Editor's note: With the continuous advancement of cancer treatment, immune checkpoint inhibitors (ICIs) have become an indispensable part of the treatment of many cancers. In the immunotherapy session of the 2024 CSCO guideline meeting, Professor Wang Jun from the First Affiliated Hospital of Shandong First Medical University shared and interpreted the key points of the update of some of the main chapters of the 2024 CSCO "Guidelines for the Clinical Application of Immune Checkpoint Inhibitors". The report is designed to help healthcare professionals and patients better understand these changes and make more informed decisions in the context of actual treatment.
Expert presentation
Wang Jun
Chief physician, doctor, doctoral supervisor
Deputy Director of the Department of Medical Oncology, The First Affiliated Hospital of Shandong First Medical University
Deputy Director of Shandong Institute of Lung Cancer
Director of the Chinese Society of Clinical Oncology (CSCO).
Vice Chairman and Secretary General of the CSCO Immunotherapy Expert Committee
Vice Chairman of the CSCO Patient Education Expert Committee
Member of the CSCO Expert Committee on Non-Small Cell Lung Cancer
Vice Chairman of the Tumor Immunotherapy Physician Branch of Shandong Medical Doctor Association
Recurrent or metastatic squamous cell carcinoma of the head and neck
1. "Pembrolizumab + paclitaxel + carboplatin" and "pembrolizumab + nab-paclitaxel + cisplatin/carboplatin" are newly added as grade II recommendations for the first-line treatment of non-nasopharyngeal carcinoma.
Updated by: Updated based on KEYNOTE-B10[1]: Pembrolizumab + paclitaxel + carboplatin in the first-line treatment of R/M HNSCC Phase IV study. The study included 92 patients with previously untreated R/M HNSCC, of whom 82 were included in the efficacy analysis set, with an ORR of 42.7%, a DCR of 58.5%, and a median DOR of 5.5 months confirmed by RECIST v1.1, and a treatment-related serious AE rate of 17.4%, with an overall favorable safety profile.
The KEYNOTE-B10 study demonstrated that pembrolizumab + paclitaxel + carboplatin may be an alternative to the current first-line standard of care for R/M HNSCC (pembrolizumab + 5-FU + platinum) and may expand the options for first-line treatment of R/M HNSCC.
2. Added "toripalimab + cetuximab" as a third-line recommendation for second-line or salvage therapy for non-nasopharyngeal carcinoma.
Rationale for update: Based on toripalimab plus cetuximab in platinum-refractory R/M-HNSCC: a phase Ib/II clinical study [2,3] of 45 patients with platinum-refractory R/M HNSCC who were treated with toripalimab 240mg IV Q3W + cetuximab 400mg/m2 followed by 250mg/m2 IV QW.
The primary endpoint of the study was 60% confirmed by IRC assessment; The secondary endpoint DCR was 80% and the median DOR was 17.9 months. The median PFS was 9.9 months and the median OS was 15.4 months. The incidence of grade ≥3 TRAEs was 22.2%, the incidence of irAEs was 24.4%, and 2 patients (4.4%) developed TRAEs leading to discontinuation.
Esophageal carcinoma
1. "sugemalimab + cisplatin + 5-FU" was added as a level I recommendation for advanced first-line treatment.
Rationale for update: Based on GEMSTONE-304[4]: a phase III clinical study of sugemalimab in combination with chemotherapy versus chemotherapy in the first-line treatment of patients with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma.
A total of 540 enrolled patients were randomly assigned to sugemalimab plus FP (358 patients) and placebo plus FP (182 patients). The median age was 63.0 years, 87.4% of the patients were male, and 78.9% of the patients had an ECOG score of 1. With a median follow-up of 15.2 months, the prolongation of PFS assessed by BICR was statistically significant between sugemalimab plus FP and placebo plus FP (mPFS: 6.2 m versus 5.4 m; HR 0.67）。 Sugemalimab plus FP also had a superior OS (mOS: 15.3 versus 11.5 m; HR 0.70）。
Based on the results of this study, on December 8, 2023, the NMPA approved sugemalimab in combination with fluorouracil and platinum-based chemotherapy drugs for the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma.
非小细胞肺癌（NSCLC）
1. Non-squamous NSCLC without driver gene mutations
(1) "Nivolumab + ipilimumab (limited to PD-L1≥1%)", "nivolumab + ipilimumab and 2 cycles of pemetrexed + platinum" were downgraded to level III recommendations for advanced first-line treatment.
(2) "toripalimab + platinum-containing chemotherapy neoadjuvant + adjuvant therapy" was added as a level I recommendation for perioperative treatment.
Rationale for update: Based on the Neotorch: toripalimab + platinum-based chemotherapy neoadjuvant + adjuvant NSCLC phase III clinical study[5]. A total of 404 patients with stage III NSCLC were included with a median follow-up of 18.3 months. In the co-primary endpoint of BIPR-assessed phase III NSCLC, toripalimab plus chemotherapy had a pathologic complete response (pCR) (28.2% vs. 1.0%) and major pathologic response (MPR) (48.5% vs. 8.4%) superiority. Event-free survival (EFS) in the investigator-assessed population with stage III NSCLC was mEFS: NR vs 15.1, HR=0.40, and mOS: NR vs 30.4, HR=0.62.
Based on this study, toripalimab was approved for the use of perioperative therapy in combination with chemotherapy and monotherapy followed by consolidation therapy in patients with resectable stage III NSCLC.
(3) "Pembrolizumab, tislelizumab or camrelizumab + platinum-containing chemotherapy neoadjuvant therapy + adjuvant therapy" was added as a level II recommendation for perioperative treatment.
Updated by 1: Updated based on RATIONALE-315: tislelizumab + platinum-containing chemotherapy neoadjuvant + adjuvant NSCLC phase III clinical study[6]. A total of 453 patients with stage II-IIIA NSCLC were randomized to tislelizumab + chemotherapy (n=226) and chemotherapy (n=227). Median follow-up of 22.0 months, common primary endpoints: 35% (41% vs 6%) improvement in MPR and 41% (56% vs 15%) improvement in pCR in the BIPR-assessed ITT population, NR versus NR (HR=0.56, P=0.0003), and a 44% reduction in the risk of disease progression/recurrence, respectively. Secondary endpoint mOS: NR vs NR, HR=0.62, P=0.0193, 38% reduction in mortality risk.
Updated by 2: Updated based on KEYNOTE-671: Pembrolizumab + platinum-based chemotherapy neoadjuvant + adjuvant NSCLC Phase III clinical study[7]. A total of 797 patients with stage II-IIIB NSCLC were included with a median follow-up of 25.2 months (range: 7.5-50.6), investigator-assessed mEFS: NR vs 17.0 months, HR=0.58 (95% CI, 0.46-0.72), P< 0.00001, median follow-up of 36.6 months (range: 18.8-62.0), investigator-assessed mOS: NR vs 52.4 months, HR=0.72 (95% CI, 0.56-0.93), P=0. 00517。 Secondary endpoints: MPR assessed by BIPR: 30.2% vs 11.0%, pCR: 18.1% vs 4.0%. Based on the KEYNOTE-671 study, the FDA approved pembrolizumab in combination with chemotherapy for the neoadjuvant treatment of resectable (T≥4cm or N+) NSCLC postoperatively as adjuvant monotherapy based on the KEYNOTE-671 study (FDA approval only).
4. Added "durvalumab or nivolumab + platinum-containing chemotherapy neoadjuvant + adjuvant therapy" as a level III recommendation for perioperative treatment
Rationale for update 1: Updated from AEGEAN: durvalumab + platinum-based chemotherapy neoadjuvant + adjuvant NSCLC Phase III clinical study [8,9]. A total of 740 patients with stage II-IIIB NSCLC were included in the study, with co-primary endpoints: 17.2 versus 4.3 percent of pCR and 33.3 versus 12.3 percent of MPR assessed by BIPR; Co-primary endpoint: mEFS in the ITT population as assessed by BICR: NR vs 25.9 months, HR=0.68 (95% CI, 0.53-0.88), P=0.003902. Secondary endpoint: OS data not reported.
Rationale for update 2: Updated Phase III clinical study of NSCLC based on CheckMate-77T: nivolumab + neoadjuvant platinum-based chemotherapy + adjuvant therapy[10]. A total of 461 patients with stage II-IIIB NSCLC were included with a median follow-up of 25.4 months (range: 15.7-44.2), and the primary endpoint was BICR-assessed mEFS: NR versus 18.4 months, HR=0.58 (95% CI, 0.42-0.81), P=0.00025. Secondary endpoints, pCR of 25.3 versus 4.7 percent, MPR of 35.4 versus 12.1 percent, OS data not reported.
2. Non-squamous NSCLC with positive driver gene mutations
(1) "Sintilimab + bevacizumab + platinum-containing chemotherapy" was upgraded to a level I recommendation for advanced second-line treatment or above.
Update: Based on the ORIENT-31 study, on May 9, 2023, the NMPA approved sintilimab in combination with bevacizumab and chemotherapy for the treatment of locally advanced or metastatic non-squamous NSCLC with EGFR gene mutations that have failed EGFR-TKI therapy.
3. Squamous NSCLC
(1) "Penpulimab + paclitaxel + carboplatin" was upgraded to a level I recommendation for advanced first-line treatment.
Updated by: A randomized, double-blind, placebo-controlled phase III study based on AK105-302: penpulimab + carboplatin + paclitaxel in the first-line treatment of late-stage squamous NSCLC was updated. On January 13, 2023, the NMPA approved penpulimab in combination with paclitaxel and carboplatin for the first-line treatment of locally advanced or metastatic squamous NSCLC.
(2) "Serplulimab + nab-paclitaxel + carboplatin" was added as a level I recommendation for advanced first-line treatment.
Updated by: A randomized, double-blind, placebo-controlled phase III study based on ASTRUM-004: serplulimab + carboplatin + nab-paclitaxel in the first-line treatment of advanced squamous NSCLC. On November 1, 2022, the NMPA approved serplulimab in combination with carboplatin and nab-paclitaxel for the first-line treatment of locally advanced or metastatic squamous NSCLC.
(3) "nivolumab + ipilimumab (limited to PD-L1 ≥ 1%)", "nivolumab + ipilimumab and 2-cycle paclitaxel + platinum" were downgraded to advanced first-line treatment level III recommendations.
Updated by: Updated based on research.
(4) "toripalimab + platinum-containing chemotherapy neoadjuvant + adjuvant therapy" was added as a level I recommendation for perioperative treatment.
(5) "Pembrolizumab, tislelizumab or camrelizumab + platinum-containing chemotherapy neoadjuvant + adjuvant therapy" was added as a level II recommendation for perioperative treatment.
(6) "durvalumab or nivolumab + platinum-containing chemotherapy neoadjuvant + adjuvant therapy" was added as a level III recommendation for perioperative treatment
广泛期小细胞肺癌（ES-SCLC）
1. "Tislelizumab + etoposide + carboplatin or cisplatin" and "toripalimab + etoposide + carboplatin or cisplatin" are newly added as first-line treatment level II. recommendations
Rationale for update 1: Based on RATIONALE-312: Tislelizumab + Etoposide + Carboplatin/Cisplatin in the first-line treatment of ES-SCLC Phase III clinical study[11]. The study included 457 patients with ES-SCLC who had not received systemic therapy. Median OS was extended to 15.5 months in the primary endpoint tislelizumab + chemotherapy (mOS: 15.5 m versus 13.5 m, HR=0.75 m, HR: 0.75, 95CI %: 0.61-0.92, P=0.0035); The 2-year OS rate was 33.2% (22.4% in the control group) and 25% (9.3% in the control group) in the tislelizumab + chemotherapy group.
更新依据2：更新基于EXTENTORCH：特瑞普利单抗+依托泊苷+卡铂或顺铂一线治疗ES-SCLC III期临床研究[12]。 中位随访11.8个月后，主要终点中位PFS：5.8 m vs 5.6 m，HR=0.667 ，P=0.0002；中位OS：14.6 m vs 13.3 m，HR=0.798 , P=0.0327。
Advanced malignant pleural mesothelioma
1. Change the original title "advanced pleural mesothelioma" to "advanced malignant pleural mesothelioma"
2. "Pembrolizumab + pemetrexed + cisplatin/carboplatin" was added as a first-line treatment level I recommendation
Rationale for update: Based on KEYNOTE-483: a Phase II/III clinical study of pembrolizumab + pemetrexed + cisplatin/carboplatin in the first-line treatment of advanced malignant pleural mesothelioma [13,14]. In a study of 440 treatment-naïve patients with advanced malignant pleural mesothelioma with a median follow-up of 16.2 months (IQR 8.3–27.8), pembrolizumab + chemotherapy was associated with significantly longer OS compared with chemotherapy (mOS: 17.3 m vs 16.1 m, HR=0.79; 95% CI 0.64-0.98, P=0.0324), with a 3-year OS rate of 25%.
breast cancer
1. "ER+/HER2- early high-risk breast cancer, preoperative nivolumab + paclitaxel sequential nivolumab + anthracycline + cyclophosphamide neoadjuvant therapy, postoperative adjuvant nivolumab combined with endocrine therapy" is added as a level III recommendation for perioperative treatment.
Rationale for update: Based on CheckMate 7FL: A Phase III clinical study of nivolumab in the neoadjuvant and adjuvant therapy of HR+/HER2- breast cancer [15]. In this study, nivolumab plus chemotherapy significantly increased the pCR rate of HR+/HER2- breast cancer compared with chemotherapy alone (mITT population: 24.5 versus 13.8 percent; PD-L1 positive population: 44.3 versus 20.2 percent).
2. "ER+/HER2- early high-risk breast cancer, preoperative pembrolizumab + paclitaxel sequential pembrolizumab + doxorubicin/epirubicin + cyclophosphamide neoadjuvant therapy, postoperative pembrolizumab combined with endocrine adjuvant therapy" is recommended as a level III recommendation for perioperative treatment.
Rationale for update: Updated based on KEYNOTE-756: Phase III clinical study of pembrolizumab for neoadjuvant and adjuvant therapy for HR+/HER2- breast cancer [16]. The primary endpoint suggests that pembrolizumab plus chemotherapy in the mITT population significantly increased the pCR rate of HR+/HER2- breast cancer by 24.3 versus 15.6 percent compared with chemotherapy alone.
3. The new "toripalimab + nab-paclitaxel" is recommended as a first-line treatment for advanced triple-negative breast cancer
更新依据：更新基于TORCHLIGHT：特瑞普利单抗联合白紫一线治疗晚期TNBC的III期临床研究[17]。 该研究主要终点显示，BICR评估的PD-L1阳性mPFS为8.4 m vs 5.6 m，HR=0.65 ，95% CI:0.47-0.91, P=0.0102；ITT人群mPFS为8.4 m vs 6.9 m，HR=0.77，95% CI:0.60-0.99, P=0.0445。 次要终点：BICR评估的PD-L1阳性mOS为32.8 m vs 19.5 m，HR=0.62，95% CI:0.41-0.91, P=0.0148；ITT人群mOS为33.1 m vs 23.5 m，HR=0.69，95% CI:0.51-0.93，P=0.0145。
Advanced gastric cancer
一、新增“XELOX/FP+帕博利珠单抗(PD-L1 CPS ≥10)”、“XELOX+舒格利单抗(PD-L1 CPS≥5)”为一线治疗(HER2阴性)Ⅰ级推荐。
Rationale for update 1: Based on KEYNOTE-895: Pembrolizumab in combination with chemotherapy in the first-line treatment of HER2-negative advanced GC/GEJC Phase III clinical study [18]. In the ITT population, the primary endpoint was pembrolizumab + chemotherapy versus chemotherapy with mOS of 12.9 m versus 11.5 m, mPFS of 6.9 m versus 5.6 m, ORR of 51.3 versus 42.0 percent, and mDoR of 8.0 m versus 5.7 m, respectively. In the PD-L1 CPS≥10 population, pembrolizumab + chemotherapy versus chemotherapy were associated with mOS of 15.7 m versus 11.8 m, mPFS 8.1 m versus 5.6 m, ORR 60.6 versus 43.0 percent, and mDoR 10.9 versus 5.8 m, respectively.
Rationale for update 2: A domestic multicenter, randomized controlled phase III study based on GEMSTONE-303: sugemalimab in combination with chemotherapy for the first-line treatment of HER2-negative, PD-L1 CPS≥5 advanced GC/GEJC was updated [19]. The primary endpoint was mPFS: 7.62 vs 6.08 months, HR=0.66, P<0.0001, and mOS: 15.64 vs 12.65 months, HR=0.75, P=0.0060, in ≥5% PD-L1 expression.
二、新增 “XELOX/FP+帕博利珠单抗(PD-L1 CPS<10或检测不可及) ”、“XELOX/FP+替雪利珠单抗(PD-L1 TAP<5%或检测不可及)”为一线治疗(HER2 阴性)Ⅱ级推荐。
Rationale for update: Based on RATIONALE-305: A phase III clinical study of tislelizumab in combination with chemotherapy in the first-line treatment of HER2-negative advanced GC/GEJC[20]. Co-primary endpoint: PD-L1 score ≥ 12.8 m, HR=0.71 (95% CI, 0.58-0.86) in the 5% population, respectively; The mOS was 15.0 m vs 12.9 m, HR=0.80 (95% CI, 0.70-0.92).
3. "XELOX combined with cadonilimab (regardless of PD-L1 expression status)" is added as a first-line treatment (HER2 negative) level III recommendation.
Rationale for update: Based on AK104-201: A Phase Ib/II clinical study of cadonilimab in combination with chemotherapy in the first-line treatment of HER2-negative advanced GC/GEJC [21]. Data as of August 13, 2021 showed that in the total population, the ORR was 65.9%, the DCR was 92.0%, the mPFS was 7.1 months, and the mOS was 17.4 months. The incidence of grade ≥3 TRAEs was 62.5%, and the incidence of drug-related serious adverse events was 41.7%. With the increase of dose, the incidence of adverse events did not increase significantly, and no new safety signals were found, and the safety profile was good.
四、将“帕博利珠单抗+曲妥珠单抗+XELOX/FP（PD-L1 CPS ≥1）”升级为一线治疗（HER2阳性）Ⅰ级推荐。
5. "SOX + camrelizumab + apatinib" was added as a first-line treatment (AFP-producing gastric cancer) grade II recommendation.
Rationale for update: An update to a Phase II clinical study based on camrelizumab in combination with apatinib and SOX in the first-line treatment of alpha-fetoprotein-producing gastric or gastroesophageal junction adenocarcinoma [22]. A total of 36 patients were included with a median follow-up of 6.4 months (range: 0.7 to 27.0), with a confirmed ORR of 55.6%, a DCR of 83.3%, and a median DOR of 10.7 months. The 12-month PFS and OS rates were 42.1% and 63.7%, respectively. The incidence of grade ≥3 TRAEs and irAEs was 36.1% and 44.4%.
6. "Tislelizumab" and "serplulimab" are newly added as Class I recommendations for second-line therapy (dMMR/MSI-H, regardless of HER2 status).
Rationale for update 1: Updated based on RATIONALE-209: A Phase II study of tislelizumab monotherapy in locally advanced unresectable or metastatic MSI-H/dMMR solid tumors [23]. The study included colorectal cancer, endometrial cancer, gastric/gastroesophageal junction cancer, cervical cancer, ovarian cancer and other tumor types, of which gastric/gastroesophageal junction cancer accounted for 11.3%.
At the end of follow-up in December 2022, the ORR was 49.3% for all patients and 55.6% for GC/GEJC patients, and the median PFS and OS were still not reached. The two-year PFS rate was 56.7% (95%CI: 44.1-67.4) and the two-year OS rate was 68.6% (95%CI: 56.6-77.9). The reported 2-year PFS rate differed by only 3% from the 1-year PFS at the time of first publication, implying that there were almost no new patients with disease progression at the most recent 1-year follow-up.
Rationale for update 2: Updated based on ASTRUM-010: A Phase II study of serplulimab monotherapy in locally advanced unresectable or metastatic MSI-H/dMMR solid tumors [24]. The study enrolled colorectal cancer, endometrial cancer, gastric cancer and other tumor types, of which gastric cancer accounted for 7.4%, and the primary endpoint was 38.2% ORR and 67.6% DCR for all patients. At a median follow-up of 7.7 months, median PFS and OS were not reached.
hepatocellular carcinoma
1. Change the title from "intermediate and advanced hepatocellular carcinoma" to "hepatocellular carcinoma".
2. "atezolizumab + bevacizumab" was added as a level I recommendation for postoperative adjuvant therapy.
Updated by: Based on IMbrave050: A phase III clinical study of atezolizumab + bevacizumab in the adjuvant setting of HCC [25]. In the IMbrave050 interim analysis, adjuvant atezolizumab + bevacizumab reduced the risk of recurrence by 28%. Atezolizumab + bevacizumab significantly improved RFS assessed by IRF compared with active surveillance, with median RFS not reached in both groups (HR=0.72, P=0.012), and RFS results assessed by INV were consistent with IRF assessment, atezolizumab + bevacizumab versus active surveillance, HR=0.7, P=0.007. OS data remained highly immature, with an event rate of 7% (n=47). Patients in the active surveillance group may be cross-treated with atezolizumab + bevacizumab after IRF confirmed recurrence or after a second operation or ablation.
With the extensive development of clinical trials and the accumulation of evidence, a number of ICIs have added new application recommendations, some of which have been raised and some have been downgraded. It is worth noting that the scope of domestic ICIs recommendations is gradually increasing, and among the 13 immunotherapy indications newly approved by the NMPA in 2023, domestic drugs account for 60%, gradually becoming the main force of immunotherapy.
In addition, immunotherapy has been moving forward and has entered the stage of preoperative neoadjuvant, postoperative adjuvant and perioperative treatment of early-stage tumors. At the same time, immunotherapy strategies are constantly enriched, such as immunotherapy combination, anti-angiogenic combination, targeted combination and immunobispecific antibody combined with chemotherapy. In addition, the target population of immunotherapy is also more refined, and can be recommended according to clinical characteristics, gene characteristics, and PD-L1 expression grade.
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Typesetting: Anna
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