NCT03262779

Ipilimumab and Nivolumab in Patients With Anti-PD-1-axis Therapy-resistant Advanced Non-small Cell Lung Cancer.

Completed Phase 2 Results posted Last updated 9 January 2025

What this trial tests

Phase 2 trial testing combination nivolumab and ipilimumab in Carcinoma, Non-Small-Cell Lung in 20 participants. Completed in 14 January 2022.

Timeline

20 July 2017

Primary endpoint
14 January 2022

14 January 2022

Quick facts

Lead sponsor	Yale University
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	20
Start date	20 July 2017
Primary completion	14 January 2022
Estimated completion	14 January 2022
Sites	1 location across United States

Drugs / interventions tested

• combination nivolumab and ipilimumab — full drug profile →

Conditions studied

• Carcinoma, Non-Small-Cell Lung — all drugs for Carcinoma, Non-Small-Cell Lung →

Sponsor

Yale University

Who can join

18 and older, any sex, with Carcinoma, Non-Small-Cell Lung. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Objective Response Rate Using RECIST v1.1 to Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre-treated Advanced NSCLC Who Have Experienced Primary Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Primary · Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks until disease progression or up to 4 years.

Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 confirmed by repeat assessment ≥4 weeks after initial documentation. The categories are: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Primary	0
Combination Nivolumab and Ipilimumab - Primary	0
Combination Nivolumab and Ipilimumab - Primary	2
Combination Nivolumab and Ipilimumab - Primary	8

Objective Response Rate in in Advanced Non-small Cell Lung Cancer (NSCLC) With ACQUIRED Resistance to Anti-programmed Death (PD)-1 Axis Therapy as Their Last Line of Systemic Therapy. Secondary · Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.

Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and confirmed by repeat assessment ≥4 weeks after initial documentation. The categories are: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). This outcome is only presented for those with advanced non-small cell lung cancer (NSCLC) with ACQUIRED resistance to anti-programmed death (PD)-1 axis therapy as their last line of systemic therapy.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Acquired	1
Combination Nivolumab and Ipilimumab - Acquired	0
Combination Nivolumab and Ipilimumab - Acquired	8
Combination Nivolumab and Ipilimumab - Acquired	1

Progression-free Survival With Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre- Treated Advanced NSCLC Who Have Experienced Primary Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy Secondary · Until disease progression, unacceptable toxicity, or study termination, up to four years.

Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1. This outcome is only presented for those pre-treated with advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Primary	1.8	1.4 – 4.2

Progression Free Survival by RECIST v1.1 With Nivolumab and Ipilimumab in Patients With Pre-treated Advanced NSCLC Who Have Experienced Acquired Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Secondary · Until disease progression, unacceptable toxicity, or study termination, up to four years from enrollment.

Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1 and immune related Response Criteria. This is in those that have experienced acquired resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Acquired	6.8	1.8 – 28.7

Overall Survival (OS) With Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre- Treated Advanced NSCLC Who Have Experienced PRIMARY Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Secondary · Until death or day of last follow-up, up to four years from enrollment.

Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up. This is in patients that have experienced PRIMARY resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Primary	6.8	1.7 – 17.8

Overall Survival With Nivolumab and Ipilimumab in Patients With Pre-treated Advanced NSCLC Who Have Experienced ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Secondary · Until death or day of last follow-up (up to four years from study enrollment).

Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Acquired	24.7	7.5 – 48.5

Objective Response Rate Using irRC to Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Last Line of Systemic Therapy. Secondary · Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.

Objective response is defined as a complete or partial response, as determined by investigator assessment using irRC and confirmed by repeat assessment ≥4 weeks after initial documentation.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Primary	0
Combination Nivolumab and Ipilimumab - Acquired	1

Safety of Nivolumab and Ipilimumab When Administered in Combination in Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Secondary · Up to 4 years

Determined based on adverse events which will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Presented are a count of those that experienced at least 1 Serious Adverse Event related to study drug.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Primary	2
Combination Nivolumab and Ipilimumab - Acquired	2

Feasibility of Sequential Biopsies in Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Secondary · Tumor biopsies performed at 9 to 10 weeks after receiving first dose of trial therapy.

Feasibility of sequential biopsies (performed or not performed) in patients with pre-treated advanced NSCLC who have experienced PRIMARY or ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy. Presented are a count of those that had biopsies performed or not performed.

Group	Value	95% CI
Combination Nivolumab and Ipilimumab - Primary	4
Combination Nivolumab and Ipilimumab - Acquired	4
Combination Nivolumab and Ipilimumab - Primary	3
Combination Nivolumab and Ipilimumab - Acquired	3

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 4 years. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Combination Nivolumab and Ipilimumab - Primary

Serious: 3/10 (30%)

Deaths: 10/10

Combination Nivolumab and Ipilimumab - Acquired

Serious: 2/10 (20%)

Deaths: 8/10

Serious adverse events (10 terms)

Reaction	System	Combination Nivolumab and …	Combination Nivolumab and …
Autoimmune Encephalitis	Infections and infestations	—	—
Cardiac Arrest	Cardiac disorders	—	—
Colitis	Gastrointestinal disorders	—	—
Lung Infection	Infections and infestations	—	—
Psychiatric disorders - Other	Psychiatric disorders	—	—
Stroke	Nervous system disorders	—	—
Surgical and medical procedures - Other	Surgical and medical procedures	—	—
Parietal craniotomy	Surgical and medical procedures	—	—
Radiation necrosis	Skin and subcutaneous tissue disorders	—	—
Atrial flutter	Cardiac disorders	—	—

Other adverse events (65 terms — click to expand)

Reaction	System	Combination Nivolumab and …	Combination Nivolumab and …
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—
Fatigue	General disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—
Musculoskeletal and connective tissue disorders - Other	Musculoskeletal and connective tissue disorders	—	—
Nervous system disorders - Other	Nervous system disorders	—	—
Colitis	Gastrointestinal disorders	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—
Skin and subcutaneous tissue disorders - Other	Skin and subcutaneous tissue disorders	—	—
General disorders - Other	General disorders	—	—
Chest wall pain	Musculoskeletal and connective tissue disorders	—	—
Metabolism and nutrition disorders - Other	Metabolism and nutrition disorders	—	—
Lipase increased	Investigations	—	—
Surgical and medical procedures - Other	Surgical and medical procedures	—	—
Depression	Psychiatric disorders	—	—
Laryngeal hemorrhage	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary edema	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory, thoracic and mediastinal disorders -Other	Respiratory, thoracic and mediastinal disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Gastrointestinal disorders - Other	Gastrointestinal disorders	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—
Rash acneiform	Skin and subcutaneous tissue disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—
Flank pain	Musculoskeletal and connective tissue disorders	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Dizziness	Nervous system disorders	—	—
Dysgeusia	Nervous system disorders	—	—
Headache	Nervous system disorders	—	—
Memory impairment	Nervous system disorders	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—
Stroke	Nervous system disorders	—	—
Anorexia	Metabolism and nutrition disorders	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—

Most-reported serious reactions: Autoimmune Encephalitis, Cardiac Arrest, Colitis, Lung Infection, Psychiatric disorders - Other, Stroke, Surgical and medical procedures - Other, Parietal craniotomy.

Data from ClinicalTrials.gov NCT03262779 adverse events section.

Sponsor's own description

The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary or acquired resistance to anti- programmed death 1 (PD-1) axis therapy can lead to objective radiographic tumor regression.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer.
   Yuan M, Huang LL, Chen JH, Wu J, et al · · 2019 · cited 482× · PMID 31871778 · DOI 10.1038/s41392-019-0099-9
2. Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets.
   Tie Y, Tang F, Wei YQ, Wei XW. · · 2022 · cited 386× · PMID 35585567 · DOI 10.1186/s13045-022-01282-8
3. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
   Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2
4. Failure of Immunotherapy-The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer.
   Błach J, Wojas-Krawczyk K, Nicoś M, Krawczyk P. · · 2021 · cited 44× · PMID 34445735 · DOI 10.3390/ijms22169030
5. Safety and efficacy of retreatment with immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis.
   Cai Z, Zhan P, Song Y, Liu H, et al · · 2022 · cited 27× · PMID 36090645 · DOI 10.21037/tlcr-22-140
6. Retreatment with immune checkpoint inhibitors in solid tumors: a systematic review.
   Yang K, Li J, Sun Z, Zhao L, et al · · 2020 · cited 21× · PMID 33294036 · DOI 10.1177/1758835920975353
7. Immune checkpoints inhibitors rechallenge in non-small-cell lung cancer: different scenarios with different solutions?
   Metro G, Signorelli D. · · 2020 · cited 17× · PMID 31983926 · DOI 10.2217/lmt-2019-0012
8. Beyond First-Line Immunotherapy: Potential Therapeutic Strategies Based on Different Pattern Progressions: Oligo and Systemic Progression.
   Prelaj A, Pircher CC, Massa G, Martelli V, et al · · 2021 · cited 15× · PMID 33803958 · DOI 10.3390/cancers13061300