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Treatment options in early NSCLC

Presented by
Dr Walter Weder, Dr Raffaele Califano
ELCC 2019
CALGB 9633
Both adjuvant and neo-adjuvant chemotherapy are standard-of-care for fit patients, at least for those with resected or resectable stage 2 or 3 non-small cell lung cancer (NSCLC). There is a strong rationale for perioperative immune checkpoint blockade and targeted therapies, such as ALK- and EGFR-directed tyrosine kinase inhibitors (TKIs).

Should we use neoadjuvant chemotherapy, and not upfront surgery in combination with adjuvant treatment of early stage NSCLC? The answer is still not clear. A previous trial showed no statistically significant differences in disease-free survival (DFS) with the addition of preoperative or adjuvant chemotherapy to surgery [1]. In contrast, a recently published analysis of the National Cancer Database showed that both adjuvant and neoadjuvant chemotherapy result in better survival rates than surgery alone in patients with stage 2 or 3 lung cancer [2].

“The guidelines of the European Society of Thoracic Surgeons (ESTS) recommend that peripherally located tumours of ≤3 cm are surgically removed, in combination with mediastinal dissection,” said Dr Walter Weder (University Hospital Zurich, Switzerland). “Patients with a tumour of >3 cm should undergo invasive staging. In case of a centrally located tumour, irrespective of the size, invasive mediastinal staging should be performed, at least according to the ESTS guidelines” [3].
Immunotherapy in early stage lung cancer

In the last years, the treatment of early stage lung cancer has changed dramatically. Some patients receive immunotherapy prior to resection in clinical trials. In 2018, the first trial evaluating neoadjuvant PD-1 blockade in resectable lung cancer was published [4]. “It was absolutely impressive”, according to Dr Weder. Neoadjuvant nivolumab (anti-PD-1) induced a major pathological response in 45% of resected tumours.

This was a bridge to the next lecture, in which Dr Raffaele Califano (The Christie and Manchester University Hospital, United Kingdom) talked about adjuvant and neoadjuvant chemotherapy in resectable early-stage NSCLC. In view of future use, he showed some data about peri-operative immune checkpoint blockade and molecular therapies. “You will see that the future is closer than you think.”
Adjuvant chemotherapy

A meta-analysis of the NSCLC Collaborative Group, published in 1995, was the first to report a clinical benefit of adjuvant chemotherapy, using a variety of chemotherapeutic backbones, over surgery alone. There was a 13% reduction in the risk of death with platinum-based chemotherapy, with an absolute benefit in overall survival (OS) for chemotherapy of 3% at two years and 5% at five years, although that did not reach statistical significance (hazard ratio 0.87, P=0.08) [5]. Based on this meta-analysis, a number of groups all over the world started trials with different chemotherapeutic backbones and in different stages of lung cancer. Only half of these trials showed a statistically significant benefit of adjuvant chemotherapy on OS [6-8].

The Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group found in a meta-analysis an improvement in OS for adjuvant cisplatin-containing chemotherapy (HR 0.89; P=0.005). The absolute benefit in OS was 3.9% at three years and 5.4% at five years [9]. “This is very similar to the previous meta-analysis”, Dr Califano added. “There was also an absolute benefit in DFS of approximately 5.8% at both three and five years. Very importantly, there was no improvement in OS or DFS for stage 1A-1B patients.”

The CALGB 9633 trial was the only study evaluating adjuvant chemotherapy in stage 1B patients. Another difference is that it evaluated adjuvant paclitaxel plus carboplatin instead of cisplatin [10]. “The trial did not reach the primary endpoint of OS”, Dr Califano said. “An unplanned, underpowered, post-hoc analysis managed to get a positive result for paclitaxel plus carboplatin over observation.”

How does adjuvant chemotherapy perform in the long run? After a median follow-up of 7.5 years, the OS Kaplan-Meier curves “were kissing each other”, Dr Califano mentions. “That means that unfortunately the benefit in OS is lost. This is different from the results of the JBR.10 study.” The latter, a randomised phase 3 trial, compared vinorelbine plus cisplatin with observation. After a median follow-up of 9.3 years, there was a sustained benefit of adjuvant chemotherapy that was only statistically significant for stage 2 NSCLC (HR 0.68; P=0.01). In contrast to the previous study, there was no difference for secondary malignancies or non-cancer related death in the chemotherapy arm” [11].
Neoadjuvant chemotherapy

There are some potential advantages for neoadjuvant treatment over adjuvant treatment. First, neoadjuvant treatment might maximise the likelihood of eradicating micrometastases. In addition, the systemic therapy may be better tolerated before surgery, which is particularly true for elderly patients. Furthermore, neoadjuvant therapy may allow to assess the sensitivity or resistance to therapy used in the induction phase. Also, there may be accelerated drug approval, if the surrogate endpoints used in the neoadjuvant studies are likely to predict OS or DFS benefit. The last point, which is particularly relevant according to Dr Califano, is that some major trial endpoints, such as pathological response, can be determined much faster than time to recurrence after surgery.

Due to slow recrual, most studies evaluating neoadjuvant chemotherapy were underpowered. The NSCLC Meta-analysis Collaborative Group meta-analysed 15 studies and found a significant benefit of preoperative chemotherapy on survival (HR 0.87, P=0.007) [12]. “This was exactly the same effect as found in the adjuvant meta-analysis”, he said. “There was an improvement in relapse-free survival, but the time to treatment failure or time to locoregional recurrence was not improved. Therefore, it is likely that OS benefit is due to a decrease in distant recurrence.”
Immunotherapy in early stage

“Immune checkpoint inhibitors (ICI) have revolutionised the treatment of advanced NSCLC”, Dr Califano mentioned. There are now data for the neoadjuvant setting. A small trial (n=21) found a major pathological response in 45% of resected tumours after treatment with nivolumab. Responses occurred in both PD-L1-positive and -negative tumours [13].
In another study, evaluating neoadjuvant atezolizumab (anti-PD-L1) plus chemotherapy in only 14 patients with resectable NSCLC, 50% had a major pathological response and 21% a complete pathological response [14]. Finally, Dr Califano finds it very important that properly planned and adequately powered studies are performed. The results of these studies will be reported in the near future. “This is the only way to find out if these strategies have a real impact for our patients.”
The importance of comorbidity

Next to comorbidities related to tobacco use, such as cardiovascular and respiratory diseases, (e.g. chronic obstructive pulmonary disease (COPD)), there are also comorbidities unrelated to tobacco use, such as diabetes mellitus and its complications. Additionally, most lung cancer patients are elderly, and it is well-known that comorbidities are more frequent and more severe with ageing, independent of the physiological alterations inherent to ageing. As such, there is a high frequency of comorbidity in patients with early stage lung cancer. For example, national databases have showed that COPD was present in 20-35% and hypertension in 25-60% of lung cancer patients. While comorbidity has a clear impact on the treatment strategy, the presence of comorbidity is probably not related to greater post-operative complication rate. Interestingly, a higher number of patients with comorbidity underwent surgery from 2001 to 2010, with an improvement in survival, particularly in case of sublobar resection. “Surgery was preferred in patients with low comorbidity burden and radiotherapy in case of COPD”, Dr Anne-Claire Toffart (Centre Hospitalier Universitaire de Grenoble, France) added. “There is also a clear impact on survival, so we should be particularly careful with the prescription of adjuvant chemotherapy in case of comorbidities.”

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