Prognostic associations between patient-reported outcomes and overall survival among patients with advanced squamous non-small cell lung cancer: results from the RATIONALE-307 trial

In the RATIONALE-307 trial, favorable overall survival (OS) outcomes with tislelizumab plus chemotherapy versus chemotherapy alone have been reported, along with improvements in patient-reported outcomes (PROs), including global health status/quality of life (GHS/QoL) and lung cancer–specific symptoms such as cough and dyspnea. Here, we aimed to evaluate the association between patient-reported symptoms and OS among patients with first-line advanced sq-NSCLC. PROs were assessed using the EORTC QLQ-C30 and QLQ-LC13 instruments. A novel three-component joint model (JM) was developed, linking linear mixed and Cox models to evaluate associations between PRO change from baseline scores, recurrent-symptomatic deterioration (RS-D) events, and OS. The association between PROs and OS was summarized via association-effect hazard ratios (HRs) from the JMs. Overall, 328 patients were included: 111 in the tislelizumab plus paclitaxel–carboplatin arm (Tisle + PC), 110 in the tislelizumab plus nab-paclitaxel–carboplatin arm (Tisle + nPC), and 107 in the paclitaxel–carboplatin (PC) alone arm. Compared to PC alone, Tisle + PC and Tisle + nPC arms significantly improved GHS/QoL (mean difference: 6.29 and 10.23, respectively; both p < 0.05). Dyspnea significantly improved in both Tisle arms; chest pain improved in the Tisle + nPC arm only. In the Tisle + PC arm, chest pain and cough were significantly associated with a 36.3% reduced risk of death (both HRs = 0.64; p = 0.02). In this analysis, compared to PC alone, Tisle + PC improved GHS/QoL and dyspnea in both arms, while chest pain improvement was observed only with Tisle + nPC. Oncology trials routinely collect patient-reported outcomes (PROs), yet between-arm differences are often hard to detect. A major reason is informative missingness: patients who worsen clinically (e.g., toxicity, progression, death) frequently stop completing PROs, so later-cycle data are missing not at random (MNAR) and averages from the remaining “survivors” can mask true symptom burden. Standard longitudinal methods typically assume missing at random and may therefore underestimate deterioration. A second, related challenge is that conventional time-to-deterioration (TTD) treats PRO decline as a single event, even though patients can deteriorate, improve, and deteriorate again; collapsing this recurrent pattern into one time point discards clinically relevant information. Third, although clinicians act on survival endpoints, the prognostic link between symptoms and overall survival (OS) is seldom quantified owing to limited model computational power. To address these gaps, we developed a novel three-component joint modeling framework in advanced squamous non-small cell lung cancer that (1) models longitudinal symptom change, (2) treats clinically meaningful PRO deteriorations as recurrent events, and (3) links both processes to OS via shared random effects. This approach was designed to reduce survivor bias (by accommodating MNAR), preserve information on repeated deteriorations, and estimate how symptom trajectories relate to survival. Using data from the RATIONALE-307 trial, we found that compared to chemotherapy alone, tislelizumab + chemotherapy improved GHS/QoL and reduced lung cancer–specific symptoms including dyspnea, cough, and chest pain. Notably, improvements in chest pain and cough were significantly associated with a 36.3% reduced risk of death, supporting the prognostic value of PROs.