Resectable Stage IIIA Non-small Cell Lung Cancer Research Articles

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy

BackgroundNeoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus...

Nivolumab + chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage IIIA NSCLC: Primary endpoint results of pathological complete response (pCR) from phase II NADIM II trial.

8501 Background: Non-small cell lung cancer (NSCLC) is incurable in most patients with locally advanced stage IIIA disease. Previous results indicate that the use of neoadjuvant chemoimmunotherapy could increase the percentage of cured patients being a promising therapeutic option that has to be tested in randomized clinical trials. Methods: NADIM II (NCT03838159) is an open-label, randomized, two-arm, phase II, multi-center clinical trial. Patients with resectable clinical stage IIIA (per AJCC 7th ed) NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to receive Nivolumab (NIVO) 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed by surgery, or Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) followed by surgery. Patients with R0 resection confirmed by pathological evaluation initiated adjuvant administration of NIVO within the 3rd to 8th week (+7 days) from surgery and for 6 months. The primary endpoint was pathological complete response (pCR) by blinded independent pathological review (BIPR) in the intent-to-treat population (ITT). pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; patients who did not undergo surgery were classified as non-responders. Major pathological response (MPR; ≤ 10% viable tumor) per BIPR, overall response rate (ORR), toxicity profile, and potential predictive biomarkers are secondary endpoints. Results: Between February 8, 2019, and November 11, 2021, 90 patients were enrolled, of whom 87 patients were valid. Neoadjuvant NIVO + chemo significantly increased the pCR rate compared to chemo in the ITT (36.2% vs 6.8%; Relative Risk (RR) 5.25 [99% CI 1.32-20.87]; P = 0.0071). NIVO + chemo also improved MPR rates vs chemo in the ITT (52 % vs 14 %), as well as ORR (74 % vs 48%). Definitive surgery occurred for 91% of pts treated with NIVO + chemo and 69% with chemo; surgery was cancelled rarely due to AEs (1 pts/experimental arm) and due to disease progression in 1 and 4 pts in the experimental and control arm respectively. Grade 3-4-related AEs were reported in 24 % vs 10% in the NIVO + chemo vs chemo arms, respectively. In the ITT experimental arm, patients with pCR had higher PD-L1 TPS (median 70%, IQR 5-90%) compared to non-responders (median 0%, IQR 0-37.5%, P = 0.0035). AUC to predict pCR was 0.734 (95% CI 0.59-0.88; P = 0.005). The pCR rate rises across increasing categories of PD-L1 TPS ( < 1% 14.3%; 1-49% 41.7%; ≥50% 61.1%; P = 0.008). Conclusions: This study confirms the superiority of the chemo-immuno combination in patients with resectable stage IIIA NSCLC in terms of pCR, as well as the feasibility of surgery, with a moderate increase in grade 3-4 toxicity. Thus, this treatment should become the standard of care in these patients. Clinical trial information: NCT03838159.

Case Report: Adjuvant Crizotinib Therapy Exerted Favorable Survival Benefit in a Resectable Stage IIIA NSCLC Patient With Novel LDLR–ROS1 Fusion

Novel adjuvant strategies are needed to optimize outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). The adjuvant treatment of ROS Proto-Oncogene 1 (ROS1) fusion-positive resected NSCLC is challenging because there is no curative confirmed randomized controlled trial. Next-generation sequencing (NGS) and immunohistochemistry (IHC) staining were performed on the biopsy sample. In this case, we identified a novel LDLR–ROS1 fusion in a resectable stage IIIA NSCLC patient. The patient received crizotinib as adjuvant treatment and achieved recurrence-free survival (RFS) for 29 months, without significant symptoms of toxicity. In this case, we report a novel LDLR–ROS1 fusion responding to crizotinib in a patient with lung adenocarcinoma, supporting the use of adjuvant treatment with the ROS1 inhibitor exerting clinical survival benefit in ROS1 fusion-positive resected NSCLC.

Clinical recommendations for perioperative immunotherapy-induced adverse events in patients with non-small cell lung cancer.

Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non‐small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD‐1 and PD‐L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small‐scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large‐scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy.

Haematological biomarkers of pathological response on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA non-small cell lung cancer (NSCLC) patients.

e20026 Background: PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described the neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocyte ratio (PLR) as indicator of systemic inflammation, that could be use as biomarker of response to immunotherapy. In our study, we described the effect of neoadjuvant chemo-immunotherapy in Complete Blood Count (CBC) parameters and evaluated their relationship with pathological responses. Methods: Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), mayor response (< 10% viable tumour) and incomplete response (> 10% viable tumour). Wilcoxon and Mann-Whitney U statistic test were used to evaluated differences between pre and post treatment and between pathological responses groups respectively. Results: From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers (x103cells/µl) of CBC were significantly reduced after neo-adjuvant treatment in patients, leucocytes (8.80 vs 6.64), Eosinophil (0.22 vs 0.15), Monocytes (0.72 vs 0.62), Neutrophils (5.53 vs 3.53), Haemoglobin (35.82 vs 29.68), Platelets (292.44 vs 227.22), NLR (2.73 vs 1.71) and PLR (143.34 vs 115.85) except Lymphocytes (2.22 vs 2.25) and Basophils (0.06 vs 0.05). Moreover, when the analysis was done by subgroups of pathological responses, PLR variation was significantly different between pCR and incomplete response (-21.33 vs -76.98) whereas NLR and the rest of the immune populations were no different between subgroups. Conclusions: In our study, NLR is not associated to chemo-immune neo-adjuvant treatment response. Nevertheless, in our cohort a higher decrease on PLR post neo-adjuvant treatment is associated to an incomplete pathological response.

1286TiP - Neo-adjuvant chemo/immunotherapy for the treatment of resectable stage IIIA non-small cell lung cancer (NSCLC): A phase II multicenter exploratory study” NADIM trial

Background: Lung cancer is the primary cause of cancer mortality in western countries. The cure is unlikely in patients with NSCLC and locally advanced stage who are not surgical candidates, with a 3-year survival rate of 27% in those patients receiving chemotherapy and concomitant radiotherapy. On the contrary, in localized stages (stage I, II, IIIA) with surgical resection and cytostatic therapy, a survival of 5 years of 51% is achieved. Currently, there is no consensus on the best standard treatment: the surgical management of stage IIIA NSCLC remains highly controversial and most patients with stage IIIB disease are generally considered inoperable. Since distant metastases remain the major site of failure, it is likely that more effective cytotoxic or other anti-tumor agents will be required. Chemotherapy stimulates an immune response against tumors, which may facilitate immunotherapy anticancer activity. Evidence of synergy between chemotherapy and immunotherapy was shown in several studies. Trial design: Phase II, single-arm, open-label multicenter study that assesses feasibility, safety and efficacy of combined neoadjuvant therapy with Nivolumab 360 mg + Paclitaxel 200mg/m2 + Carboplatin AUC 6 Q3W, three cycles, in resectable stage IIIA NSCLC patients followed by adjuvant treatment for 1 year with Nivolumab 240 mg Q2W for 4 months and Nivolumab 480mg Q4W for 8 months. The primary endpoint will be Progression Free Survival at 24 months from diagnosis and to assess the efficacy of the combination. The secondary endpoints will be time to progression and overall survival at 3 years, response rate, toxicity profile of the combination, the down-staging rate and complete resection rate. Also, surgical outcome and complications will be assessed. Perform correlatives studies with the objectives of exploring the expression of other biomarkers, such as PD-L1, in tumor tissue, free DNA and circulating tumor cells in liquid biopsy. Describe whether PD-L1 expression is a predictive biomarker for ORR, describe PFS in PD-L1 + (≥1%) population and report imaging response versus pathological response rate. Clinical trial identification: EudraCT Number: 2016-003732-20 Legal entity responsible for the study: Spanish Lung Cancer Group Funding: Bristol-Myers Squibb Disclosure: All authors have declared no conflicts of interest. Keywords: Neadjuvant chemotherapy, NSCLC.

Management of locally advanced non-small cell lung cancer (NSCLC) at a community hospital: A retrospective analysis.

e17506 Background: The optimal management of stage IIIA NSCLC has not been clearly defined. Much of this controversy is due to the heterogenity of this group. The current standard for unresectable stage IIIA disease is concurrent chemoradiotherapy. In patients with resectable stage IIIA disease however, neoadjuvant treatment followed by surgery provides better outcomes but not a significant survival benefit. Our study analyzed the management of stage IIIA NSCLC patients diagnosed at Kettering Health Network (KHN) and the observed 5-year survival as compared to the current NCCN guidelines and national 5-year relative and observed survival using the SEER database and National Cancer Database statistics. Methods: This retrospective study included all patients treated at KHN for Stage IIIA NSCLC from January 2004 to December 2009. 117 cases were analyzed, 53% female and 47% male. 42% were squamous cell, 28% adenocarcinoma, and the final 30% accounting for the remaining histology. 20 patients were not candidates for therapy due to poor performance status or comorbidity. 37 of the 97 patients under active treatment underwent resection at some point during treatment and 60 patients were deemed unresectable. Results: 68% of individuals with unresectable NSCLC received definitive concurrent chemoradiation, 32% received chemotherapy alone. In regards to resectable stage IIIA, 25% were treated with neoadjuvant therapy. 54% received postoperative therapy. 21% were treated with surgery alone due to multiple factors. The observed 5-year survival was 12.2% as compared to 10% nationally. The SEER data 5-year relative survival from 2001 to 2007 for stage IIIA NSCLC is 14%. Conclusions: In this heterogenous group of patients, treatment provided at KHN was individualized and followed national trends. The majority of unresectable stage IIIA NSCLC patients at KHN received the standard approach of concurrent chemoradiation. In terms of resectable stage IIIA NSCLC, approximately 25% were treated with either neoadjuvant chemotherapy or chemoradiotherapy. Overall, the 5-year survival rate for stage IIIA NSCLC at KHN is comparable to other community hospitals however slightly lower than the national average.

Chemotherapy in resectable non-small cell lung cancer

Although radical surgery is the primary treatment for early non-small cell lung cancer (NSCLC), the longterm survival of patients who undergo surgery alone is largely disappointing. More than half of those patients who present with stage I-IIIA disease and are resected will experience distant relapse. Postoperative adjuvant chemotherapy has been evaluated in several randomized trials but the results of these trials have been inconclusive with increased survival reported in few trials. However, the largest randomized adjuvant study presented to date, reported a 4.1% improvement in survival at 5 years, a benefit comparable to that observed using adjuvant chemotherapy in breast and colon cancer. A meta-analysis of new generation adjuvant trials is planned, it will include over 4,000 patients and will be of major relevance in this field. In resectable stage IIIA NSCLC the findings of randomized trials have indicated that the survival of these patients is better with neoadjuvant chemotherapy plus surgical resection than with resection alone. Phase II trials using preoperative concurrent chemoradiotherapy have been carried out with encouraging results. The majority of patients with stage IIIA NSCLC require multimodality therapy if they are to achieve a 5-year survival. Combined modality treatment in NSCLC continues to evolve and is a subject of ongoing research. Some data suggest that induction chemotherapy in stage I-II is feasible, does not appear to compromise surgery and yields high response rates. Neoadjuvant chemotherapy is potentially useful not only in locally advanced disease, but also in patients with earlier disease.

Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a systemic illness. More than half of those patients who present with stage I-IIIA disease and are resected will experience distant relapse. Postoperative adjuvant chemotherapy has been evaluated in several randomized trials but the results of these trials have been inconclusive with increased survival reported in few trials. In resectable stage IIIA NSCLC the findings of three randomized trials have indicated that the survival of these patients is better with neoadjuvant chemotherapy plus surgical resection than with resection alone. Phase II trials using preoperative concurrent chemoradiotherapy have been carried out with encouraging results. The majority of patients with stage IIIA NSCLC require multimodality therapy if they are to achieve a 5-year survival. Combined modality treatment in locally advanced NSCLC continues to evolve and is a subject of ongoing research. One focus for present research is to integrate new active agents into the neoadjuvant setting. Another challenge is to find better treatment approaches in earlier stages of disease. Some data suggest that induction chemotherapy in stage I-II is feasible, does not appear to compromise surgery and yields high response rates. A further aim is to use molecular biological markers of malignancy to identify patients at highest risk of metastatic relapse.

Role of multimodality treatment for lung cancer.

Locally advanced non-small cell lung cancer (NSCLC) is, in fact, a systemic disease requiring a multimodality approach for optimal treatment. The role of preoperative chemotherapy has been established and is now an accepted treatment for resectable Stage IIIA NSCLC. Several studies have addressed the feasibility and efficacy of preoperative chemotherapy followed by surgery. All these induction chemotherapy trials have reported a high radiographic response rate, high respectability rate and improved survival in completely resected patients. The findings of three published randomized trials indicate that the survival rate of Stage IIIA patients is better with induction chemotherapy plus surgical resection than with resection alone. More recently, Phase II trials using concurrent chemoradiotherapy have been tested with encouraging results. Chemo-therapy combined with thoracic radiotherapy has emerged as a primary treatment option for locally advanced, unresectable NSCLC. Randomized trials and subsequent meta-analyses have shown a clear survival benefit with platinum-based combination chemotherapy administered with thoracic radiation-as compared to radiation alone-in treating inoperable Stage IIIA and IIIB lung cancer. Combined modality treatment in locally advanced NSCLC continues to evolve and is the subject of ongoing research. Despite clinical advances, many aspects of the management of these patients are yet to be fully clarified: Is surgical resection really necessary for Stage IIIA patients? What is the value of altered-fractionation radiotherapy and three-dimensional conformal radiation therapy? What is the optimal sequencing of radiotherapy and chemotherapy? In this regard, new chemotherapeutic agents may provide additional benefits in the multimodality approach, and it is for this reason that various studies are underway which have incorporated new agents in the front line setting. Finally, a better understanding of the biology of tumors could well help us to optimize treatments. In the future, molecular classification of NSCLC may provide a useful tool when making therapy-related decisions.

Phase II trial of induction high-dose chemotherapy followed by surgical resection and radiation therapy for patients with marginally resectable non-small cell carcinoma of the lung

The combination of carboplatin and paclitaxel is an active regimen in non-small cell lung cancer (NSCLC). Historically, patients with stage III disease have manifested higher response rates than patients with metastatic disease, and patients achieving a pathologic complete response to induction chemoradiation therapy prior to surgery have shown better long-term outcome. Based upon our pilot data using high-dose carboplatin and paclitaxel, we designed a phase II trial in patients with marginally resectable stage IIIA NSCLC. Ten patients, with bulky nodal stage IIIA disease, initially received etoposide (2 g/m 2) and granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells (PBSC). Two cycles, 28 days apart, of carboplatin (AUC 12 in seven patients; AUC 16 in three patients) and paclitaxel (250 mg/m 2) were administered with filgrastim (5 μg/kg) and PBSC support. After re-evaluation, patients underwent a thoracotomy followed by radiotherapy (44–60 Gy) if deemed resectable, or radiotherapy alone (60 Gy) if not resectable. The median age was 58.5 years (48–66) with a median ECOG performance status of 0 (0–1). Histology was adenocarcinoma in seven patients; the remainder had either squamous cell, large cell or bronchoalveolar carcinoma. Based on CT radiography, the overall response rate was 40%. Eight of ten patients underwent resection with four right pneumonectomies, three right upper lobectomies and one wedge resection of the right upper lobe. Six patients had a complete resection. Of eight patients resected, four were downstaged by induction therapy, three remained unchanged and one was found to have more extensive disease. The remaining two patients developed metastatic disease while receiving chemotherapy. The median dose of postoperative radiotherapy was 54 Gy (35–66 Gy). Actual median follow-up for all patients was 89 weeks (25 to 136+). The actuarial median overall survival was 124 weeks (25 to 136+) and time to progression was 57 weeks (17 to 136+). The median dose of carboplatin delivered expressed as mg/m 2 was 779 (615–1540). Neutropenic fever occurred in two patients during the initial mobilization cycle only. The median number of units of RBC and/or platelets transfused was 0 (0–2 and 0–6, respectively). There were no significant non-hematologic toxicities. High-dose induction chemotherapy with stem cell rescue is feasible and safe with an acceptable response rate. Thoracotomy, including pneumonectomy and postoperative radiotherapy, were well tolerated by patients after undergoing high-dose induction chemotherapy with no apparent increase in peri-operative morbidity. The pathologic complete response rate was low — one out of ten patients. These results indicate that dose escalation of induction chemotherapy does not improve response rates even in this highly selected patient population. Accordingly, the complexity and potential toxicity of high-dose chemotherapy, as delivered in this trial as neoadjuvant treatment of non-small cell lung cancer, is not warranted.

Role of Chemotherapy in Stages I to III Non-small Cell Lung Cancer

The management of resectable non-small cell lung cancer (NSCLC) has been the focus of extensive investigation over the last decade. Nonetheless, existing management strategies are suboptimal for all stage groupings. The only exception is complete resection for stage IA NSCLC, in which a cure is achieved in 70 to 85% of patients. A number of studies demonstrate that adjuvant chemotherapy may be associated with some biological effect. Nonetheless, chemotherapy remains experimental and cannot be definitively recommended outside the context of a randomized trial. Radiation therapy appears to be associated with a reduction in local recurrence in stage II NSCLC. With regard to potentially resectable stage IIIA NSCLC, the results of randomized trials support the conclusion that induction chemotherapy followed by resection (with or without postoperative radiation) may enhance survival compared to that achieved with resection alone. Among patients with stage IIIA and IIIB NSCLC who are treated without resection, numerous phase III studies demonstrate that induction chemotherapy with definitive radiation improves outcome when compared to thoracic radiation therapy alone. While there may be an advantage for concurrent chemoradiation compared to sequential therapy, definitive results are not yet available to support this conclusion. While the magnitude of benefit associated with induction chemotherapy or chemoradiation in regionally advanced NSCLC is debatable, the results of multimodality studies provide a basis for optimism that real therapeutic progress is being achieved. Further study of therapeutic strategies that incorporate aggressive systemic treatment and local-regional therapy in stage IIIA and IIIB NSCLC is warranted. Moreover, completion of randomized studies focusing on the role of adjuvant chemotherapy in stage IB and stage II NSCLC should be given priority.

Agranulocytosis coincident with amodiaquine therapy.

<h3>Background</h3> Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. <h3>Methods</h3> Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. <h3>Results</h3> CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of <i>IFNG, GZMB, NKG7</i>, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) &gt;0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including <i>AKT1, BST2, OAS3,</i> or <i>CD8B</i>; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. <h3>Conclusions</h3> Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.