What is the current status of Stage III NSCLC immunotherapy development?

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What is the current status of Stage III NSCLC immunotherapy development?

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What is the current status of Stage III NSCLC immunotherapy development?

Stage III Non-Small Cell Lung Cancer (NSCLC) accounts for approximately one-third of new NSCLC cases, making it a significant population with substantial heterogeneity and posing significant challenges for clinical treatment.

While the definition of “unresectable” remains controversial, and some Stage IIIA and specific Stage IIIb-N2 patients may benefit from comprehensive surgical treatment, overall, “unresectable” patients still constitute the majority in Stage III NSCLC.

The PACIFIC study has demonstrated that for such patients, consolidation therapy with durvalumab after concurrent chemoradiotherapy (CCRT) significantly improves overall survival (OS), with a median OS of 47.5 months.

Therefore, for Stage III NSCLC patients with good performance status (PS), the “PACIFIC regimen” has become the standard of care, recommended by guidelines both domestically and internationally.

However, a series of retrospective studies have shown that in the real world, only half of the patients receive curative treatment. Among patients who receive curative chemoradiotherapy, only two-thirds use CCRT, and one-third undergo sequential chemoradiotherapy (SCRT).

Furthermore, about 20% of patients achieve a cure after CCRT and do not require immunotherapy consolidation. Some patients are unable to continue durvalumab immunotherapy due to residual toxic side effects, compromised physical condition, disease progression, or local indications.

In this context, further development of treatment modalities and optimization of treatment strategies are still needed to benefit more patients.

Current Standard Treatment: Immunotherapy after Chemoradiotherapy

The Phase III clinical trial PACIFIC showed that Stage III NSCLC patients who receive immunotherapy with durvalumab after CCRT achieve 5-year overall survival (OS) and progression-free survival (PFS) rates of 42.9% and 33.1%, respectively, compared to the placebo group, demonstrating significant improvement. In terms of safety, adding durvalumab to CCRT did not increase treatment toxicity. Subsequently, the real-world study PACIFIC-R further validated the results of the PACIFIC study, with a median PFS of 25.6 months in the CCRT population, showing a plateau and long-term benefit.

Results from the Phase III clinical trial GEMSTONE-301 demonstrated that Stage III NSCLC patients who received consolidation therapy with sintilimab after CCRT or SCRT had median PFS of 10.5 months and 8.1 months, respectively, significantly improving outcomes compared to the placebo group.

Currently, immunotherapy consolidation after chemoradiotherapy has become the standard treatment for Stage III NSCLC patients, with unanimous recommendations from domestic and international guidelines. However, exploration continues, and recent clinical research has evaluated various new strategies to further improve patient survival, including combination immunotherapy regimens, concurrent immunotherapy with chemoradiotherapy, and induction immunotherapy before chemoradiotherapy.

Combination Immunotherapy Regimens

An open-label, randomized Phase II study, BTCRC-LUN 16-081, showed that the combination of PD-1 and CTLA-4 inhibitors did not provide additional benefits in terms of PFS compared to PD-1 monotherapy.

The COAST study, a three-arm, randomized Phase II trial, indicated that for Stage IV NSCLC patients, the objective response rates (ORR) were 30.0% for PD-L1 inhibitor plus anti-CD73 antibody (Group A), 35.5% for PD-L1 inhibitor plus NKG2A inhibitor (Group B), and 17.9% for PD-L1 monotherapy (Group C).

Phase II trials have preliminarily shown that combination immunotherapy regimens can improve outcomes. Several Phase III randomized controlled trials are currently ongoing to further evaluate this strategy.

Concurrent Immunotherapy with Chemoradiotherapy

A single-arm Phase II trial, NICOLAS, assessed the safety and efficacy of concurrent immunotherapy with CCRT. Subjects received platinum-based chemotherapy and concurrent radiotherapy, followed by the addition of nivolumab from the second cycle of chemotherapy, with one year of consolidation therapy. Safety data showed a 11.7% incidence of grade ≥3 pneumonitis at 6 months. In terms of efficacy, the 1-year PFS rate was 53.7%, with a median PFS of 12.7 months, median OS of 38.8 months, and 1- and 2-year OS rates of 75.7% and 63.7%, respectively.

DETRRED, another single-arm Phase II trial with a similar design to NICOLAS, included patients receiving atezolizumab concurrently with CCRT and subsequent one-year consolidation immunotherapy. Results showed that 20% of patients experienced grade ≥3 immune-related adverse events (irAEs). Median PFS was 13.2 months, with 1-year OS and PFS rates of 80% and 55%, respectively.

These two studies had similar designs but different results, possibly due to Phase II design, small sample sizes, and differences in inclusion criteria. However, despite variations in results, concurrent triple therapy shows promise in terms of efficacy but may increase the occurrence of pneumonia and severe AEs. Future research will need to focus on identifying the optimal patient population for this approach. Several Phase III randomized controlled trials exploring this strategy are currently underway, which will provide more robust evidence.

Induction Immunotherapy Followed by Chemoradiotherapy

In the AFT-16 Phase II study, 64 Stage III NSCLC patients received two cycles of atezolizumab treatment, followed by restaging. If there was no progression, patients received two more cycles of atezolizumab, followed by CCRT and one year of atezolizumab consolidation therapy. If patients experienced progression at the first restaging, they received immediate CCRT. Results showed a median PFS of 23.7 months (including the induction treatment phase), with 18-month and 1-year PFS rates of 66% and 57%, respectively, and an 18-month OS rate of 84%.

Another Phase II trial, KETNOTE-799, employed an immunotherapy-based regimen, with patients initially receiving immunotherapy induction, followed by CCRT concurrently with pembrolizumab, and then one year of pembrolizumab consolidation therapy. Results showed that both Group A (non-squamous and non-small cell lung cancer) and Group B (squamous cell lung cancer) achieved an objective response rate (ORR) of 70.5%, with a median PFS of 30.6 months for Group A (not reached, including the induction phase).

Moving immunotherapy ahead of chemotherapy, or even maintaining immunotherapy throughout the treatment course, is another exploration of immunotherapy advancement. Nonetheless, adverse reactions and the optimal patient population for such approaches still require further investigation. It is anticipated that more Phase III randomized controlled trials will provide further evaluation of these strategies in the future.

Immunotherapy for Stage III NSCLC Patients with Driver Gene Mutations

Current evidence suggests that immunotherapy benefits are limited for Stage IV NSCLC patients with non-smoking-related driver mutations. For Stage III NSCLC patients with driver gene mutations, such as classic EGFR mutations and ALK rearrangements, immunotherapy consolidation is generally not recommended. Current Phase III clinical studies are exploring the efficacy and

safety of targeted therapy in Stage III patients with EGFR mutations after chemoradiotherapy, offering hope for additional clinical data and solutions.

Future Directions

Immunotherapy consolidation after chemoradiotherapy has become the current standard of care for Stage III NSCLC patients.

Ongoing clinical trials are expected to expand the patient population benefiting from immunotherapy and improve clinical practice guidelines.

However, current clinical trials still have significant limitations—they are not driven by biomarkers, and they encompass all unresectable Stage III NSCLC patients. To further improve patient survival, a “one-size-fits-all” treatment approach needs refinement.

In-depth understanding of tumor biology and behavior, identification of different patient subgroups, and the development of personalized anti-cancer strategies could potentially transform the current treatment landscape.

Additionally, Stage III lung cancer exhibits strong heterogeneity, making diagnosis and treatment relatively complex, requiring multidisciplinary team discussions to formulate the best comprehensive diagnosis and treatment plans, with the full participation of various departments throughout the disease course.

These factors will be critical in further extending the survival of locally advanced Stage III NSCLC patients.

What is the current status of Stage III NSCLC immunotherapy development?

References:

[1] Cortiula F, et al. Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches. Ann Oncol. 2022 Sep;33(9):893-908.

[2] Spigel DR, Faivre-Finn C, Gray JE, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage Ⅲ Non-Small-Cell Lung Cancer. J Clin Oncol. 2022;40（12）:1301-1311.

[3] Girard N, Smit H.J.M, Sibille A, et al. 1171MO PACIFIC-R real-world study: Treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy. Ann Oncol. 2021; 32: S939-S940.

[4] Zhou Q, Chen M, Jiang O, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):209-219.

[5] Durm G.A, Mamdani H, Althouse S.K, et al. Consolidation nivolumab plus ipilimumab or nivolumab alone following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: BTCRC LUN 16-081. J Clin Oncol. 2022; 40 (8509-8509).

[6] Majem M, Barlesi F, et al. COAST: an open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non–small-cell lung cancer. J Clin Oncol. 2022; (In press).

[7] Peters S, Felip E, Dafni U, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer—the ETOP NICOLAS trial. Lung Cancer. 2019; 133: 83-87.

[8] Peters S, Felip E, Dafni U, et al. Progression-free and overall survival for concurrent nivolumab with standard concurrent chemoradiotherapy in locally advanced stage IIIA-B NSCLC: results from the European Thoracic oncology platform NICOLAS phase II Trial (European Thoracic Oncology Platform 6-14). J Thorac Oncol. 2021; 16: 278-288.

[9] Lin S.H, Lin Y, Yao L, et al. Phase II trial of concurrent atezolizumab with chemoradiation for unresectable NSCLC. J Thorac Oncol. 2020; 15: 248-257.

[10] Ross H.J, Kozono D.E, Urbanic J.J, et al. AFT-16: Phase II trial of neoadjuvant and adjuvant atezolizumab and chemoradiation (CRT) for stage III non-small cell lung cancer (NSCLC). J Clin Oncol. 2021; 39 (8513-8513).

[11] Reck M, Lee K.H, Frost N, et al. Two-year update from KEYNOTE-799: pembrolizumab plus concurrent chemoradiation therapy (cCRT) for unresectable, locally advanced, stage III NSCLC. J Clin Oncol. 2022; 40 (8508-8508).

(source:internet, reference only)

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