess safety, tolerability, and select the candidate RP2D(s) and MTD

4 weeks

Multiple visits for dose escalation and monitoring

Phase 1b Dose Expansion

Further evaluation of safety and activity to confirm the RP2D(s) of NVL-330

Ongoing until RP2D is confirmed

Regular visits for safety and efficacy assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-3 years

Treatment Details

Interventions

• NVL-330

Trial Overview The HEROEX-1 trial is testing NVL-330's safety, tolerability, and effectiveness against tumors. It includes an initial phase to find the best dose and a later phase to confirm this dose's safety and how well it works on a larger group.

Participant Groups

Group I: Phase 1b dose expansion Experimental Treatment 1 Intervention

NVL-330 oral daily dosing

Group II: Phase 1a dose escalation Experimental Treatment 1 Intervention

NVL-330 oral daily dosing

Who Is Running the Clinical Trial?

Nuvalent Inc.

Lead Sponsor

Trials

6

Recruited

1,400+

Findings from Research

In a study of 25 patients with stage IIIa lung adenocarcinoma, the combination of bevacizumab with pemetrexed and carboplatin as neoadjuvant chemotherapy showed a safety profile with manageable adverse events, including some cases of fatigue, neutropenia, and hypertension.

No severe perioperative complications such as hemorrhage or thromboembolic events were observed, suggesting that the neoadjuvant treatment is well-tolerated and safe for patients undergoing surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin in Patients with IIIa Lung Adenocarcinoma]. Zhang, S., Xu, P., Yuan, C., et al.[2019]

Nivolumab significantly improved overall survival, progression-free survival, and overall response rates in 4705 patients with advanced or recurrent non-small-cell lung cancer (NSCLC) across seven phase III trials.

While nivolumab did not increase the risk of common side effects like fatigue or liver issues, it did raise the risk of immune-related adverse events, including pneumonitis, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nivolumab for advanced/recurrent non-small-cell lung cancer: an up-to-date meta-analysis of large-scale phase III randomized controlled trials. Zhang, H., Zhang, L., Chen, K., et al.[2022]

In a study of patients with non-small cell lung cancer treated with nivolumab, those who experienced serious adverse events (grade ≥3) had significantly better overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared to those without such events.

The findings suggest that while serious adverse events are typically concerning, they may be associated with a more favorable treatment response in patients receiving nivolumab, indicating a complex relationship between adverse effects and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serious Immune-related Adverse Events Are Associated With Greater Efficacy of Nivolumab Therapy Against Non-small Cell Lung Cancer. Blazek, J., Hosek, P., Hrabcova, K., et al.[2023]

In a study of 229 advanced Non-Small Cell Lung Cancer (NSCLC) patients treated with Nivolumab, the Overall Response Rate (ORR) was 22.4%, indicating that a significant portion of patients experienced some level of tumor reduction.

The safety profile of Nivolumab in this real-world setting was consistent with clinical trial data, suggesting it is a viable treatment option for previously treated NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC). Figueiredo, A., Almeida, MA., Almodovar, MT., et al.[2020]

In a pilot trial involving 6 previously treated NSCLC patients with mild idiopathic interstitial pneumonia (IIP), nivolumab was administered biweekly without causing any severe drug-related adverse events or pneumonitis, indicating a favorable safety profile.

All patients remained alive after 12 weeks of treatment, with 3 showing a partial response, suggesting that nivolumab may be an effective option for NSCLC patients with mild IIP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia. Fujimoto, D., Morimoto, T., Ito, J., et al.[2018]

In a phase 3 study involving 272 patients with advanced squamous-cell non-small-cell lung cancer, nivolumab significantly improved overall survival (9.2 months) compared to docetaxel (6.0 months), with a 41% lower risk of death.

Nivolumab also had a better safety profile, with only 7% of patients experiencing severe treatment-related adverse events, compared to 55% in the docetaxel group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. Brahmer, J., Reckamp, KL., Baas, P., et al.[2022]

Chemotherapy, typically involving cisplatin or carboplatin combined with a third-generation cytotoxic agent, is the standard treatment for patients with metastatic non-small cell lung cancer who have a good performance score, with a recommended duration of at least 3 to 4 cycles unless the disease progresses.

For older patients over 70 with a good performance score, chemotherapy remains the standard treatment, although the specific regimen is still uncertain; this approach aims to enhance survival and quality of life, especially for those experiencing tumor relapse or disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy for metastased non-small cell lung cancer]. Groen, HJ., Smit, EF., Sleijfer, DT.[2013]

In a phase 2 trial involving 117 patients with advanced, refractory squamous non-small-cell lung cancer, nivolumab demonstrated a 14.5% objective response rate, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with 17% of patients experiencing severe treatment-related adverse events, suggesting that while there are risks, the benefits may outweigh them for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Rizvi, NA., Mazières, J., Planchard, D., et al.[2022]

Nivolumab is the first approved immunotherapy for advanced non-small cell lung cancer (NSCLC), showing a partial or complete tumor response in 15-20% of patients, regardless of prior treatments.

The side effects of nivolumab are generally milder and less frequent than traditional chemotherapy, with most adverse events being reversible, although serious immune-related effects like fatal pneumonitis can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of nivolumab in advanced (metastatic) non-small cell lung cancer. Tanvetyanon, T., Creelan, BC., Antonia, SJ.[2018]

Recent approvals of novel therapies, such as antiangiogenics (nindetanib and ramucirumab) and immunotherapies (nivolumab, pembrolizumab, and atezolizumab), provide new treatment options for patients with advanced non-small cell lung cancer (NSCLC) who have limited benefits from traditional therapies.

The paper emphasizes the need to understand how these new therapies are integrated into clinical practice and proposes a shared algorithm for second-line treatment in advanced NSCLC, highlighting the importance of optimizing patient care with these emerging options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line Treatment of Advanced Non-small Cell Lung Cancer Non-oncogene Addicted: New Treatment Algorithm in the Era of Novel Immunotherapy. Gridelli, C., Ascierto, PA., Grossi, F., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

[Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin in Patients with IIIa Lung Adenocarcinoma]. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nivolumab for advanced/recurrent non-small-cell lung cancer: an up-to-date meta-analysis of large-scale phase III randomized controlled trials. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

Serious Immune-related Adverse Events Are Associated With Greater Efficacy of Nivolumab Therapy Against Non-small Cell Lung Cancer. [2023]

4. Spain pubmed.ncbi.nlm.nih.gov

Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC). [2020]

5. Ireland pubmed.ncbi.nlm.nih.gov

A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

[Chemotherapy for metastased non-small cell lung cancer]. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

The safety and efficacy of nivolumab in advanced (metastatic) non-small cell lung cancer. [2018]

10. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Second-line Treatment of Advanced Non-small Cell Lung Cancer Non-oncogene Addicted: New Treatment Algorithm in the Era of Novel Immunotherapy. [2021]