Petosemtamab: A Strong Survival Signal from Combination Therapy Without Chemotherapy in Head and Neck Cancer
In this article
A New Era for Chemotherapy-Free First-Line Treatment? What the LiGeR-HN1 Results Tell Us
For the first time in recurrent or spread (metastatic) head and neck cancer, a two-drug treatment that contains no chemotherapy has extended survival in a randomized phase 3 trial. In the LiGeR-HN1 trial announced by Genmab on October 28, 2026, petosemtamab + pembrolizumab reduced the relative risk of loss of life by half compared with pembrolizumab alone in PD-L1–positive patients (hazard ratio 0.50; 95% CI 0.37–0.67). Petosemtamab is a dual-specificity (bispecific) antibody that targets EGFR and LGR5 together. This result is important, but it still comes from a first interim analysis and a company announcement; median survival, response rates and side-effect details have not been released, and the drug is not approved in any country. We have previously covered the best first-line treatment for recurrent or metastatic head and neck cancer, a new chemotherapy-free approach for PD-L1–negative patients and the effect of immunotherapy on survival.
- What was found? In the LiGeR-HN1 phase 3 trial, petosemtamab + pembrolizumab significantly extended overall survival compared with pembrolizumab alone (hazard ratio 0.50) and increased the response rate (odds ratio 3.17) as first-line treatment for PD-L1–positive (CPS ≥1) recurrent or metastatic head and neck cancer. The benefit was independent of HPV status.
- What does 50% mean? It means that the risk of loss of life at any given moment was cut in half in relative terms; it does not mean "50 of every 100 patients were saved." The absolute gain will become clear once median survival and yearly rates are released.
- Why be cautious? The result comes from a first interim analysis and a company announcement; there is no peer-reviewed paper. The trial is open-label and the comparison arm is pembrolizumab alone; there was no direct comparison with standard chemotherapy-containing regimens.
- For patients today: Petosemtamab is not approved; access is possible only through clinical trials. The current standard (pembrolizumab alone or with chemotherapy) remains valid.
Why does this matter?
Head and neck cancers are diagnosed in about 900,000 people worldwide each year, and in a substantial proportion of patients the disease comes back or spreads after initial treatment. At this stage, the goal is often not a lasting cure but extending survival and keeping problems that directly affect quality of life, such as swallowing, speech and pain, under control. Since 2019, the standard first-line treatment for PD-L1–positive patients has been pembrolizumab, alone or together with platinum and 5-FU chemotherapy. However, when pembrolizumab is used alone, the tumor shrinks in only about one in five patients; adding chemotherapy increases response but also increases side effects (immunotherapy and radiotherapy in head and neck cancer).
What makes LiGeR-HN1 important is that, without adding chemotherapy, it combined immunotherapy with an antibody that targets the tumor's growth signal and showed a large relative difference in survival. If the result is confirmed with full data, a change in first-line treatment could be on the table for many patients, including older people and those who cannot tolerate chemotherapy. That is why it is important both to understand the result correctly and not to overstate it.
What is petosemtamab, and what did LiGeR-HN1 show?
Petosemtamab is a dual-specificity antibody, given intravenously, that binds simultaneously to the EGFR and LGR5 receptors on tumor cells. In the LiGeR-HN1 phase 3 trial, when given with pembrolizumab as first-line treatment for PD-L1–positive recurrent or metastatic head and neck cancer, it reduced the relative risk of loss of life by 50% and increased tumor response compared with pembrolizumab alone. The drug is not yet approved.
Head and neck cancer: A brief reminder
Head and neck cancers are tumors arising from the oral cavity, the pharynx (nasopharynx, oropharynx, hypopharynx) and the larynx; the vast majority are squamous cell carcinomas. The main causes are tobacco and alcohol use and, especially in cancers of the tonsils and base of the tongue, HPV infection; the HPV vaccine can prevent a large share of these cancers (20 years of the HPV vaccine, HPV in head and neck cancers). Nasopharyngeal cancer has a different biology and treatment and is considered a separate disease (nasopharyngeal cancer). For symptoms and early diagnosis, see our article on the symptoms of head and neck cancer.
Figure 1 · Where head and neck cancers begin
Side view: nose, mouth, pharynx and larynx
How does petosemtamab work?
In the vast majority of squamous cell head and neck cancers, EGFR (epidermal growth factor receptor) is present in large amounts and carries a "grow, multiply" signal to the tumor. Cetuximab was the first antibody to target this receptor. LGR5, on the other hand, is a receptor found on the tumor's self-renewing, stem cell–like cells. Petosemtamab is a bispecific antibody that binds to both receptors at the same time; amivantamab, which targets EGFR and MET together in lung cancer, is an approved example of this class. According to laboratory studies, it acts in three ways:
- It blocks growth factors from binding to EGFR, cutting off the growth signal.
- In cells that carry LGR5, it causes EGFR to be taken into the cell and broken down, reducing the number of receptors.
- The stem of the antibody (Fc) directs immune cells such as NK cells to the tumor cell (antibody-dependent cell-mediated cytotoxicity, ADCC).
Figure 2 · How does petosemtamab act on the tumor cell?
EGFR blockade, EGFR breakdown and recruitment of immune cells
Pembrolizumab works through an entirely different route: It releases the PD-1/PD-L1 "brake" that the tumor uses to stop T cells (what is pembrolizumab?). The rationale for using the two drugs together is to engage the immune system while cutting off the tumor's growth signal, and to do so without the side effects of chemotherapy.
Figure 3 · Two drugs, two separate pathways
Releasing the immune brake and cutting off the tumor signal
The LiGeR-HN1 trial: Design and first results
LiGeR-HN1 (NCT06525220) is a global, multicenter, open-label, randomized phase 3 trial. Adults with recurrent or metastatic disease that could not be cured with surgery or radiation, who had not previously received drug treatment at this stage, whose PD-L1 combined positive score (CPS) was at least 1 and who were in good general condition were assigned 1:1 to two groups: petosemtamab + pembrolizumab or pembrolizumab alone. The trial had two primary endpoints: overall survival and tumor response rate by blinded independent central review.
Figure 4 · Design of the LiGeR-HN1 trial
Who took part, how they were compared, what was found?
| Feature | LiGeR-HN1 |
|---|---|
| Phase and design | Phase 3, randomized (1:1), open-label, multicenter |
| Patients | Recurrent or metastatic squamous cell head and neck cancer, first-line, PD-L1 CPS ≥1, ECOG 0–1 |
| Treatments | Petosemtamab + pembrolizumab vs pembrolizumab alone |
| Primary endpoints | Overall survival and response rate (blinded independent central review) |
| Overall survival | Hazard ratio 0.50 (95% CI 0.37–0.67; p <0.0001) |
| Response rate | Odds ratio 3.17 (95% CI 2.06–4.89; p <0.0001) |
| Subgroups | Survival and response benefit independent of HPV status |
| Safety | Acceptable; consistent with the known profile of both drugs, no unexpected signals |
| Not yet released | Number of patients, median survival, response percentages, progression-free survival, side-effect rates |
Source: Genmab announcement (October 28, 2026) and OncLive report. Full results will be presented at a medical meeting.
What a hazard ratio of 0.50 means, and what it does not
The hazard ratio is the ratio of the risk of loss of life at any given moment in two groups. A value of 0.50 shows that, over the follow-up period, this risk was on average half as high in patients receiving petosemtamab + pembrolizumab as in those receiving pembrolizumab alone. A 95% confidence interval of 0.37–0.67 means that the true effect is most likely a relative reduction of between 33% and 63%; because the interval does not include 1, the difference cannot be explained by chance.
But a "50% reduction" does not mean "50 of every 100 patients were saved" or "survival doubled." The absolute difference depends on how long the control group lives and on whether the effect stays constant over time. The example below assumes rates in the control group close to the pembrolizumab-alone results of KEYNOTE-048 and shows what the picture could look like if the hazard ratio stayed constant at 0.50. These are not LiGeR-HN1 results.
Figure 5 · Hazard ratio 0.50: two hypothetical survival curves
Assumed median of 12 months with a single drug; calculated curve for the combination
What could a hazard ratio of 0.50 change? A hypothetical example
Proportion of patients alive, %. Control rates are assumed to be close to the pembrolizumab-alone levels in KEYNOTE-048; combination rates are calculated assuming a constant hazard ratio of 0.50.
This chart is not a LiGeR-HN1 result; it is an example of how a hazard ratio can translate into an absolute difference. The actual median survival and yearly rates will become clear when the full results are published. A hazard ratio of 0.50 does not mean "50 of every 100 patients were saved."
What had the phase 2 data shown?
Before the phase 3 result, interim data from a 45-patient, single-arm phase 2 study of first-line petosemtamab + pembrolizumab were presented at ASCO 2025. In this study, the tumor shrank in 27 of 43 patients (63%); in 6 patients, the tumor disappeared completely. Median progression-free survival was 9 months, and 1-year survival was 79%. For comparison, in KEYNOTE-048 the response rate in CPS ≥1 patients was about 19% with pembrolizumab alone and about 36% with pembrolizumab + chemotherapy; however, these rates from different trials cannot be compared directly.
Phase 2: First-line petosemtamab + pembrolizumab
PD-L1–positive, recurrent or metastatic head and neck cancer; 45 patients (43 evaluable for efficacy). ASCO 2025 interim data.
Single-arm study; no comparison group. Responses are based on investigator assessment. Median progression-free survival was 9 months; median duration of response and median survival could not yet be estimated. Infusion reactions were seen mostly at the first administration and resolved.
| Study | Patients | Main results |
|---|---|---|
| Phase 2 · first-line · with pembrolizumab (ASCO 2025) | 45 patients (43 evaluable for efficacy), PD-L1–positive | Response 63%, complete response in 6 patients, median progression-free survival 9 months, 1-year survival 79% |
| Phase 2 · second line and beyond · single agent (ESMO Asia 2024) | 75 patients (evaluable for efficacy), after platinum and immunotherapy | Response 36%, median progression-free survival 4.9 months, median survival 11.4 months |
| LiGeR-HN1 · phase 3 · first-line (October 2026) | Not released, PD-L1 CPS ≥1 | Hazard ratio 0.50 for survival; odds ratio 3.17 for response |
| LiGeR-HN2 · phase 3 · second to third line | Ongoing | Petosemtamab alone compared with the investigator's choice of treatment |
In the phase 2 studies, petosemtamab was given as a 1500 mg intravenous infusion every two weeks.
Comparison with today's standard treatment
In recurrent or metastatic head and neck cancer, first-line treatment is chosen according to the PD-L1 level (CPS) in the tumor. The KEYNOTE-048 trial showed that pembrolizumab alone in CPS ≥1 patients, and pembrolizumab + chemotherapy in all patients, provided longer survival than the cetuximab-containing EXTREME regimen. The control arm of LiGeR-HN1 is pembrolizumab alone; it is therefore unknown whether the combination is better than pembrolizumab + chemotherapy. This distinction matters in the clinic: For extensive, symptomatic disease that needs rapid shrinkage, a chemotherapy-containing regimen is often preferred today.
Today's standard: Median survival in KEYNOTE-048
Months. First-line, recurrent or metastatic head and neck cancer. Gray: cetuximab + platinum + 5‑FU (EXTREME).
KEYNOTE-048 made pembrolizumab alone the standard in PD-L1–positive patients and pembrolizumab + chemotherapy the standard in all patients. The comparison arm of LiGeR-HN1 is pembrolizumab alone; there is no direct comparison with chemotherapy-containing regimens.
Figure 6 · First-line options and the possible place of petosemtamab
Today's options according to the PD-L1 (CPS) result
Side effects: What can be expected?
Genmab reported that the safety profile of the combination was consistent with the known side effects of both drugs and that no unexpected signal was seen; the rates have not yet been released. Based on the phase 2 data and the known effects of these drug classes, the main expected problems are:
- Infusion reaction: In phase 2, in 38% of patients, grade 3 in 7%; mostly at the first administration and temporary. Its frequency was reduced by changing the administration schedule.
- Effects typical of EGFR-targeted drugs: Acne-like rash, dry skin, inflammation around the nails, low magnesium, diarrhea and mouth sores are expected.
- Immunotherapy-related effects: Immune-related side effects such as thyroid disorders and inflammation of the lungs, bowel, liver and skin may occur (immunotherapy side effects, side effects involving the hormone glands).
Why should we be cautious?
Figure 7 · What is known and what is not yet known
Limits of the first interim analysis
- Interim analysis: In trials stopped or reported early, the size of the effect can sometimes appear larger than it really is; with longer follow-up, the hazard ratio may change.
- Open-label design: Patients and physicians knew which treatment was being given. Survival is not affected by this, but assessments of response and side effects can be; that is why measuring response by blinded independent central review matters.
- Comparison arm: The control arm was pembrolizumab alone. There is no direct comparison with pembrolizumab + chemotherapy or other new combinations.
- Subsequent treatments: Which treatments patients in the control arm received after progression will be important in interpreting the survival difference.
- Cost and administration: Intravenous administration every two weeks, the cost of two antibodies and the burden of long-term treatment have not yet been assessed.
What comes next?
Genmab announced that it plans to present the full results at a medical meeting and to share the data with regulatory authorities worldwide; no filing timeline was given. The LiGeR-HN2 phase 3 trial, testing petosemtamab alone in previously treated patients, is ongoing. Other chemotherapy-free combinations that target EGFR and the immune system together, as well as therapeutic vaccines for HPV16-positive patients, are also being studied in head and neck cancer (PDS0101 + pembrolizumab). The full publication, with median survival, duration of response, quality of life and subgroup results, will determine whether this treatment becomes standard.
What does this mean for patients and their families?
This result may signal an important change in the treatment of recurrent or metastatic head and neck cancer, but for now, treatment options have not changed. Petosemtamab is not approved in any country and can be used only within clinical trials. PD-L1 testing, HPV status, the extent of the disease, symptoms and general condition remain the basis for choosing first-line treatment today.
Alongside treatment, some steps are valuable for every patient: Quitting smoking extends survival even in metastatic disease (the benefit of quitting smoking even at stage 4), and cutting back on alcohol lowers treatment side effects and the risk of new tumors (risky alcohol use in people with cancer). Support from a dietitian and a swallowing therapist for swallowing and nutrition problems (nutrition and side effects), early palliative care for pain and symptoms (access to palliative care) and psychological support for the emotional burden of changes in appearance and speech (the psychological and social effects of head and neck cancer) should be part of treatment.
Questions you can ask your doctor
- What is the PD-L1 (CPS) value of my tumor? Has my HPV status been tested?
- Is the first-line treatment recommended for me pembrolizumab alone or together with chemotherapy? Why?
- Is there a clinical trial I could join that is testing petosemtamab or similar chemotherapy-free combinations?
- Which side effects should I expect during treatment, and which symptoms should prompt me to call right away?
- What support can I get for my swallowing, nutrition, pain and speech problems?
- How and how often will we assess my response to treatment? Are blood tests (liquid biopsy) an option in addition to imaging?
- "A 50% reduction means half of the patients were cured." No. The hazard ratio shows the relative reduction in the risk of loss of life at any given moment. The absolute gain depends on the survival of the control group and can be calculated once the full data are released.
- "The new drug has been approved." No. Petosemtamab is not approved in any country; the announced result is the first interim analysis of a phase 3 trial.
- "Chemotherapy is no longer needed." Not yet. The combination was not compared with pembrolizumab + chemotherapy, and PD-L1–negative (CPS <1) patients were not included in the trial.
- "Cetuximab also targets EGFR, so it is the same thing." No. Petosemtamab binds to both EGFR and LGR5 and causes EGFR to be broken down; for the cetuximab + pembrolizumab combination, there are no phase 3 survival data.
- "It does not work in HPV-positive patients." According to the initial announcement, the survival and response benefit was independent of HPV status; detailed subgroup data are awaited.
- Petosemtamab is not licensed in Türkiye or in any other country in the world, and it cannot be brought in through the foreign drug supply route either. The only route of access is clinical trials (what is a clinical trial?).
- Whether the LiGeR trials have sites in Türkiye can be checked on ClinicalTrials.gov (NCT06525220, NCT06496178).
- Pembrolizumab is licensed in Türkiye; for the reimbursement conditions of SGK (Türkiye's Social Security Institution) in head and neck cancer, see our article on immunotherapy reimbursement.
- For how long it takes and by which routes new cancer drugs reach Türkiye, see our access map, and for how unlicensed drugs can be imported once approved elsewhere, see our article on foreign drug supply.
Frequently Asked Questions
- What is petosemtamab?
- Petosemtamab is a dual-specificity (bispecific) antibody, given intravenously, that binds simultaneously to the EGFR and LGR5 receptors on tumor cells. It cuts off the growth signal, causes EGFR to be broken down and directs immune cells to the tumor. It is being developed by Genmab and is not yet approved.
- What did the LiGeR-HN1 trial show?
- As first-line treatment for PD-L1–positive recurrent or metastatic head and neck cancer, petosemtamab + pembrolizumab reduced the relative risk of loss of life by half (hazard ratio 0.50) and increased tumor response compared with pembrolizumab alone. The result comes from a first interim analysis; detailed data have not yet been released.
- Does a hazard ratio of 0.50 mean half of the patients were cured?
- No. A hazard ratio of 0.50 shows that the risk of loss of life at any given moment was cut in half in relative terms compared with the control group. How many more patients lived longer, that is, the absolute gain, will become clear once median survival and yearly rates are released.
- How can patients access petosemtamab?
- Petosemtamab is not currently approved in any country, so it can be used only within clinical trials. You can talk with your doctor about whether a suitable trial is available and check the sites of the LiGeR trials on ClinicalTrials.gov.
Glossary
- Bispecific (dual-specificity) antibody
- A laboratory-made antibody that can bind to two different targets at the same time.
- EGFR
- Epidermal growth factor receptor; a receptor that is present in excess in most head and neck cancers and carries a growth signal.
- LGR5
- A receptor found on the tumor's self-renewing, stem cell–like cells.
- PD-L1 and CPS
- PD-L1 is a protein the tumor uses to put the brakes on the immune system; CPS is a score showing how widespread PD-L1 is on tumor and immune cells.
- Hazard ratio
- The ratio of the risk of an event (e.g., loss of life) at any given moment in two groups; a value below 1 shows that the risk is lower in the experimental group.
- Confidence interval (CI)
- The range of values within which the true effect most likely lies.
- Odds ratio
- The ratio of the odds of an outcome (e.g., tumor response) in two groups.
- Interim analysis
- An assessment carried out at a prespecified point before a trial is completed.
- Open-label
- A trial design in which patients and physicians know which treatment is being given.
- ADCC
- Antibody-dependent cell-mediated cytotoxicity; the destruction, by immune cells such as NK cells, of a cell marked by an antibody.
DROZDOGAN Academy Commentary
A hazard ratio of 0.50 is one of the largest relative survival differences we have seen in recent years in first-line head and neck cancer. That a chemotherapy-free combination has shown this against pembrolizumab alone raises the possibility of a real change in the field. But a decision requires full data, not a company announcement.
⚡ Why it matters
A large proportion of people with head and neck cancer are older, have other illnesses and tolerate chemotherapy poorly. An effective chemotherapy-free option could be especially valuable for these patients.
✅ Strengths
Randomized phase 3 design, overall survival as a primary endpoint, response measured by blinded independent central review, a narrow confidence interval and benefit independent of HPV. The high response rate seen in phase 2 appears to have been confirmed in phase 3.
⚠️ Limitations
First interim analysis, open-label design and a control arm of pembrolizumab alone. There are no data yet on median survival, response percentages, side-effect rates or quality of life; there was no comparison with pembrolizumab + chemotherapy.
🩺 In practice
Today, we recommend current standard treatments to our patients according to their PD-L1 and HPV results and evaluate suitable patients for clinical trials testing chemotherapy-free combinations. We will update our recommendations when the full results are published.
❓ Open questions
How large is the absolute survival gain? Is the benefit maintained over the long term? How does the combination compare with pembrolizumab + chemotherapy? Does the effect differ by CPS level? How do EGFR-related skin and magnesium side effects affect quality of life during long-term treatment?
Bottom line: LiGeR-HN1 gives a strong signal that the chemotherapy-free combination of petosemtamab + pembrolizumab could change first-line treatment for PD-L1–positive recurrent or metastatic head and neck cancer. However, the drug is not approved and the results come from a first interim analysis; until the full data are released, current standard treatments remain valid.
- This article was prepared in October 2026.
- The LiGeR-HN1 results are based on Genmab's announcement of October 28, 2026, and on news sources reporting that announcement; there is not yet a peer-reviewed paper or a meeting presentation. The number of patients, median survival and side-effect rates have not been released.
- The phase 2 data were taken from company announcements and meeting abstracts (ASCO 2025, ESMO Asia 2024).
- The chart and illustration showing how the hazard ratio translates into an absolute difference are hypothetical; the control group rates were chosen to be close to the levels in KEYNOTE-048 and are not LiGeR-HN1 results.
- Response and survival figures taken from different trials cannot be compared directly. The illustrations are simplified. The Academy commentary is our own.
- This article is not medical advice; treatment decisions should be made by the team that knows the patient.
References
- OncLive. Petosemtamab plus pembrolizumab hits phase 3 OS, ORR primary end points in PD-L1+ R/M HNSCC. October 28, 2026. onclive.com
- BioPharm International. Genmab's petosemtamab plus pembrolizumab LiGeR-HN1 phase 3 results. October 2026. biopharminternational.com
- ClinicalTrials.gov. LiGeR-HN1 (NCT06525220). clinicaltrials.gov
- ClinicalTrials.gov. LiGeR-HN2 (NCT06496178). clinicaltrials.gov
- Merus. Petosemtamab with pembrolizumab interim data in 1L PD-L1+ r/m HNSCC (ASCO 2025, Abstract 6024). June 2025. santelog.com
- Merus. Petosemtamab monotherapy interim data in 2L+ r/m HNSCC (ESMO Asia 2024). December 2024. 1stoncology.com
- Oncology Nursing News. Petosemtamab/pembrolizumab receives FDA breakthrough therapy designation for PD-L1+ HNSCC. February 28, 2025. oncnursingnews.com
- pharmaphorum. Genmab agrees $8bn takeover of cancer biotech Merus. September 2025. pharmaphorum.com
- Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:1915-1928. doi:10.1016/S0140-6736(19)32591-7
- Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-1127. doi:10.1056/NEJMoa0802656
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