New progress in neoadjuvant therapy for lung cancer!

For reference only by medical professionals

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Results of the trial design

Surgical Overview

Downstaging data

PFS results

Analysis of PFS according to pCR status showed that

OS results

Analysis of OS according to pCR status

Results of the trial design

Further GSEA analysis of differences in gene expression between CPR and non-CPR patients

Differences in gene expression between progressors and non-progressors (10 genes)

A characteristic survival analysis

TOGATHER study design

Baseline characteristics

Surgery result

The updated results of pCR and DFS data in the surgical population
further demonstrate that neoadjuvant treatment of potentially resectable NSCLC with toripalimab combined with platinum-doublet chemotherapy is highly effective and well tolerated
.

What's more, the expected survival rate is expected to improve
.
Neoadjuvant Toripalimab combination in patients with stage IIB-IIIB NSCLC: a single-arm, phase 2 trial (Renaissance Study)
▌ Toripril combined with platinum-based doublet chemotherapy in neoadjuvant treatment of stage IIB-IIIB NSCLC: a phase II, single Arm study (Renaissance study)
(Abstract number: WS08.
22)
PD-1 inhibitors have shown potential antitumor activity in NSCLC
.

This study is a single-center, prospective study to explore the efficacy and safety of toripalimab combined with platinum-based doublet chemotherapy in the neoadjuvant treatment of stage IIB-IIIB NSCLC
.
This study included stage IIB-IIIB, EGFR/ALK wild-type NSCLC patients with ECOG PS 0-1
.

Patients received 2-4 cycles of toripalimab (240mg, q3w) combined with platinum-containing doublet chemotherapy as neoadjuvant therapy, and underwent imaging/surgical evaluation after the second cycle of treatment
.

Patients who are inoperable will be reevaluated after an additional 1-2 cycles of neoadjuvant therapy
.

The primary endpoints were MPR and pCR
.

Secondary endpoints were objective response rate (ORR), R0 resection rate, and safety
.

Trial design
Since March 2021, a total of 53 patients (median age: 62 years, IQR: 45-76; women: 5, 9.
4%; squamous cell carcinoma: 42, 79.
2%) were enrolled and received 2-4 cycles of neoadjuvant therapy
.

Among them, there were 15, 30 and 8 patients with stage IIB, IIIA and IIIB, respectively
.

Fifteen cases were in the preoperative stage or were not suitable for surgery
.

Patient Baseline Data
Thirty-nine patients underwent surgery (median interval between neoadjuvant therapy and surgery: 67 days, IQR: 39-113)
.

Twenty-five patients (25/39, 64.
1%) achieved MPR, of which 20 (20/39, 51.
3%) achieved pCR
.

All 39 cases (100%) achieved R0 resection
.

Twenty-nine (29/31, 93.
5%) patients underwent cN2/N1 surgery at baseline and achieved lymph node reduction
.

Treatment planning and imaging review were completed in 49 patients, with an ORR of 85.
7% (42/49)
.

Radiographic response data
46 (46/49, 93.
9%) and 15 (15/49, 30.
6%) patients reported grade 1-2 and grade 3-4 TRAEs, respectively
.

Of the patients who underwent surgery, 3 patients (3/39, 7.
7%) experienced a grade 2-3 irAE (enteritis or rash) and received glucocorticoid therapy
.

Interestingly, all 3 patients achieved pCR with a median interval between neoadjuvant therapy and surgery of 56 days (IQR: 56-70)
.

Compared with all patients who underwent surgery, these 3 patients had no treatment-related surgical delay and additional surgical difficulty
.

This may predict a better pCR rate in patients experiencing grade 2-3 irAEs (100% vs 47.
2%)
.
Among patients who were ready for surgery or who were not candidates for surgery, 2 patients experienced a grade 2-3 irAE (enteritis or pneumonitis) and received glucocorticoids, and 1 had a partial response (PR) after neoadjuvant therapy and The disease remained stable (SD) after 10 months of observation; the other case received clinical complete remission (cCR) after neoadjuvant therapy
.
Among all 5 patients who experienced irAEs and received glucocorticoids, the median time to onset of irAEs was 12 days (IQR: 7-54) and the median duration of glucocorticoid therapy was 12 days (IQR: 7-79 )
.

The results of irAE data of patients
show that toripril combined with platinum-containing doublet chemotherapy in neoadjuvant treatment of patients with stage IIB-IIIB NSCLC is effective, safe and tolerable, and has application prospects
.

Grade 2-3 irAEs may be potentially related to the efficacy of this regimen
.
Aumolertinib Versus Erlotinib/Chemotherapy for Neoadjuvant Treatment of Stage IIIA EGFR-mutant NSCLC (ANSWER)
▌ ANSWER Study: A study of Aumetinib versus Erlotinib/Chemotherapy for Neoadjuvant Treatment of Stage IIIA EGFR-mutant NSCLC
(Abstract No.
: EP05.
02-009)
For stage IIIA-N2 EGFR-mutant NSCLC, multiple randomized controlled studies have compared various EGFR-TKI-targeted therapies combined with chemotherapy as neoadjuvant therapy
.

However, the role of third-generation EGFR-TKIs in the neoadjuvant setting remains inconclusive
.

Ametinib is a novel third-generation EGFR TKI approved in China for the treatment of EGFR-mutant NSCLC
.

The ANSWER study will evaluate the efficacy and safety of almetinib versus erlotinib/dual platinum chemotherapy (pemetrexed plus carboplatin or cisplatin) in neoadjuvant treatment of resectable EGFR-mutant stage IIIA NSCLC
.

Trial Design
This was a multicenter, open-label, randomized controlled trial
.

Patients with previously untreated, histologically proven resectable or potentially resectable stage IIIA-N2 non-squamous NSCLC with sensitive EGFR mutations were eligible for this study
.

Approximately 168 patients will be randomized (1:1) to almetinib (arm A) or erlotinib/chemotherapy (arm B), stratified by EGFR mutation (Ex19del vs.
L858R)
.

Group A patients received oral almetinib 110 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months), and group B patients received oral erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy) , up to 12 months) + pemetrexed 500 mg/m ² + carboplatin AUC 5 or cisplatin 75 mg/m ² (neoadjuvant therapy, 2 cycles; adjuvant therapy 2 cycles)
.

The primary endpoint was ORR
.

Secondary endpoints included pCR, MPR, DFS, event-free survival (EFS), OS, R0 resection rate, downstaging rate, and safety
.

Adverse reactions were graded according to CTCAE v.
4.
0
.

The first patient was enrolled in September 2021, with completion expected in Q4 2025
.

Looking forward to good news from the Chinese team!

Trial
Enrollment Neoadjuvant DS-8201 for Stage III Non-small Cell Lung Cancer with HER2 20ins ▌ Efficacy
of Neoadjuvant DS-8201 in HER2 20ins Stage III NSCLC Patients
(Abstract Number: EP05.
02-006) Stage
III-N2 NSCLC is a highly heterogeneous disease requiring multimodal therapy
.

Neoadjuvant therapy is required when the goal of tumor shrinkage is difficult to achieve by previous surgery
.

Trastuzumab deruxtecan (DS-8201) is a novel antibody-drug conjugate (ADC) with four topoisomerase I inhibitors linked to a HER2-targeting antibody
.

Previous studies have demonstrated an ORR of 55% and durable efficacy in previously treated metastatic HER2-mutant NSCLC
.

However, the efficacy and safety of DS-8201 in patients with early and locally advanced NSCLC have not been studied
.
This study reports a patient with 20ins stage IIIA3 NSCLC who received 3 cycles of neoadjuvant DS-8201 (345mg q3w) followed by R0 resection
.

PET-CT and brain MR examinations were performed before and after treatment
.

According to RECIST version 1.
1, radiological response was assessed by 2 independent physicians, and pathological response was assessed and reviewed by 2 independent pathologists
.

Side effects and surgical outcomes were recorded
.
The patient, a 58-year-old female, never smoked, was diagnosed with stage IIIA (cT1cN2M0) lung adenocarcinoma
.

On arrival at our hospital, there were no tumor-related symptoms, and the (ECOG) PS was 0
.

PET-CT before treatment showed solid nodules in the left upper lobe, enlarged ipsilateral inferior paratracheal, subaortic, and hilar lymph nodes, and increased glucose intake
.

DIAGNOSTIC INFORMATION
Given the potential resectability of HER2-mutant NSCLC and the lack of optimal treatment options, the multidisciplinary committee recommended local intervention after DS-8201 treatment
.

Partial relief after 3 cycles of treatment
.

Heterogeneity in response was observed between primary and metastatic lesions, with 25% shrinkage of primary tumors and 65% shrinkage of metastatic lymph nodes
.

Left upper lobectomy with systemic lymph node dissection was performed 3 weeks after the last dose of DS-8201, resulting in complete resection (R0)
.

The operation lasted 100 minutes, and the blood loss during the operation was 20ml
.

No extensive chest wall adhesions, fibrosis and neovascularization were found during the operation
.

She was discharged 3 days after the operation with no postoperative complications
.

Systemic pathological evaluation during treatment
showed 80% residual tumor cells
.

Except for the lower tracheal lymph nodes, the lymph nodes that were removed were free of cancer cells
.

Grade 1 drug-related adverse events such as nausea, vomiting, and hair loss occurred during treatment
.

Immunohistochemical (IHC) detection showed CD4 (10%), CD8 (10%), CD20 (10%), CD163 (30%), and CD38 (10%) cell infiltration
.

After immunohistochemistry, tumor cells showed low expression of HER2 protein (IHC 1+) and negative expression of PD-L1 (22C3) (TPS<1%)
.

Analysis of peripheral blood showed that the treatment induced a diversification of the T cell repertoire
.

Details of Pathological Findings
DS-8201 has demonstrated anticancer activity in locally advanced NSCLC with minimal side effects and no delay to surgery
.

DS-8201 works regardless of HER-2 protein expression
.

This case provides an insight into the potential application of ADCs in neoadjuvant therapy
.

Expert Reviews

Neoadjuvant immunotherapy is the focus of this year's WCLC.
The meeting reported the results of a number of blockbuster clinical studies and marker studies, which aroused great attention and heated discussions
.

Among them, the latest survival data of the NADIM 1 study confirmed the high efficacy and good safety of neoadjuvant chemotherapy, while toripalimab, through a similar rigorous design, also reported a very good follow-up update this year.
The efficacy and safety of the combined chemotherapy and immunity model in the neoadjuvant treatment of lung cancer are further promising
.

In related marker studies, it was found that the abnormal expression of RNA in some tumor genes was associated with poor curative effect, and immune-related adverse reactions may be a predictor of the benefit of chemo-immune combination therapy, which may be a future optimization of neoadjuvant combination therapy.
Provide a reference
.

In addition, neoadjuvant therapy for driver gene-positive patients has also received attention, with a report at this year's meeting reporting the design of a head-to-head study (alectinib vs erlotinib) of chemotherapy combined with targeted therapy in patients with EGFR mutations, and A case report of DS-8201 neoadjuvant therapy for patients with HER-2 mutant lung cancer.
Although these treatment options lack strong research data support, there is reason to believe that this type of treatment model is expected to further optimize the multidisciplinary management of lung cancer, and further Improve patient outcomes
.

 
Expert Profile

Hu Zhihuang

• Doctor of Medicine, Deputy Chief Physician, Affiliated Cancer Hospital of Fudan University

• Assistant Director of the Department of Thoracic Oncology

• Member of the American Society of Clinical Oncology (ASCO)

• Member of the Special Committee of Clinical Oncology Chemotherapy of China Anti-Cancer Association

• COE Secretary of Lung Cancer Special Committee of China Medical Education Association

• Member of Chinese Society of Clinical Oncology (CSCO)

• Member of Shanghai Anti-Cancer Association

• Member of the Standing Committee of CRPC Youth Committee of Shanghai Anti-Cancer Association

• He is engaged in the medical treatment and research of thoracic tumors such as lung cancer and esophageal cancer.
  He has conducted in-depth research in the fields of new tumor target identification, molecular marker research, and tumor palliative treatment.
  He has published more than ten SCI papers and presided over 2 scientific research funds
  .