Resumen

Determine anti-tumor efficacy by characterizing response rates on positron emission tomography (PET) following three cycles of induction immunotherapy with cemiplimab and fianlimab without chemotherapy for locally advanced non-small cell lung cancer (LA-NSCLC).

Edad: 18 años o más

Género: Todos

Fecha de inicio: 08/07/2025

Fecha de finalización principal (estimada): 08/01/2027

Fecha estimada de finalización del estudio: 08/01/2027

Acepta voluntarios sanos: No

Propósito y descripción del ensayo

Non-small cell lung cancer (NSCLC) represents more than 80% of lung cancers, and approximately 35% of NSCLC patients present with stage III disease. Standard treatment for patients with locally advanced NSCLC, which may be defined as American Joint Committee on Cancer (AJCC) stage III disease or unresectable stage II disease, typically consists of conventionally fractionated (1.8-2.0 Gray (Gy) per day) radiotherapy (RT) to a total dose of approximately 60 Gy with concurrent chemotherapy. Based on the PACIFIC trial (NCT02125461), patients without disease progression after concurrent chemoradiotherapy are typically offered a one-year course of the adjuvant PD-L1 inhibitor durvalumab, regardless of PD-L1 tumor proportion score (TPS). Recent results from the PACIFIC-2 trial (NCT03519971) failed to demonstrate a survival benefit of adding concurrent durvalumab to chemoradiotherapy, and therefore the PACIFIC regimen of adjuvant immunotherapy following chemoradiation remains the standard of care for unresectable LA-NSCLC. Based on the PACIFIC trial standard, both the RT and systemic therapy utilized to treat LA-NSCLC patients in standard of care follow a non-biomarker selected "one-size-fits-all" approach in the US. In advanced NSCLC, however, patients with high PD-L1 TPS score (≥ 50%) benefit more from the immune checkpoint inhibitors pembrolizumab, atezolizumab, and cemiplimab compared to cytotoxic chemotherapy alone, and single agent immunotherapy (IO) has become a first-line standard of care for such patients. Omitting chemotherapy from the treatment of LA-NSCLC patients with high PD-L1 expression who will receive IO is a logical step. On the other hand, patients with low PD-L1 TPS score (\< 50%) benefit less from single agent IO in advanced NSCLC, and IO is typically offered together with chemotherapy. Given the poor response to IO for patients with low PD-L1 TPS expression, the investigator team believes that combination IO plus chemotherapy could be particularly beneficial in the low-TPS LA-NSCLC setting. Induction (also referred to as neoadjuvant) IO before RT for LA-NSCLC has several potential advantages. For example, the native tumor functioning as an in-situ vaccine in the neoadjuvant setting, with an intact lymphatic system and unirradiated nodal status, could promote optimal immune priming. Indeed, neoadjuvant IO has shown impressive efficacy in both deficient mismatch repair (dMMR) rectal cancer and melanoma. For early-stage NSCLC, this approach is highlighted in recent neoadjuvant trials of immune checkpoint inhibition in combination with chemotherapy for resectable NSCLC, such as CheckMate 816 (NCT02998528), Keynote-671 (NCT03425643), and NADIMII (NCT03838159). Furthermore, results from the PACIFIC trial and real-world data show that approximately 25% of LA-NSCLC patients started on chemoradiotherapy never receive consolidation durvalumab, and approximately 50% of patients started on consolidation durvalumab do not complete the intended year of treatment. Thus, administering induction IO may be particularly advantageous for LA-NSCLC patients to enhance IO treatment delivery. SPRINT (NCT03523702) was a multi-institutional Phase II trial where biomarker-selected (PD-L1 TPS ≥ 50%) LA-NSCLC patients were treated with 3 cycles of induction pembrolizumab to reduce the extent of thoracic RT, and cytotoxic chemotherapy was omitted from the treatment regimen. Patients with PD-L1 TPS \< 50% received standard concurrent chemoradiotherapy (chemoRT) followed by standard adjuvant treatment, to serve as a non-randomized comparator for evaluating toxicities and clinical outcomes. Following induction, PD-L1 TPS ≥ 50% patients received PET-based dose-painted RT according to a novel and personalized approach that was studied in two prior trials (NCT02073968, NCT03481114) that can decrease toxicities by utilizing shortened courses of RT and reducing doses administered to small tumors and nodes. Based on these studies, PET response to induction IO using PERCIST criteria may serve as a useful prognostic factor to identify LA-NSCLC patients more likely to respond to novel IO regimens at an earlier time point in treatment (prior to administration of RT). This observation is also supported by prior prospective and retrospective studies showing that response on PET rather than CT may be a better predictor of survival for NSCLC patients receiving IO. Furthermore, early identification of IO response provides added insight to a tumor's unique immune biology that could be used to individualize subsequent RT, IO, and/or chemotherapy treatment plans. Overall, SPRINT demonstrated high treatment efficacy with limited toxicity and introduces PET response to induction IO as a novel endpoint that allows for early assessment of treatment activity, and which could potentially serve as a new paradigm in LA-NSCLC interventional studies. Based on this experience, the investigator team believes that the SPRINT treatment approach (induction IO followed by RT and consolidation IO) can be used to investigate other novel IO combinations for biomarker-selected LA-NSCLC. One such immune target is lymphocyte activation gene 3 (LAG3), which is expressed by various immune cells, and regulates effector T-cell activation and responses. LAG-3 inhibition restores the effector function of exhausted T cells, enhancing their ability to attack tumor cells. In addition, LAG-3's inhibitory effects on T cells appear distinct from those of PD-L1, serving as a potential rationale for combining LAG-3 and PD-1/PD-L1 inhibition. In metastatic melanoma, the RELATIVITY-047 trial (NCT03470922) showed that combination PD-1 and LAG-3 blockade with nivolumab and relatlimab, respectively, improves progression-free survival (PFS) compared to nivolumab alone with a favorable toxicity versus nivolumab plus the CTLA-4 inhibitor ipilimumab. These findings suggest that combination PD-1 and LAG-3 inhibition may have potential utility for treatment of other malignancies, such as NSCLC. Furthermore, a Phase I study of cemiplimab and fianlimab in unresectable stage IIIB-C or IV NSCLC (NCT03005782) showed that the combination demonstrated clinical activity with a similar safety profile compared to cemiplimab alone. Given the promising findings observed in SPRINT, RELATIVITY-047, and NCT03005782, the research team believes that dual immune checkpoint blockade with the PD-1 inhibitor cemiplimab plus the LAG-3 inhibitor fianlimab administered before and after thoracic RT, as per the SPRINT approach, has valuable therapeutic potential for LA-NSCLC patients. Treatment will be administered in three phases as detailed in this registration: (1) three cycles of induction IO, with histology-specific platinum doublet chemotherapy (PDC) added for subjects with PD-L1 TPS \<50%; (2) thoracic RT (with concurrent PDC recommended for subjects with PD-L1 TPS \<50%); (3) 13 cycles of consolidation IO.

Criterios de elegibilidad

Edad: 18 años o más

Género: Todos

Acepta voluntarios sanos: No

Inclusion criteria:

* Previously untreated and biopsy-proven NSCLC, with measurable disease (at least 1 unidimensional, radiographically measurable lesion based on RECIST v1.1) and one of the following stages: (prior resection or stereotactic radiotherapy for early-stage disease is allowed)

* AJCC version 8 Stage II disease, medically or technically unresectable

* AJCC version 8 Stage III disease, eligible for non-surgical treatment

* Determination of PD-L1 expression on pretreatment tumor specimen using a clinically validated assay

* Eligible for standard nonsurgical treatment for Stage III NSCLC, i.e., chemotherapy and concurrent RT followed by adjuvant durvalumab

* Whole body PET/CT within 42 days prior to study entry demonstrating hypermetabolic pulmonary lesion(s) and/or thoracic lymph node(s)

* Resonancia magnética cerebral o tomografía computarizada craneal con contraste realizada dentro de los 42 días previos al inicio del estudio.

* PFTs within 42 days of study entry

* Eastern Cooperative Oncology Group (ECOG) performance status 0-2

* Adequate end-organ function for study therapy, as per clinician assessment and including:

* Hemoglobina ≥ 9,0 g/dL

* Recuento absoluto de neutrófilos (RAN) ≥ 1,5 x 10⁹/L (> 1500 por mm³)

* Recuento de plaquetas ≥ 100 x 10⁹/L (>100.000 por mm³)

* Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician

* AST (SGOT)/ALT (SGPT), and alkaline phosphatase ≤ 2.5 x institutional upper limit of normal (ULN)

* Serum creatinine clearance \>30 mL/min by the Cockcroft-Gault formula (as below) or by 24-hour urine collection for determination of creatinine clearance: (except for patients planned to receive pemetrexed, in which case serum creatinine clearance needs to \>45 ml/min)

* Males: Weight (kg) x (140 - Age) ÷ (72 x serum creatinine (mg/dL))

* Females: 0.85 x Weight (kg) x (140 - Age) ÷ (72 x serum creatinine (mg/dL))

* A female participant is eligible to participate if she is not pregnant (see Exclusion Criteria), not breastfeeding, and at least one of the following conditions applies:

* Not a woman of childbearing potential (WOCBP) as defined in the Appendix

* A WOCBP who agrees to follow the contraceptive guidance in the Appendix during the treatment period and for at least 6 months (180 days) after the last dose of study treatment with cemiplimab and fianlimab

* A WOCBP who agrees to follow the contraceptive guidance in the Appendix and for at least 6 months after the last dose of chemotherapy or as specified in FDA prescribing labels (e.g. 14 months after the last dose of cisplatin)

* A male participant must agree to use contraception during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period

* The participant (or legally acceptable representative if applicable) provides written informed consent for the trial

Criterios de exclusión:

* Presence of known sensitizing epidermal growth factor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion

o Determination of EGFR/ALK mutation status is required for non-squamous cell carcinoma histologies and recommended for squamous cell carcinoma

* Prior therapy with an anti-PD-1, anti-PD-L1, or LAG-3 inhibitor

* Paciente que participa actualmente o ha participado en un estudio de un agente en investigación o que ha utilizado un dispositivo en investigación en las 4 semanas previas a la primera dosis del tratamiento del estudio.

* Neoplasia maligna activa distinta del cáncer de pulmón que (1) requiere tratamiento activo distinto de la terapia hormonal y (2) los médicos tratantes consideran que es probable que afecte la esperanza de vida del paciente.

* Antecedentes de neumonitis (no infecciosa) que requirió esteroides o neumonitis actual

* Antecedentes conocidos de miocarditis

* Troponina T (TnT) o troponina I (TnI) > 2 veces el límite superior normal institucional al inicio del estudio. Se permite la participación de pacientes con niveles de TnT o TnI entre > 1 y 2 veces el límite superior normal si los niveles repetidos dentro de las 24 horas son ≤ 1 vez el límite superior normal. Si los niveles de TnT o TnI son > 1 a 2 veces el límite superior normal dentro de las 24 horas, el sujeto puede someterse a una evaluación cardíaca y el investigador puede considerar el tratamiento según su criterio médico en beneficio del paciente.

* Bacillus Tuberculosis (TB) activo conocido

* Trastornos psiquiátricos o de abuso de sustancias conocidos que pudieran interferir con la cooperación con los requisitos del juicio.

* Embarazo, evaluado mediante una prueba de embarazo en orina dentro de las 72 horas previas a la asignación del tratamiento del estudio. Si la prueba de embarazo en orina es positiva o no se puede confirmar como negativa, se requiere una prueba de embarazo en suero. Si transcurren más de 72 horas entre la prueba de embarazo de detección y la primera dosis del tratamiento del estudio, se debe realizar otra prueba de embarazo (en orina o suero) y esta debe ser negativa.

* Evidencia actual o reciente (en los últimos 2 años) de una enfermedad autoinmune que requirió tratamiento sistémico con agentes inmunosupresores. Los siguientes casos no son excluyentes: vitíligo, asma infantil resuelta, hipotiroidismo residual que solo requiere terapia de reemplazo hormonal, psoriasis que no requiere tratamiento sistémico.

* Antecedentes o evidencia actual de infección local o sistémica significativa (grado CTCAE ≥2) (p. ej., celulitis, neumonía, septicemia) que requiera tratamiento antibiótico sistémico dentro de las 2 semanas previas a la primera dosis del medicamento de prueba.

* Infección activa que requiere tratamiento

* Infección no controlada por VIH, virus de la hepatitis B (VHB) o virus de la hepatitis C (VHC); o diagnóstico de inmunodeficiencia relacionada con, o que resulta en, una infección crónica.

* Se permite la participación de pacientes con VIH conocido que tengan la infección controlada (carga viral indetectable y recuento de CD4 superior a 350, ya sea de forma espontánea o con un régimen antiviral estable). Para los pacientes con infección por VIH controlada, el seguimiento se realizará según las normas locales.

Se permite la participación de pacientes con hepatitis B conocida (HepBsAg+) que tengan la infección controlada (ADN del virus de la hepatitis B en suero detectado mediante PCR por debajo del límite de detección Y que estén recibiendo terapia antiviral para la hepatitis B). Los pacientes con infecciones controladas deben someterse a un control periódico del ADN del VHB según las normas locales y deben continuar con la terapia antiviral durante al menos 6 meses después de la última dosis del fármaco en investigación.

* Se permite la entrada a pacientes que sean positivos para anticuerpos contra el virus de la hepatitis C (HCV Ab+) y que tengan la infección controlada (ARN del VHC indetectable mediante reacción en cadena de la polimerasa (PCR), ya sea de forma espontánea o en respuesta a un tratamiento previo exitoso contra el VHC).

* Los pacientes con VIH o hepatitis deben ser evaluados por un especialista cualificado (por ejemplo, infectólogo o hepatólogo) que trate esta enfermedad antes de comenzar y periódicamente durante toda la duración de su participación en el ensayo.

* Diagnóstico de inmunodeficiencia o terapia sistémica crónica con esteroides en curso (en dosis superiores a 10 mg diarios de equivalente de prednisona) o cualquier otra forma de terapia inmunosupresora dentro de los 7 días previos a la primera dosis del fármaco en estudio.

* Hipersensibilidad conocida a las sustancias activas o a alguno de los excipientes.

* Recibió una vacuna viva dentro de los 30 días del inicio previsto del medicamento del estudio o Vacuna viva o atenuada con potencial de replicación. Si un paciente tiene previsto recibir una vacuna contra la COVID-19 antes del inicio del medicamento del estudio, su participación en el estudio debe retrasarse al menos 1 semana después de cualquier vacunación contra la COVID-19. Durante el período de tratamiento, se recomienda retrasar la vacunación contra la COVID-19 hasta que los pacientes estén recibiendo y tolerando una dosis estable del medicamento del estudio. Una dosis de vacuna no debe administrarse menos de 48 horas antes o después de la administración del medicamento del estudio.