A multicenter retrospective study has revealed that induction chemoimmunotherapy before chemoradiotherapy may achieve non-inferior outcomes compared to the standard consolidation immunotherapy approach in patients with unresectable stage III non-small cell lung cancer (NSCLC), potentially offering a new treatment paradigm for this challenging patient population.
The study, conducted across four major cancer centers in China, analyzed 262 consecutive patients with unresectable stage III NSCLC treated between February 2018 and May 2023. Patients were divided into two groups: 124 patients received induction chemoimmunotherapy before chemoradiotherapy (Ind group), while 138 patients received consolidation immunotherapy after chemoradiotherapy (Con group).
Comparable Survival Outcomes with Fewer Treatment Cycles
The primary findings demonstrated remarkably similar survival outcomes between the two treatment approaches. Median progression-free survival (PFS) was 25.5 months in the induction group compared to 25.9 months in the consolidation group (P=0.966). The 1-year PFS rates were 75.5% versus 72.9%, and 2-year PFS rates were 52.2% versus 53.1%, respectively.
Overall survival results were equally compelling, with median OS of 46.0 months in the induction group versus not reached in the consolidation group (P=0.495). The 1-year OS rates were 91.0% versus 95.6%, and 2-year OS rates were 78.0% versus 79.5%.
Notably, patients in the induction group achieved these outcomes with significantly fewer cycles of immunotherapy - a median of 4 cycles compared to 10 cycles in the consolidation group (P<0.001).
High Response Rates and Safety Profile
The induction chemoimmunotherapy approach demonstrated impressive efficacy metrics. The objective response rate (ORR) after induction treatment was 66.1%, with a disease control rate (DCR) of 96.0%. Only 4.0% of patients (5/124) experienced disease progression during the induction immunotherapy phase.
The study utilized nine different PD-1/PD-L1 inhibitors, including Durvalumab (30.9%), Sintilimab (24.0%), Tislelizumab (13.7%), Pembrolizumab (11.8%), and Camrelizumab (11.1%), among others. All patients in the induction group received combination chemoimmunotherapy, while most patients in the consolidation group received immunotherapy monotherapy.
Clinical Rationale and Patient Selection
The primary reasons for selecting induction chemoimmunotherapy included high tumor burden (70.2%), ineligibility for concurrent chemoradiotherapy (16.1%), ineligibility for surgery after preoperative neoadjuvant treatment (8.9%), and patient preference (4.8%). This approach addresses a significant clinical need, as many patients with stage III NSCLC are ineligible for the standard PACIFIC regimen due to excessive target volume or poor tolerability.
Optimal Treatment Duration Considerations
An exploratory analysis examined the impact of treatment cycle numbers on outcomes. Patients receiving fewer than 4 cycles of induction immunotherapy showed similar PFS but numerically prolonged OS compared to those receiving 4 or more cycles. This finding suggests that prolonged induction therapy may not provide additional survival benefits and could potentially delay definitive local treatment.
The study's lead investigators noted that "early local radical treatment for stage III NSCLC is crucial. Prolonging cycles of induction immunotherapy excessively may not only fail to provide further survival benefits, but may also lead to disease progression and an increased incidence of treatment-related adverse events."
Safety and Tolerability
The safety profile favored the induction approach, with numerically lower incidence of treatment-related adverse events compared to the consolidation group. Particularly noteworthy was the lower incidence of pneumonitis, a major concern in this patient population. The induction group also showed numerically lower rates of locoregional recurrence (28.8% vs. 40.9%) and distant metastases (18.2% vs. 27.3%).
Study Limitations and Future Directions
The researchers acknowledged several limitations, including the retrospective nature of the study, incomplete PD-L1 expression data, and the relatively modest sample size. The study also did not differentiate between various immune checkpoint inhibitors, though previous research suggests no significant differences in safety and efficacy profiles among different agents.
Despite these limitations, this represents the first multicenter study to evaluate upfront chemoimmunotherapy before chemoradiotherapy in unresectable stage III NSCLC using real-world data and directly compare it with consolidation immunotherapy.
Clinical Implications
The findings challenge the current treatment paradigm and suggest that induction chemoimmunotherapy could serve as a viable alternative, particularly for patients with high tumor burden or those unable to receive concurrent chemoradiotherapy. The approach may be especially valuable given that only 49% of patients in the landmark PACIFIC trial completed the full year of consolidation therapy.
The study concludes that "upfront chemoimmunotherapy before chemoradiotherapy appears to be feasible and safe, and may achieve comparable outcomes to consolidation immunotherapy with fewer cycles of immunotherapy." These results may inform future clinical trial design and provide treatment options for patients who cannot receive standard care approaches.
