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LIBRETTO-001: What the Lung Cancer Trial Found
LIBRETTO-001 tested selpercatinib in RET-fusion cancers in lung cancer, measuring objective response. Plain-language summary of a positive result on its main measure — and what it doesn't mean.
Original commentary from the Cancer Explained editorial team.
Please note: this page is educational only — it is not medical advice, and it does not speculate about anyone’s health beyond reliable public reporting. For questions about your own health, talk with your healthcare team.
A gene fusion, and a drug built for it
RET stands for "rearranged during transfection." It is a gene that codes for a protein sitting in the cell membrane, one that tells cells to grow.
Sometimes a piece of a chromosome breaks and rejoins in the wrong place. If RET ends up fused to a different gene, the result can be a protein stuck in the on position. That is a RET fusion, and it drives 1 to 2 percent of non-small cell lung cancers.
Before selpercatinib, doctors used drugs that hit RET among many other targets. Those drugs worked poorly and caused a lot of side effects, because most of what they blocked was not the problem. Selpercatinib was designed to hit RET specifically.
LIBRETTO-001 is the trial that tested it. Our page on biomarker testing and precision medicine explains how a fusion like this is found in the first place.
How the trial was built
The ClinicalTrials.gov record, NCT03157128, describes a phase 1/2 trial that opened on 2 May 2017 and enrolled 857 people. It was single-group, with no masking. The phase 2 primary endpoint was objective response rate judged by an independent review committee.
Single-group matters. Everyone got the drug. Nobody got a comparison treatment. That design can show that a drug does something. It cannot show that it does more than the alternative.
The NEJM report covered two lung cancer groups. The first 105 consecutively enrolled people had RET fusion-positive disease and had already had platinum chemotherapy. A separate group of 39 had never been treated. The safety analysis covered 531 people. Our page on clinical trial phases explains what a phase 1/2 design does and does not settle.
What it found
Among the 105 previously treated patients, 64 percent had an objective response, meaning the tumor shrank by a defined amount. The 95 percent confidence interval was 54 to 73 percent.
The median duration of response was 17.5 months. At a median follow-up of 12.1 months, 63 percent of responses were still going.
Among the 39 previously untreated patients, 85 percent responded, with a confidence interval of 70 to 94 percent. Ninety percent of those responses were ongoing at 6 months.
Eleven patients had measurable cancer in the brain. The intracranial response rate was 91 percent, with a confidence interval of 59 to 100 percent. Reaching the brain is hard for most cancer drugs, so this mattered.
The most common severe side effects, grade 3 or higher, were high blood pressure in 14 percent, raised ALT in 12 percent, raised AST in 10 percent, low sodium in 6 percent, and low lymphocyte counts in 6 percent. Only 12 of 531 people, or 2 percent, stopped because of a drug-related event.
The randomized trial that came later
The single-arm design left the obvious question open, and a second trial answered it.
LIBRETTO-431 randomized 261 people with untreated RET fusion-positive advanced lung cancer. One arm got selpercatinib. The other got platinum chemotherapy with pemetrexed, with or without pembrolizumab. People in the control arm could cross over after their disease progressed.
In the 212 patients intended for chemotherapy plus pembrolizumab, median progression-free survival was 24.8 months with selpercatinib against 11.2 months. The hazard ratio was 0.46. Response rates were 84 percent and 65 percent. Median duration of response was 24.2 months against 11.5 months.
Overall survival was still immature at that analysis. That is the number that has not yet been answered.
What the label warns about
Selpercatinib is sold as Retevmo. Its label now covers RET fusion-positive lung cancer, RET-mutant medullary thyroid cancer, RET fusion-positive thyroid cancer, and RET fusion-positive solid tumors more broadly. Each requires an FDA-approved test.
The warnings section names liver toxicity, interstitial lung disease and pneumonitis, high blood pressure, QT interval prolongation, bleeding, hypersensitivity reactions, and low thyroid hormone. In LIBRETTO-431, serious adverse reactions occurred in 35 percent of people who took it, and 10 percent stopped permanently because of one.
When to call the team during treatment
The label ties specific actions to specific problems. Anyone on this drug should report promptly:
- New or worsening cough, breathlessness, or chest tightness, which can signal lung inflammation
- Home blood pressure readings that climb above the target their team set
- Yellowing of skin or eyes, dark urine, or right-sided abdominal pain
- Bleeding that will not stop, or blood in stool, urine, or vomit
- Rash that blisters or peels, or swelling of the face or throat
- Fatigue, cold intolerance, or weight gain, which can signal an underactive thyroid
Liver enzymes and blood pressure are monitored on schedule for this reason.
What this trial cannot tell you
LIBRETTO-001 had no control group. A 64 percent response rate is a real measurement, but response rate is not survival. This trial cannot say whether people lived longer than they would have on chemotherapy.
The brain result rests on 11 people. A confidence interval running from 59 to 100 percent is another way of saying the true figure is not pinned down.
Median follow-up was about 12 months at that report, so durability beyond a year was uncertain then. LIBRETTO-431 has since extended the picture, but overall survival remains unanswered there too.
And all of it applies only to the 1 to 2 percent of non-small cell lung cancers carrying a RET fusion. Without molecular testing, nobody knows who those people are. Our page on lung cancer covers where that testing fits in a workup.
Sources
- Drilon A and colleagues, Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer, N Engl J Med 2020;383(9):813-824 — https://pubmed.ncbi.nlm.nih.gov/32846060/
- ClinicalTrials.gov, LIBRETTO-001 (NCT03157128) — https://clinicaltrials.gov/study/NCT03157128
- DailyMed, RETEVMO (selpercatinib) prescribing information — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7fa848ba-a59c-4144-9f52-64d090f4d828
- NCI, Selpercatinib — https://www.cancer.gov/about-cancer/treatment/drugs/selpercatinib
How this article was prepared
An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.
The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.
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Prevention and risk reduction
Not every cancer can be prevented. Avoiding tobacco, protecting skin from ultraviolet radiation, limiting alcohol, staying active, and receiving recommended HPV or hepatitis B vaccination can lower the risk of certain cancers. A risk factor is not a prediction or a cause in one individual.
Symptoms and possible early signs
Possible signs vary and are often caused by conditions other than cancer. Changes worth discussing include a new lump, unexplained bleeding or weight loss, a persistent cough, lasting bowel or bladder changes, a changing skin spot, or symptoms that persist or worsen. Some early cancers cause no symptoms.
Screening and early detection
Screening looks for certain cancers before symptoms begin. Recommended tests exist only for some cancers and depend on age and risk. Screening can have benefits and harms; it is not the same as evaluating a new symptom, and there is no single routine scan or blood test that reliably screens for every cancer.
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