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Immunotherapy to the next level?
On September 26, 2022, the National Comprehensive Cancer Network (NCCN) released the 5th edition of the clinical practice guidelines for non-small cell lung cancer, which is also the second update
made by the NCCN since September.
This guideline update is mainly based on new evidence, and the new adjuvant systemic treatment regimen is updated below
.
The neo-adjuvant systemic treatment regimen has been updated again
As one of the top three malignant tumors in global morbidity and mortality, lung cancer has always attracted much attention, of which non-small cell lung cancer (NSCLC) accounts for about 80%.
In patients with non-metastatic resectable NSCLC, surgery is the preferred treatment option, but 30%~55% of patients undergoing surgery are still at risk of recurrence or distant metastasis [1].
This guideline supplements the neoadjuvant therapy regimen, mainly focusing on neoadjuvant immunotherapy, that is, on the basis of the 2022 4th edition of the guideline "neoadjuvant chemotherapy nivolumab + platinum-containing dual chemotherapy", the "cisplatin + paclitaxel" regimen suitable for all histological types is added, and the regimen
that cannot be used cisplatin chemotherapy for various reasons is supplemented.
Nivolumab 360mg + platinum-containing dual-agent chemotherapy for 1 course every 3 weeks, for a total of 3 courses
.
1.
Platinum-containing dual-agent chemotherapy regimens include:
Carboplatin AUC 5 or AUC 6, day 1; paclitaxel 175 mg/m2 or 200 mg/m2 day 1 (for all histotypes);
cisplatin 75 mg/m2, day 1; Pemetrexed 500 mg/m2, day 1 (for non-squamous cell carcinoma);
cisplatin 75 mg/m2, day 1; gemcitabine 1000 mg/m2 or 1250 mg/m2, days 1 and 8 (for squamous cell carcinoma);
(New) cisplatin 75mg/m2, day 1; Paclitaxel 175 mg/m2 or 200 mg/m2 Day 1 (for all histological types).
2.
Chemotherapy regimen for patients with comorbidities or patients who cannot tolerate cisplatin therapy:
- Carboplatin AUC 5 or AUC 6, day 1; Pemetrexed 500 mg/m2 Day 1 (for non-squamous cell carcinoma);
- Carboplatin AUC 5 or AUC 6, day 1; Gemcitabine 1000 mg/m2 or 1250 mg/m2, days 1 and 8 (for squamous cell carcinoma).
in patients with resectable NSCLC.
In addition, the addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or prevent surgery
.
▌Experimental design:
- Studies included resectable stage IB (≥4 cm) to stage IIIA, ECOG PS score of 0 or 1 (on a 5-point scale, higher scores indicate higher levels of disability), and adult patients with NSCLC who had not received prior anticancer therapy (assessed for PD-L1 expression in tumor tissue prior to treatment to exclude known ALK rearrangements or EGFR mutations).
- A total of 505 patients received randomized chemotherapy before surgery, including 179 patients in the nivolumab (360 mg) plus platinum-based dual-agent chemotherapy group and 179 patients in the platinum-double-agent chemotherapy group alone, with one course every 3 weeks, for a total of 3 courses
. - The primary outcomes were EFS and pCR rates assessed by blinding; Secondary outcomes were primary pathologic response rate (MPR), time to death or distant metastases, and overall survival (OS).
▌ Study results:
At at at least 21 months follow-up, the median EFS was 31.
6 months (95% CI 30.
2-NR) in the nivolumab + platinum-double-agent chemotherapy group and 20.
8 months (95% CI 14.
0-26.
7) in the platinum-double-agent chemotherapy group (HR 0.
63; 97.
38% CI).
0.
43-0.
91；P=0.
005）
。 At 1 year follow-up, the EFS rate was 76.
1% in patients with nivolumab + chemotherapy compared with 63.
4% in patients treated with chemotherapy alone, and at 2 years, the EFS rate in both groups was 63.
8% and 45.
3%, respectively (see Figure 1A).
[Figure 1A]
In most key subgroups, nivolumab + platinum-containing chemotherapy had higher EFS (see Figure 1B).
[Figure 1B]
In all patients in the primary analyzed population, the pCR rate with nivolumab + platinum-double-agent chemotherapy was 24.
0% (95% CI 18.
0-31.
0), regardless of surgical resection, compared with 2.
2% (95% CI 0.
6-5.
6) in the platinum-based dual-agent chemotherapy group alone (OR 13.
94; 99% CI 3.
49-55.
75; P<0.
001) (see Figure 2A).
<b20>
[Figure 2A]
In all key subgroups, such as disease stage at baseline, tumor PD-L1 expression level, and tumor histology type, the combination of nivolumab with chemotherapy can improve pCR rates (see Figure 2B).
[Figure 2B]
Median OS (HR 0.
57; 99.
67CI 0.
30-1.
07; P=0.
008) was not achieved in either nivolumab + platinum-containing dual-agent chemotherapy or platinum-based dual-agent chemotherapy alone (see Figure 3).
【Figure 3】
▌Safety and surgical complications:
Grade 3 or 4 treatment-related adverse events occurred in the nivolumab + platinum-double-agent chemotherapy group and platinum-double-agent chemotherapy alone at 33.
5% and 36.
9%, respectively, and in patients receiving nivolumab + platinum-based dual-agent chemotherapy, 11.
4% of patients with grade 3 or 4 surgery-related adverse events occurred, compared with 14.
8%
of patients in the platinum-based dual-agent chemotherapy group alone.
Two patients in the nivolumab + platinum-containing dual chemotherapy group reported grade 5 surgery-related adverse events (one each for pulmonary embolism and aortic rupture), which the investigators attributed to be unrelated to the experimental drug (see Figure 4).
[Figure 4]
Based on this study, the 5th edition of the guideline has been revised in several footnotes, removing the restriction that "if an immune checkpoint inhibitor is used preoperatively, it should no longer be used in adjuvant therapy" in the fourth edition of the guideline, broadening the use scenarios of nivolumab
。
NSCL-3 Footnote: Patients who may be receiving adjuvant chemotherapy may be treated with an option of induction systemic therapy
after surgical evaluation.
【Screenshot of NSCL-3 footnote modification】
NSCL-E 1 of 2 Footnote: nivolumab plus platinum-based dual-agent chemotherapy can be used in resectable (tumor ≥ 4 cm or nodule-positive) patients
with NSCLC in neoadjuvant therapy.
【NSCL-E 1 of 2 footnote partial modification screenshot】
▌ Updates to guideline NSCL-36 have improved the previous statement:
NSCL-36 Footnote d Modification: Contraindications to treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune diseases and/or immunosuppressants currently used; Some oncogenic drivers (i.
e.
, EGFR exon 19 deletion or L858R, ALK rearrangement) have been shown to be associated
with less benefit from PD-1/PD-L1 inhibitors.
【Screenshot of NSCL36 footnote modification】
In summary, the update of this guideline marks a new progress in the research of immune checkpoint inhibitors, and the regimen of nivolumab combined with platinum-based dual-agent chemotherapy is likely to become a new standard of neoadjuvant therapy for early resectable NSCLC, igniting new hope
for reducing the risk of recurrence and metastasis in postoperative patients.
References:
[1] Taylor MD,Nagji AS,Bhamidipati CM,et al.
Tumor recurrence after complete resection for non-small cell lung cancer.
Ann Thorac Surg 2012; 93:1813-1820.
