Chinese Society of Clinical Oncology Non-small Cell Lung Cancer (CSCO NSCLC) guidelines in 2024: key update on the management of early and locally advanced NSCLC

Addition of NSCLC molecular typing: immunotherapy and focused remedy in postoperative adjuvant remedy

The IMpower010 trial was designed to find out the efficacy of atezolizumab vs. greatest supportive care after adjuvant chemotherapy in resectable stage IB-IIIA NSCLC sufferers¹. The research demonstrated that atezolizumab provides superior median disease-free survival (mDFS) advantages in comparison with greatest supportive take care of sufferers with stage II-IIIA NSCLC and the diploma of DFS profit correlates with increased PD-L1 expression. The info indicated that the mDFS within the intention-to-treat (ITT) inhabitants [atezolizumab group vs. best supportive care group, not reached (NR) vs. 37.2 months, respectively, with a hazard ratio (HR) of 0.81], suggesting that atezolizumab reduces the danger of recurrence, new major tumors, or loss of life by 19% for all sufferers with II-IIIA NSCLC. A stratified evaluation primarily based on PD-L1 tumor cell (TC) expression confirmed the next: the mDFS in sufferers with a PD-L1 TC expression ≥ 1% [atezolizumab group vs. best supportive care group, not evaluable (NE) vs. 35.3 months, respectively, with an HR of 0.66; Table 1]; the mDFS in sufferers with a PD-L1 TC expression between 1% and 49% (atezolizumab group vs. greatest supportive care group, 32.8 vs. 31.4 months, respectively, with an HR of 0.87); and the mDFS in sufferers with a PD-L1 TC expression ≥ 50% (atezolizumab group vs. greatest supportive care group, NE vs. 35.7 months, respectively, with an HR of 0.43). Atezolizumab was authorised by the China Nationwide Medical Merchandise Administration (NMPA) on 16 March 2022 as monotherapy for adjuvant remedy of stage II-IIIA NSCLC PD-L1-positive (TC ≥ 1%) sufferers who’ve undergone surgical resection and accomplished platinum-based chemotherapy primarily based on the IMpower010 research findings². Due to this fact, the rules have added “Postoperative stage II/III NSCLC ought to endure PD-L1 expression testing to information adjuvant immunotherapy” as a Class I advice. Moreover, up to date information from the American Affiliation for Most cancers Analysis (AACR) on the IMpower010 trial indicated that the unstratified total survival (OS) HR for the Asian ITT inhabitants was 0.73, which is in step with the worldwide HR of 0.71. Information from the 5-year follow-up analysis of the Asian inhabitants within the IMpower010 research introduced on the CSCO annual assembly in September 2024 confirmed that within the stage II-IIIA inhabitants with PD-L1 TC expression ≥ 1%, the mDFS within the atezolizumab group was not reached with an unstratified HR of 0.69. OS information weren’t mature within the second interim evaluation. The 5-year OS charges within the stage II-IIIA Asian sufferers with PD-L1 TC expression ≥ 1% and stage II-IIIA Asian sufferers with PD-L1 TC expression ≥ 50% have been 83.5% and 90.9%, respectively, confirming the superb efficacy of atezolizumab as adjuvant remedy³.

Even ALK-positive NSCLC sufferers receiving platinum-based adjuvant chemotherapy nonetheless expertise a excessive recurrence fee post-surgery. The ALINA research, a worldwide, section III, open-label, randomized trial, aimed to find out the efficacy of alectinib vs. platinum-based chemotherapy in adjuvant remedy for sufferers with resectable stage IB-IIIA ALK-positive NSCLC⁴. The mDFS information have been as follows: sufferers with stage II-IIIA NSCLC, NR vs. 44.4 months for the adjuvant alectinib vs. platinum-based chemotherapy group, respectively (HR = 0.24); and sufferers with stage IB-IIIA, NR vs. 41.3 months for the adjuvant alectinib vs. platinum-based chemotherapy group, respectively (HR = 0.24). The two-year DFS for the alectinib group vs. the chemotherapy group was 93.8% vs. 63.0%, respectively, and the 3-year DFS was 88.3% vs. 53.3%, respectively. The two-year DFS for the alectinib group vs. the chemotherapy group was 93.6% vs. 63.7%, respectively, within the ITT inhabitants. Moreover, alectinib demonstrated a profit within the central nervous system-DFS in comparison with chemotherapy with an HR of 0.22. It’s noteworthy that the indication for adjuvant alectinib remedy was authorised by the U.S. Meals & Drug Administration (FDA) in April 2024. Adjuvant alectinib remedy obtained approval from the European Fee and the NMPA in June 2024, attaining virtually simultaneous world approval for adjuvant remedy of sufferers with stage IB-IIIA ALK-positive NSCLC primarily based on the 8^th version of the American Joint Committee on Most cancers staging guide. Nonetheless, as a result of pharmacoeconomic issues, the 2024 CSCO tips have added “For sufferers with postoperative pathologic detection of ALK fusion, adjuvant alectinib remedy after surgical procedure” as a Class II advice for operable stage IIA-IIIB NSCLC remedy.

Novel remedy possibility for inoperable early-stage NSCLC: radiotherapy mixed with immunotherapy

Surgical resection has historically been the popular customary remedy for sufferers with early-stage NSCLC. Nonetheless, surgical procedure is invasive and a few sufferers could not tolerate radical surgical remedy. Stereotactic ablative physique radiotherapy (SABR) is the usual remedy for early-stage lung most cancers sufferers who aren’t candidates for surgical procedure, offering an OS just like surgical sufferers. Though the intrathoracic native management fee after SABR exceeds 90%, extrapulmonary recurrence is comparatively widespread, indicating the need for mixed systemic remedy with SABR. Combining SABR with immunotherapy elevated the 4-year event-free survival (EFS) from 53% with SABR alone to 77% in a section II randomized managed trial involving sufferers with inoperable early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC⁵. The mixture remedy routine didn’t result in the prevalence of ≥ 3 grade pneumonia or ≥ 4 grade opposed occasions. Due to this fact, combining immunotherapy with SABR represents a remedy possibility. Based mostly on the above information, the rules have been up to date to incorporate “SABR mixed with immunotherapy” as a Class II advice for treating inoperable stage IA and IB NSCLC (Table 2).

“The sandwich cookie” remedy paradigm: the period of mixture perioperative immunotherapy and chemotherapy

The KEYNOTE-671 trial demonstrated that the mEFS in sufferers with resectable stage II-IIIB NSCLC receiving neoadjuvant pembrolizumab plus chemotherapy adopted by adjuvant pembrolizumab was 47.2 months in comparison with 18.3 months with chemotherapy alone with an HR of 0.59. The mOS was NR within the pembrolizumab group vs. 52.4 months within the chemotherapy-alone group with an HR of 0.72. The 36-month OS was 71% vs. 64% and the incidence of grade 3–5 treatment-related opposed occasions was 45% vs. 38%⁶. The U.S. FDA authorised pembrolizumab together with chemotherapy for neoadjuvant remedy of resectable NSCLC (T ≥ 4 cm or N+), adopted by adjuvant monotherapy with pembrolizumab post-surgery on 16 October 2023 primarily based on the KEYNOTE-671 research findings.

The RATIONALE-315 research confirmed that the most important pathologic response (MPR) with neoadjuvant tislelizumab plus chemotherapy adopted by adjuvant tislelizumab vs. chemotherapy alone was 56.2% vs. 15.0% in sufferers with resectable stage II-IIIA NSCLC. The pathologic full response (pCR) was 40.7% vs. 5.7%⁷. The NMPA authorised a brand new indication of tislelizumab on 21 October 2024 primarily based on the RATIONALE-315 research for mixture platinum-containing chemotherapy as neoadjuvant remedy, adopted by adjuvant monotherapy with tislelizumab after surgical procedure for sufferers with resectable stage II or IIIA NSCLC.

The AEGEAN research findings instructed that mixture neoadjuvant durvalumab with chemotherapy adopted by adjuvant durvalumab vs. chemotherapy alone yields an mEFS of NR vs. 25.9 months (HR = 0.68) with a pCR of 17.2% vs. 4.3% in sufferers with resectable stage IIA-IIIB NSCLC, highlighting some great benefits of perioperative immunotherapy⁸.

The CheckMate 77T research confirmed that neoadjuvant nivolumab mixed with chemotherapy adopted by adjuvant nivolumab vs. chemotherapy alone leads to an mEFS of NR vs. 18.4 months (HR = 0.58) in sufferers with resectable stage II-IIIB NSCLC, indicating that nivolumab earlier than and after surgical procedure considerably extends the mEFS⁹.

The Neotorch research indicated that the mEFS with neoadjuvant toripalimab mixed with chemotherapy adopted by adjuvant toripalimab vs. chemotherapy alone is NR vs. 15.1 months (HR = 0.40) in sufferers with resectable stage II or III NSCLC, respectively. The MPR was 48.5% vs. 8.4%, respectively, and the pCR was 24.8% vs. 1.0%, respectively. The Neotorch research primarily reported outcomes of sufferers with stage IIIA-IIIB NSCLC¹⁰. The NMPA authorised mixture toripalimab with chemotherapy for neoadjuvant remedy adopted by adjuvant toripalimab monotherapy for grownup sufferers with resectable stage IIIA-IIIB NSCLC on 26 December 2023 primarily based on the Neotorch research findings.

The TD-FOREKNOW research confirmed that the pCR with neoadjuvant camrelizumab mixed with chemotherapy adopted by adjuvant camrelizumab vs. chemotherapy alone is 32.6% vs. 8.9% and MPR is 65.1% vs. 15.6% in sufferers with stage IIIA or IIIB NSCLC, respectively, indicating that camrelizumab is a possible remedy possibility for perioperative NSCLC¹¹.

The outcomes of those research confirmed that “sandwich cookie” perioperative remedy combines some great benefits of neoadjuvant and adjuvant immunotherapy, which provides larger advantages. This method initiates antitumor immunity within the presence of major tumors and lymph node metastases and helps get rid of residual micrometastases earlier than and after surgical procedure. The rules have been up to date primarily based on the info from the above scientific research, as follows: resectable stage IIA and IIB NSCLC, (1) “platinum-based chemotherapy mixed with pembrolizumab or tislelizumab for neoadjuvant and adjuvant remedy” was added as a Class II advice, (2) “platinum-based chemotherapy mixed with durvalumab for neoadjuvant and adjuvant remedy” was added as a Class III advice, and (3) “adjuvant nivolumab after neoadjuvant platinum-based chemotherapy mixed with nivolumab remedy” was added as a Class III advice; and sufferers with resectable stage IIIA or IIIB NSCLC, (1) “platinum-based chemotherapy mixed with toripalimab for neoadjuvant and adjuvant remedy” was added as a Class I advice, (2) “platinum-based chemotherapy mixed with pembrolizumab, tislelizumab, or camrelizumab for neoadjuvant and adjuvant remedy” was added as a Class II advice, (3) “platinum-based chemotherapy mixed with durvalumab for neoadjuvant and adjuvant remedy” was added as a Class III advice, and (4) “adjuvant nivolumab after neoadjuvant platinum-based chemotherapy mixed with nivolumab remedy” was added as a Class III advice (Table 2). Nonetheless, it stays unclear whether or not the efficacy of this remedy mannequin is considerably correlated with PD-L1 expression. Due to this fact, testing for PD-L1 expression previous to remedy isn’t advisable.

The presence of EGFR mutations or ALK fusions is a contraindication for neoadjuvant/perioperative and adjuvant immunotherapy. Due to this fact, it is very important carry out molecular profiling (ideally in a multiplex platform) in early-stage NSCLC.

Conclusions

The 2024 CSCO NSCLC tips have undergone important updates for early and regionally superior NSCLC. The updates primarily deal with focused remedy and immunotherapy (particularly the latter), reflecting the current traits in drug improvement. The inclusion of atezolizumab adjuvant remedy primarily based on PD-L1 expression and alectinib adjuvant remedy primarily based on ALK fusion detection have led to extra exact molecular typing-based NSCLC remedy. The mixture of immunotherapy, comparable to nivolumab, with radiotherapy provides a brand new therapeutic possibility for inoperable stage IA and IB NSCLC. Based mostly on the outcomes of a number of perioperative immunotherapy scientific research, the “neoadjuvant plus adjuvant” remedy mannequin has turn into the predominant method, constructing upon the earlier “neoadjuvant” or “adjuvant” remedy fashions. Pembrolizumab, tislelizumab, durvalumab, toripalimab, and camrelizumab have turn into the brokers advisable for this remedy mannequin, heralding a brand new period of “sandwich cookie” perioperative mixed immunotherapy and chemotherapy for NSCLC.

The well timed incorporation of those new findings into tips is crucial to offer clinicians in China with a reference for scientific observe, which is the essence of guideline improvement. We consider that the CSCO NSCLC tips will proceed to be grounded in evidence-based observe, ranging from the precise circumstances of sufferers in China, and progressively enhancing the worldwide affect.

Creator contributions

Conceived and designed the evaluation: Zhijie Wang, Boyang Solar.

Collected the info: Siyuan Chen, Boyang Solar.

Contributed information or evaluation instruments: Siyuan Chen, Boyang Solar.

Carried out the evaluation: Siyuan Chen, Boyang Solar.

Wrote the paper: Siyuan Chen, Boyang Solar, Zhijie Wang.