Thyroid Dysfunction May Predict Better Response to Lung Cancer Immunotherapy

New study links immune-related thyroid issues to improved outcomes in patients with advanced non-small cell lung cancer.

Non-Small Cell Lung Cancer: An Ongoing Challenge

Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer diagnoses. It remains a major global health issue, ranking among the leading causes of cancer-related deaths. For patients with metastatic disease, survival prospects continue to be limited despite advancements in systemic therapies.

In recent years, immune checkpoint inhibitors (ICIs) have changed the treatment landscape. By blocking inhibitory immune pathways—specifically PD-1 and PD-L1—agents like pembrolizumab and atezolizumab enhance T-cell responses against cancer cells. Clinical trials have demonstrated that these therapies can extend survival, particularly in patients with high PD-L1 expression. However, they are also associated with immune-related adverse events (irAEs), which can affect various organs, including the endocrine system.

Among endocrine irAEs, thyroid dysfunction is one of the most frequently observed, yet its clinical implications remain unclear. Does it signal a complication, or could it actually correlate with therapeutic benefit?

Study Overview: Tracking Thyroid Changes During Treatment

A retrospective cohort study conducted at the Clinical Center University of Sarajevo investigated the relationship between thyroid dysfunction and clinical outcomes in metastatic NSCLC patients treated with ICIs. The study included 50 patients treated between January 2020 and January 2022. Patients received either pembrolizumab or atezolizumab, depending on PD-L1 expression levels and clinical factors.

Researchers monitored thyroid function before and during treatment using standard laboratory tests. Thyroid dysfunction was diagnosed based on defined thresholds for TSH, FT4, and FT3 levels, and treatment was initiated when necessary.

Key Findings: A Common and Potentially Helpful Side Effect

Thyroid dysfunction occurred in 48% of patients during treatment:

• 12 patients (24%) developed hypothyroidism.

• 4 patients (8%) developed hyperthyroidism.

• 8 patients (16%) showed a pattern of progression from hyperthyroidism to hypothyroidism.

The median time to onset was:

• 10 treatment cycles for hypothyroidism.

• 6 cycles for hyperthyroidism.

Most notably, 87.5% of patients who developed thyroid dysfunction were receiving atezolizumab, and the difference in incidence between treatment groups was statistically significant (P = 0.04). There were no significant associations with age or gender.

Progression-Free Survival: A Notable Difference

Patients who experienced thyroid dysfunction had significantly longer progression-free survival (PFS) compared to those who did not:

• Median PFS was not reached in the dysfunction group.

• Median PFS was 14 months in the non-dysfunction group.

• This difference was statistically significant (P = 0.038).

Even after adjusting for lead-time bias using a time-dependent covariate analysis, patients with thyroid dysfunction continued to show better outcomes.

Among patients treated with atezolizumab, the median PFS was significantly longer for those with thyroid dysfunction than for those without (not reached vs. 13 months, P = 0.006). In the pembrolizumab group, statistical comparisons were limited due to the small number of cases with thyroid dysfunction.

Treatment and Management: Following Established Guidelines

Of the 24 patients with thyroid dysfunction:

• 16 (67%) required treatment.

• Hypothyroidism was managed with levothyroxine.

• Hyperthyroidism, when transient, was managed with beta-blockers, and antithyroid drugs were not needed.

All management followed European Thyroid Association recommendations. No patients discontinued ICI therapy due to thyroid-related adverse events, and overall safety and tolerability remained acceptable.

Multivariate and Subgroup Insights

While thyroid dysfunction showed a favorable trend for PFS in unadjusted analysis, PD-L1 expression was the only independent predictor of improved survival in multivariate modeling. Neither age nor gender significantly influenced outcomes. The presence of other irAEs was also considered but was not an independent factor.

These findings suggest that while thyroid dysfunction alone may not independently drive improved outcomes, it may still reflect an active immune response associated with more effective tumor control.

Implications for Clinical Practice and Future Research

This study adds to growing evidence that immune-related thyroid dysfunction may carry prognostic value in the context of ICI therapy for NSCLC. Though the exact biological mechanisms remain to be clarified, it is plausible that immune activation responsible for thyroid dysfunction also contributes to antitumor effects.

Routine thyroid monitoring during ICI therapy is not only essential for managing side effects but may also provide insight into treatment efficacy. While thyroid dysfunction is manageable with standard care, its association with longer PFS underscores the importance of recognizing and addressing this condition early.

However, the study’s retrospective and single-center design, along with the small sample size and incomplete long-term survival data, limit the ability to draw definitive conclusions. Larger, prospective trials will be necessary to confirm these observations and explore the potential of thyroid dysfunction as a biomarker of ICI response.

Conclusion: More Than Just a Side Effect

Thyroid dysfunction is a common immune-related adverse event in patients receiving ICIs for metastatic NSCLC—especially in those treated with atezolizumab. Rather than signaling harm, it may be a marker of therapeutic benefit, particularly with regard to progression-free survival. For clinicians and researchers, these findings highlight the value of systematic endocrine monitoring and the potential for immune-related events to guide treatment assessment.

 

The translation of the preceding English text in Bosnian:

 

Nova studija povezuje imunološki povezane probleme sa štitnom žlijezdom s poboljšanim ishodima kod pacijenata s uznapredovalim nemikrocelularnim karcinomom pluća.

Nemikrocelularni karcinom pluća: Stalni izazov

Nemikrocelularni karcinom pluća (NSCLC) čini približno 85% svih dijagnoza karcinoma pluća. I dalje predstavlja veliki globalni zdravstveni problem i jedan je od vodećih uzroka smrti povezanih s rakom. Kod pacijenata s metastatskom bolešću, prognoze preživljavanja ostaju ograničene uprkos napretku u sistemskoj terapiji.

U posljednjim godinama, inhibitori imunoloških kontrolnih tačaka (ICI) značajno su promijenili pristup liječenju. Blokiranjem inhibitornog imunološkog puta—posebno PD-1 i PD-L1—lijekovi poput pembrolizumaba i atezolizumaba poboljšavaju odgovor T-ćelija protiv ćelija raka. Kliničke studije su pokazale da ove terapije mogu produžiti preživljavanje, naročito kod pacijenata s visokom ekspresijom PD-L1. Međutim, povezane su i s neželjenim dejstvima izazvanim imunološkim odgovorom (irAE), koja mogu zahvatiti različite organe, uključujući i endokrini sistem.

Među endokrinim irAE, disfunkcija štitne žlijezde je jedna od najčešće zabilježenih, ali njene kliničke posljedice još nisu potpuno jasne. Da li je riječ o komplikaciji ili bi mogla ukazivati na potencijalnu korist od terapije?

Pregled studije: Praćenje promjena u funkciji štitne žlijezde tokom terapije

Retrospektivna kohortna studija provedena na Kliničkom centru Univerziteta u Sarajevu ispitivala je povezanost između disfunkcije štitne žlijezde i kliničkih ishoda kod pacijenata s metastatskim NSCLC koji su liječeni ICI terapijom. U istraživanje je bilo uključeno 50 pacijenata liječenih u periodu od januara 2020. do januara 2022. godine. Pacijenti su primali pembrolizumab ili atezolizumab, u zavisnosti od nivoa ekspresije PD-L1 i kliničkih faktora.

Istraživači su pratili funkciju štitne žlijezde prije i tokom terapije koristeći standardne laboratorijske testove. Disfunkcija štitne žlijezde je dijagnosticirana na osnovu definisanih referentnih vrijednosti za TSH, FT4 i FT3, a terapija je započeta kada je to bilo potrebno.

Ključni nalazi: Česta i potencijalno korisna nuspojava

Disfunkcija štitne žlijezde zabilježena je kod 48% pacijenata tokom terapije:

• 12 pacijenata (24%) razvilo je hipotireozu.

• 4 pacijenta (8%) razvila su hipertireozu.

• 8 pacijenata (16%) pokazalo je prelaz iz hipertireoze u hipotireozu.

Medijan vremena do pojave bio je:

• 10 ciklusa terapije za hipotireozu.

• 6 ciklusa za hipertireozu.

Posebno je značajno da je 87,5% pacijenata koji su razvili disfunkciju štitne žlijezde primalo atezolizumab, a razlika u učestalosti među grupama liječenja bila je statistički značajna (P = 0,04). Nije uočena značajna povezanost sa starosnom dobi ni spolom.

Preživljavanje bez progresije bolesti: Značajna razlika

Pacijenti kod kojih je došlo do disfunkcije štitne žlijezde imali su značajno duže preživljavanje bez progresije bolesti (PFS) u poređenju s onima kod kojih do disfunkcije nije došlo:

• Medijan PFS nije dostignut u grupi s disfunkcijom.

• Medijan PFS iznosio je 14 mjeseci u grupi bez disfunkcije.

Ova razlika bila je statistički značajna (P = 0,038).

Čak i nakon prilagodbe za pristrasnost početka terapije korištenjem vremenski zavisne kovarijantne analize, pacijenti s disfunkcijom štitne žlijezde nastavili su pokazivati bolje ishode.

Kod pacijenata liječenih atezolizumabom, medijan PFS bio je značajno duži kod onih s disfunkcijom štitne žlijezde u odnosu na one bez nje (nije dostignut naspram 13 mjeseci, P = 0,006). U grupi koja je primala pembrolizumab, statistička poređenja bila su ograničena zbog malog broja slučajeva s disfunkcijom.

Liječenje i upravljanje: Pridržavanje preporuka

Od 24 pacijenta s disfunkcijom štitne žlijezde:

• 16 (67%) je zahtijevalo liječenje.

• Hipotireoza se liječila levotiroksinom.

• Hipertireoza, kada je bila prolazna, liječena je beta-blokatorima, bez potrebe za antitireoidnim lijekovima.

Svi postupci upravljanja su bili u skladu s preporukama Evropskog udruženja za štitnu žlijezdu. Niti jedan pacijent nije prekinuo ICI terapiju zbog problema sa štitnom žlijezdom, a ukupna sigurnost i podnošljivost ostale su prihvatljive.

Multivarijantna analiza i podgrupe

Iako je disfunkcija štitne žlijezde pokazala povoljan trend u PFS-u u neadjustiranoj analizi, jedini nezavisni prediktor boljeg preživljavanja u multivarijantnom modelu bila je ekspresija PD-L1. Ni starosna dob ni spol nisu imali značajan uticaj na ishod. Prisustvo drugih irAE je također razmatrano, ali nije pokazalo nezavisnu povezanost.

Ovi nalazi ukazuju da, iako disfunkcija štitne žlijezde sama po sebi možda nije direktni uzrok poboljšanih ishoda, može predstavljati znak aktivnog imunološkog odgovora povezanog s boljom kontrolom tumora.

Implikacije za kliničku praksu i buduća istraživanja

Ova studija doprinosi rastućem broju dokaza da imunološki izazvana disfunkcija štitne žlijezde može imati prognostički značaj u kontekstu ICI terapije za NSCLC. Iako biološki mehanizmi još nisu u potpunosti razjašnjeni, vjerovatno je da imunološka aktivacija koja uzrokuje disfunkciju štitne žlijezde također doprinosi antitumorskim efektima.

Rutinsko praćenje funkcije štitne žlijezde tokom ICI terapije nije samo važno za upravljanje nuspojavama, već može pružiti uvid u efikasnost liječenja. Disfunkcija štitne žlijezde je uglavnom podložna standardnom liječenju, a njena povezanost s dužim PFS-om naglašava važnost ranog prepoznavanja i liječenja.

Međutim, retrospektivni i jednocentrični dizajn studije, uz mali broj pacijenata i nepotpune podatke o dugoročnom preživljavanju, ograničavaju mogućnost donošenja konačnih zaključaka. Veće, prospektivne studije biće potrebne kako bi se ovi nalazi potvrdili i dodatno istražio potencijal disfunkcije štitne žlijezde kao biomarkera odgovora na ICI terapiju.

Zaključak: Više od nuspojave

Disfunkcija štitne žlijezde je česta nuspojava izazvana imunološkim odgovorom kod pacijenata koji primaju ICI terapiju za metastatski NSCLC—posebno kod onih liječenih atezolizumabom. Umjesto da označava štetu, ova pojava može predstavljati pokazatelj terapijske koristi, posebno u pogledu preživljavanja bez progresije bolesti. Za kliničare i istraživače, ovi nalazi naglašavaju značaj sistematskog praćenja endokrine funkcije i potencijal imunološki izazvanih događaja kao pokazatelja efikasnosti liječenja.

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Reference:

Šejla Cerić, Timur Cerić, Emir Sokolović, Jasmina Dalač, Dragana Miletić, Inga Marijanović, Layan Mattar, Amina Aljić, Selma Agić-Bilalagić, Amera Šadija, Miran Hadžiahmetović, Semir Bešlija

Impact of thyroid immune-related adverse events on clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with checkpoint inhibitor therapy: A single center study.

Biomol Biomed [Internet]. 2025 Mar. 24 [cited 2025 Jun. 13];

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12321

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