NVL-330 for Advanced Lung Cancer

Recruiting at 22 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

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called NVL-330 for individuals with advanced lung cancer that involves a specific change in the HER2 gene. The main goal is to determine the safety and effectiveness of NVL-330 against the cancer. Researchers seek participants whose lung cancer has spread and is associated with HER2 mutations. Those living with this type of lung cancer who haven't responded well to other treatments might be suitable candidates. As a Phase 1 trial, participants could be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

Is there any evidence suggesting that NVL-330 is likely to be safe for humans?

Research shows that NVL-330 remains in the early testing stages, so limited safety information in humans is available. The primary goal is to determine if people can take NVL-330 without major side effects. In this initial testing phase, researchers closely observe how the body responds to the new drug.

Earlier lab studies designed NVL-330 to target specific cancer cells while minimizing harm to healthy cells. This is promising, but human studies are necessary for confirmation. Currently, doctors aim to find the safest dose with minimal side effects. No major negative effects have been widely reported so far, but more information is needed as testing continues.

Prospective trial participants should know that researchers are committed to ensuring safety and will closely monitor participants for any issues. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for advanced lung cancer, which often include chemotherapy, targeted therapies, and immunotherapies, NVL-330 is unique because it is administered orally, offering a potentially more convenient option for patients. What's particularly exciting about NVL-330 is its novel mechanism of action, targeting specific pathways involved in the growth of cancer cells. This could lead to more effective and possibly less toxic treatment outcomes compared to traditional therapies. Researchers are hopeful that NVL-330 will provide new hope for patients with advanced lung cancer by tackling the disease in a completely new way.

What evidence suggests that NVL-330 might be an effective treatment for advanced lung cancer?

Research shows that NVL-330 is a promising new treatment for certain lung cancers with HER2 mutations. Early lab studies found that NVL-330 effectively blocks different types of HER2 changes, which are common in some advanced lung cancers. This targeted action might help slow cancer growth and spread. Initial studies in patients with similar HER2 mutations suggest that targeted treatments can lead to better outcomes. This trial tests NVL-330 in two phases, Phase 1a dose escalation and Phase 1b dose expansion, to determine if it can provide similar benefits to patients with advanced HER2-altered lung cancer. ^{4 6 7 8 9}

Who Is on the Research Team?

Steve Margossian, MD PhD

Principal Investigator

Nuvalent Inc.

Are You a Good Fit for This Trial?

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.

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.

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. targetedonc.com targetedonc.com/view/heroex-1-trial-begins-for-her2-selective-inhibitor-nvl-330-in-nsclc

HEROEX-1 Trial Begins for HER2-Selective Inhibitor NVL- ... The first pretreated patient with HER2-altered non–small cell lung cancer was dosed with NVL-330, a novel HER2-selective inhibitor, in the HEROEX-1 trial.

2. investors.nuvalent.com investors.nuvalent.com/2024-07-22-Nuvalent-Announces-First-Patient-Dosed-in-HEROEX-1-Phase-1a-1b-Clinical-Trial-of-NVL-330,-its-Novel-HER2-selective-Inhibitor

Nuvalent Announces First Patient Dosed in HEROEX-1 ... NVL-330 is currently being investigated in the HEROEX-1 Phase 1a/1b clinical trial for pre-treated patients with advanced HER2-altered NSCLC.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12226463/

HER2 alterations in non-small cell lung cancer (NSCLC) With the advent of new-targeted therapies explicitly targeting HER2 mutations, the prognosis for patients with HER2-mutant NSCLC is improving. However, ...

4. aacrjournals.org aacrjournals.org/cancerres/article/84/6_Supplement/1979/738028/Abstract-1979-Preclinical-characterization-of-NVL

Preclinical characterization of NVL-330, a selective and brain ... Results: NVL-330 broadly inhibited HER2 oncogenic alterations, including amplified wild-type HER2, HER2 exon20ins and non-exon20ins mutants, ...

5. withpower.com withpower.com/trial/phase-1-solid-metastatic-tumor-6-2024-6b35a

NVL-330 for Advanced Lung Cancer 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 ...

6. prnewswire.com prnewswire.com/news-releases/nuvalent-to-present-new-preclinical-data-for-her2-selective-inhibitor-nvl-330-at-aacr-nci-eortc-international-conference-on-molecular-targets-and-cancer-therapeutics-302582286.html

Nuvalent to Present New Preclinical Data for HER2- ... Nuvalent to Present New Preclinical Data for HER2-Selective Inhibitor, NVL-330, at AACR-NCI-EORTC International Conference on Molecular Targets ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06521554

NCT06521554 | A Study of NVL-330 in Patients With ... 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), ...

8. investors.nuvalent.com investors.nuvalent.com/2025-04-23-Nuvalent-to-Present-Trial-in-Progress-Posters-for-the-ALKAZAR-Trial-of-Neladalkib-and-HEROEX-1-Trial-of-NVL-330-at-the-2025-American-Society-of-Clinical-Oncology-Annual-Meeting

Nuvalent to Present Trial in Progress Posters for the ... NVL-330 is a novel brain-penetrant HER2-selective tyrosine kinase inhibitor designed to address the combined medical need of treating HER2- ...

9. clin.larvol.com clin.larvol.com/trial-detail/NCT06521554

A Study of NVL-330 in Patients With Advanced or ... HEROEX-1 is a Phase 1a/1b, multicenter, open-label, dose-escalation and expansion trial evaluating NVL-330 in pre-treated patients with advanced HER2-altered ...