Tomivosertib for Non Small Cell Lung Cancer

(KICKSTART Trial)

No longer recruiting at 106 trial locations

Overseen By Mark Densel

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 2

Sponsor: Effector Therapeutics

Must be taking: Pembrolizumab

Must not be taking: Prednisone

Disqualifiers: EGFR, ALK, GI disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs, tomivosertib and pembrolizumab (an immunotherapy drug), for treating non-small cell lung cancer (NSCLC). The researchers aim to determine if adding tomivosertib can improve outcomes for patients with specific types of NSCLC. Different groups in the trial assess how the combination works at various treatment stages, including those already on pembrolizumab or who have completed certain chemotherapy cycles. The trial seeks participants with advanced or metastatic NSCLC who are currently managing their condition with pembrolizumab or are eligible for such treatments. This Phase 2 trial focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important advancements in NSCLC treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that participants must not have been treated with certain chemotherapy recently, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using tomivosertib with pembrolizumab to treat non-small cell lung cancer (NSCLC) has had limited success, with studies noting this modest effectiveness. However, detailed information about safety issues or side effects remains scarce.

For pembrolizumab alone, more information is available. It is a well-known treatment for NSCLC and has been thoroughly researched, proving to help patients live longer.

Adding pemetrexed, a chemotherapy drug, to pembrolizumab has also been studied. This combination has been associated with better survival rates in patients with non-squamous NSCLC and is generally well-tolerated.

Since this trial is in the middle stage of testing (Phase 2), the treatment is still being assessed for safety and effectiveness. Researchers are gathering more data to understand how well patients handle the combination of tomivosertib with pembrolizumab, and with pemetrexed in certain cases. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about tomivosertib for non-small cell lung cancer (NSCLC) because it offers a novel approach by targeting a unique mechanism in cancer cells. Unlike standard treatments that primarily focus on blocking immune checkpoints like PD-1/PD-L1 with drugs such as pembrolizumab, tomivosertib works by inhibiting MNK1/2 kinases, which play a role in cancer growth and survival. This dual-action strategy, combining tomivosertib with pembrolizumab, has the potential to enhance the immune system's attack on cancer cells more effectively than current options alone. This novel combination might lead to improved outcomes for patients by potentially overcoming resistance to existing treatments.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research shows that pembrolizumab, part of the combination treatment in this trial, effectively treats non-small cell lung cancer (NSCLC) by extending the time patients live without their cancer worsening. In this trial, some participants will receive pembrolizumab with tomivosertib, although previous studies have shown only limited benefits for this combination in NSCLC. Results from the KICKSTART trial indicated that tomivosertib, when used with pembrolizumab, did not significantly improve treatment effectiveness for NSCLC. Another arm of this trial combines pembrolizumab with pemetrexed and platinum chemotherapy, which other studies have shown helps patients live longer and reduces the risk of death compared to chemotherapy alone. This suggests that while pembrolizumab is effective, the additional benefit of adding tomivosertib remains unclear. ^{1 2 3 4 5}

Who Is on the Research Team?

Douglas Warner, MD

Principal Investigator

EFFECTOR Therapeutics, Inc.

Are You a Good Fit for This Trial?

Inclusion Criteria

Are you taking medication for you depression?

Answer YES if you have not been treated with platinum-based chemotherapy (e.g., cisplatin, carboplatin, and oxaliplatin)

Do you have a tumor PD-L1 that is at least 50%? PD-L1 protein prevents immune cells from attacking harmless cells. Check your biomarker test results for PD-L1 level.

Exclusion Criteria

You have advanced or metastatic non-small cell lung cancer and your tumor tests positive for PD-L1 with a score of 50 or more. You also meet the requirements for treatment with pembrolizumab.

Can you move around easily and do light work during the day? Answer YES or NO.

The doctors need to review the two most recent scans, which show that your condition is getting worse.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tomivosertib in combination with pembrolizumab, with or without pemetrexed, depending on NSCLC type

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Pemetrexed
• Tomivosertib

How Is the Trial Designed?

Group I: C1 Tomi + Pembro + Pemetrexed (Non-sqamous) or Tomi + Pembro (Squamous) Experimental Treatment 3 Interventions

Subjects who have completed 4 to 6 cycles of platinum-based chemotherapy doublet will receive tomi plus pembrolizumab and pemetrexed (non-squamous NSCLC) or tomi plus pembro as a single agent (squamous) in accordance with the package insert.

Group II: B1 Tomi + Pembro Experimental Treatment 2 Interventions

Subjects will initiate pembrolizumab as first-line therapy and receive tomivosertib.

Group III: A1 Tomi + Current Pembro Experimental Treatment 2 Interventions

Subjects who have initiated pembrolizumab as a single agent and in accordance with the package insert will receive tomivosertib in addition to pembrolizumab.

Group IV: Pbo + Pembro Placebo Group 1 Intervention

Subjects will initiate pembrolizumab as first-line therapy and receive matching placebo.

Group V: Pbo + Current Pembro Placebo Group 1 Intervention

Subjects who have initiated pembrolizumab as a single agent and in accordance with the package insert, will receive matching placebo in addition to pembrolizumab.

Group VI: Pbo + Pembro + Pemetrexed (Non-sqamous) or Pbo + Pembro (Squamous) Placebo Group 2 Interventions

Subjects who have completed 4 to 6 cycles of platinum-based chemotherapy doublet will receive placebo plus pembrolizumab and pemetrexed (non-squamous NSCLC) or placebo plus pembro as a single agent (squamous) in accordance with the package insert.

Who Is Running the Clinical Trial?

Effector Therapeutics

Lead Sponsor

Trials

11

Recruited

600+

ICON plc

Industry Sponsor

Trials

88

Recruited

28,900+

Dr. Steve Cutler

ICON plc

Chief Executive Officer since 2017

PhD from the University of Sydney, MBA from the University of Birmingham

Dr. Greg Licholai

ICON plc

Chief Medical Officer since 2023

Degrees from Harvard Business School, Yale School of Medicine, Columbia University, and Boston College

Medpace, Inc.

Industry Sponsor

Trials

98

Recruited

30,400+

Dr. August J. Troendle

Medpace, Inc.

Chief Executive Officer since 1992

MD from the University of Maryland, School of Medicine; MBA from Boston University

Dr. Reinilde Heyrman

Medpace, Inc.

Chief Medical Officer since 2017

MD

Published Research Related to This Trial

In a phase 3 trial involving 1177 participants with completely resected stage IB-IIIA non-small-cell lung cancer (NSCLC), pembrolizumab significantly improved median disease-free survival to 53.6 months compared to 42.0 months for placebo, indicating its efficacy as an adjuvant therapy.

The safety profile of pembrolizumab was consistent with previous studies, showing no new safety signals, although serious adverse events were more common in the pembrolizumab group (24%) compared to placebo (15%), highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. O'Brien, M., Paz-Ares, L., Marreaud, S., et al.[2022]

In a study of 97 non-small cell lung cancer patients treated with pembrolizumab, 40% experienced treatment-related adverse events (trAEs), with common ones being rash, fatigue, and hypothyroidism.

Patients who experienced trAEs had significantly better clinical outcomes, including a higher objective response rate (38.5% vs. 8.9%), longer progression-free survival (248 days vs. 60 days), and longer overall survival (493 days vs. 144.5 days), suggesting that trAEs may be indicative of a positive response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center. Lisberg, A., Tucker, DA., Goldman, JW., et al.[2022]

In a study of 43 patients with non-small cell lung cancer, nivolumab showed the highest median progression-free survival (12.6 months) and overall survival (13.4 months), particularly in patients with fewer metastases and better performance status.

While 85% of patients experienced some adverse effects, the development of vitiligo in patients treated with nivolumab was associated with a more durable response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of atezolizumab, nivolumab and pembrolizumab in metastatic non-small cell lung cancer. Burgos-San José, A., Colomer-Aguilar, C., Martínez-Caballero, D., et al.[2021]

Pembrolizumab combined with adjuvant chemotherapy significantly improves one-year survival rates, overall response rates, and progression-free survival in patients with advanced non-small cell lung cancer (NSCLC), based on a meta-analysis of 14 studies.

This treatment not only enhances efficacy but also reduces the incidence of adverse drug reactions, indicating a favorable safety profile, although further validation through larger randomized controlled trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Guo, WW., Zhang, TW., Wang, BL., et al.[2023]

In a phase 3 trial involving 305 patients with advanced non-small-cell lung cancer (NSCLC), pembrolizumab significantly improved quality of life (QOL) compared to chemotherapy, with a notable increase in the global health status score by 6.9 points versus a decrease of 0.9 points for chemotherapy.

Patients treated with pembrolizumab experienced a longer time to deterioration in symptoms like cough and chest pain, with 31% showing deterioration compared to 39% in the chemotherapy group, indicating that pembrolizumab may be a preferable first-line treatment for patients with PD-L1-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Brahmer, JR., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

In a study of patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab, a higher overall tumor burden was associated with a lower incidence of severe immune-related adverse events (irAEs), suggesting that tumor size may influence treatment safety.

Good performance status and high PD-L1 expression were significant predictors of developing severe irAEs, with odds ratios of 3.27 and 4.44, respectively, indicating that patients with these characteristics should be closely monitored during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors for severe immune-related adverse events after first-line pembrolizumab monotherapy or combination chemotherapy for non-small-cell lung cancer. Sumi, T., Koshshino, Y., Sekikawa, M., et al.[2022]

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Abdel-Rahman, O.[2018]

In a study of 72 treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) and high PD-L1 expression, pembrolizumab showed an objective response rate of 45.8%, with even higher rates of 70.0% in patients with pre-existing interstitial lung disease (ILD).

Patients with ILD had similar overall survival rates compared to those without ILD, suggesting that pembrolizumab can be safely administered to NSCLC patients with ILD without compromising their prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-existing interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression ≥50% on first-line pembrolizumab. Yamaguchi, O., Kaira, K., Shinomiya, S., et al.[2021]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

The combination of vibostolimab and pembrolizumab is well tolerated by patients, indicating a favorable safety profile for this treatment regimen.

This combination therapy demonstrates antitumor activity, suggesting it may be an effective option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Anti-TIGIT Antibody with a PD-1 Inhibitor Shows Promise in Solid Tumors. [2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04622007

Study Details | NCT04622007 | Tomivosertib Combined ... A randomized, double-blind, placebo-controlled trial of Tomivosertib in combination with anti-PD-(L)1 therapy in subjects with non-small cell lung cancer.

2. onclive.com onclive.com/view/tomivosertib-development-in-frontline-nsclc-ending-after-findings-from-kickstart-trial

Tomivosertib Development in Frontline NSCLC Ending ... Data from the phase 2 KICKSTART trial of tomivosertib plus pembrolizumab do not support the combination's use in patients with non–small cell lung cancer.

3. targetedonc.com targetedonc.com/view/tomivosertib-development-in-frontline-nsclc-is-terminated

Tomivosertib Development in Frontline NSCLC Is ... Tomivosertib showed only modest activity in non–small cell lung cancer (NSCLC), according to the findings from the phase 2 KICKSTART trial.

4. withpower.com withpower.com/trial/phase-3-carcinoma-non-small-cell-lung-4-2021-91b28

Tomivosertib for Non Small Cell Lung Cancer (KICKSTART ... Research shows that pembrolizumab, a part of this drug combination, has been effective in treating non-small cell lung cancer by improving progression-free ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37429923/

phase 2 KEYNOTE-495/KeyImPaCT trial interim results Although pembrolizumab confers clinical benefit in non-small cell lung cancer (NSCLC), only a subset of patients will respond due to a ...