Introduction
Materials and methods
Objectives
Study design
Scientific committee
Expert panel
Delphi
Generation of statements
Consensus levels
Statistical analysis
Development of the consensus manuscript
Results
General aspects of the current treatment of advanced wild-type lung adenocarcinoma
Round | Range of responses (N = 26) | % of panela | Final consensus | |||||
---|---|---|---|---|---|---|---|---|
1 (%) | 2 (%) | 3 (%) | 4 (%) | 5 (%) | ||||
1. Currently, after recent positive first-line Phase 3 studies of immunotherapy alone or in combination with chemotherapy, there are uncertainties about which would be the best treatment sequence for patients with advanced lung adenocarcinoma who have progressed after receiving these new therapeutic strategies | 1 | 3.8 | 3.8 | 11.5 | 38.5 | 42.3 | Consensus | |
2 | 7.7 | 0 | 19.2 | 73.1 | 92.3 | |||
2. It is not feasible to repeat the Phase 3 studies of approved treatments in a patient population that had previously received the newer front-line therapeutic strategies to obtain high-level “conventional” scientific evidence | 1 | 0 | 0 | 19.2 | 46.2 | 34.6 | Unanimity | |
2 | 0 | 0 | 34.6 | 65.4 | 100 | |||
3. Under these circumstances, the opinion and clinical experience of experts managing patients with lung cancer are essential to define the best therapeutic strategy and/or sequence of treatments | 1 | 0 | 7.7 | 23.1 | 38.5 | 30.8 | Consensus | |
2 | 0 | 7.7 | 30.8 | 61.5 | 92.3 | |||
4. The absence of the aforementioned “conventional” scientific evidence should not hinder access to the best therapeutic sequence according to the criteria of lung cancer experts | 1 | 3.8 | 7.7 | 15.4 | 50.0 | 23.1 | Consensus | |
2 | 0 | 3.8 | 26.9 | 69.2 | 96.1 |
Durvalumab as consolidation therapy after platinum-based chemoradiotherapy in Stage III wild-type lung adenocarcinoma: impact on subsequent treatment lines
Round | Range of responses (N = 26) | % of panela | Final consensus | |||||
---|---|---|---|---|---|---|---|---|
1 (%) | 2 (%) | 3 (%) | 4 (%) | 5 (%) | ||||
1. In patients with locally advanced lung adenocarcinoma treated with platinum-based chemoradiotherapy who progress during consolidation treatment with durvalumab, the progression-free interval may condition subsequent salvage treatment | 1 | 0 | 3.8 | 23.1 | 30.8 | 42.3 | Consensus | |
2 | 0 | 3.8 | 15.4 | 80.8 | 96.2 | |||
2. If the interval between the end of chemoradiotherapy and disease progression is less than 6 months, subsequent salvage therapy would be considered as a second line of treatment, so nintedanib and docetaxel could be a reasonable alternative | 1 | 0 | 11.5 | 15.4 | 30.8 | 42.3 | Consensus | |
2 | 3.8 | 7.7 | 15.4 | 73.1 | 88.5 | |||
3. If the interval between the end of chemoradiotherapy and disease progression is greater than 6 months but less than 12 months, it is reasonable to evaluate treatment with platinum-based chemotherapy, or docetaxel ± nintedanib, or pemetrexed depending on the interval itself (closer to 6 months vs. 12 months), the aggressiveness of the progression and accumulated toxicity | 1 | 0 | 11.5 | 19.2 | 38.5 | 30.8 | Consensus | |
2 | 7.7 | 7.7 | 23.1 | 61.5 | 84.6 | |||
4. If the interval between the end of chemoradiotherapy and disease progression is greater than 12 months, treatment with a platinum-based chemotherapy could be a reasonable alternative | 1 | 0 | 0 | 7.7 | 42.3 | 50.0 | Consensus | |
2 | 0 | 3.8 | 19.2 | 76.9 | 96.1 | |||
5. In patients with locally advanced lung adenocarcinoma treated with platinum-based chemoradiotherapy who progress after completing treatment with durvalumab, treatment with platinum-based chemotherapy may be a reasonable alternative | 1 | 0 | 0 | 19.2 | 34.6 | 46.2 | Consensus | |
2 | 0 | 3.8 | 15.4 | 80.8 | 96.2 | |||
6. There is no evidence that the reintroduction of immunotherapy is effective, so it is reasonable to only offer it in the context of a clinical study. However, the following variables should be assessed when considering reintroducing immunotherapy: the time elapsed since the last cycle of durvalumab, tumour expression of PD-L1, and TMB | 1 | 0 | 3.8 | 7.7 | 50.0 | 38.5 | Consensus | |
2 | 0 | 11.5 | 19.2 | 69.2 | 88.4 |
First-line immunotherapy ± chemotherapy in advanced wild-type lung adenocarcinoma: impact on optimal treatment sequencing in second- and further treatment lines
Round | Range of responses (N = 26) | % of panela | Final consensus | |||||
---|---|---|---|---|---|---|---|---|
1 (%) | 2 (%) | 3 (%) | 4 (%) | 5 (%) | ||||
1. Given the positive results of KEYNOTE 024 (pembrolizumab in PD-L1 ≥ 50%), KEYNOTE 042 (pembrolizumab in PD-L1 ≥ 1%), KEYNOTE 189 (pembrolizumab and chemotherapy), IMpower 150 (atezolizumab, bevacizumab and chemotherapy) and CheckMate 227 (nivolumab and ipilimumab in TMB ≥ 10 mut/MB) Phase 3 studies, we expect that the majority of patients with advanced lung adenocarcinoma will be treated with first-line immunotherapy ± chemotherapy | 1 | 0 | 3.8 | 3.8 | 34.6 | 57.7 | Consensus | |
2 | 3.8 | 0 | 3.8 | 92.3 | 96.1 | |||
2. In the near future, calculating the mutational load in individual patients using sequencing techniques (NGS) is likely to become routine, since its value as a predictive biomarker of efficacy for immunotherapy has been confirmed | 1 | 7.7 | 7.7 | 19.2 | 34.6 | 30.8 | Consensus | |
2 | 3.8 | 3.8 | 42.3 | 50.0 | 92.3 | |||
3. Considering the high percentage of patients who will be treated with first-line immunotherapy, the implementation of economic measures ensuring patients’ access to these drugs and sustainability of the healthcare system is essential | 1 | 0 | 0 | 0 | 26.9 | 73.1 | 100 | Consensus |
2 | NA | NA | NA | NA | ||||
4. Due to the enormous increase in first-line immunotherapy use, its administration as second-line or later treatment lines is likely to be significantly reduced in the coming years | 1 | 0 | 0 | 19.2 | 26.9 | 53.8 | Unanimity | |
2 | 0 | 0 | 7.7 | 92.3 | 100 | |||
5. Upon progression with first-line combination of chemotherapy (platinum + pemetrexed) and pembrolizumab, docetaxel and nintedanib could be a recommended treatment option | 1 | 0 | 3.8 | 3.8 | 38.5 | 53.8 | Consensus | |
2 | 0 | 3.8 | 15.4 | 80.8 | 96.2 | |||
6. Upon progression with first-line combination of chemotherapy (carboplatin + paclitaxel), bevacizumab and atezolizumab, docetaxel and nintedanib could be a recommended treatment option | 1 | 0 | 11.5 | 30.8 | 23.1 | 34.6 | Consensus | |
2 | 0 | 11.5 | 34.6 | 53.8 | 88.4 | |||
7. In patients treated with first-line immunotherapy without chemotherapy (pembrolizumab or nivolumab + ipilimumab), platinum-based chemotherapy would be the first treatment option when disease progression occurs | 1 | 0 | 0 | 3.8 | 34.6 | 61.5 | Unanimity | |
2 | 0 | 0 | 19.2 | 80.8 | 100 | |||
8. Patients who have progressed both to first-line immunotherapy (pembrolizumab or nivolumab + ipilimumab) and second-line platinum-based chemotherapy should consider a third-line of treatment with docetaxel and nintedanib, docetaxel alone, or pemetrexed alone | 1 | 0 | 0 | 7.7 | 38.5 | 53.8 | Consensus | |
2 | 3.8 | 3.8 | 23.1 | 69.2 | 92.3 | |||
9. If a patient is treated with first-line immunotherapy (pembrolizumab or nivolumab + ipilimumab) followed by platinum-based chemotherapy at progression, at the time of the second progression, the use of docetaxel and nintedanib could be considered. This administration of docetaxel and nintedanib would be considered second-line chemotherapy (according to the SmPC, the docetaxel and nintedanib combination is approved “after first-line chemotherapy”) even though the patient will be receiving their third-line of treatment | 1 | 0 | 3.8 | 7.7 | 46.2 | 42.3 | Consensus | |
2 | 0 | 3.8 | 19.2 | 76.9 | 96.2 | |||
10. Upon progression to platinum-based chemotherapy, the more aggressive the disease progression (early progression and symptomatic tumour burden), the more recommendable it is to use the combination of docetaxel and nintedanib rather than docetaxel or pemetrexed alone | 1 | 3.8 | 3.8 | 19.2 | 34.6 | 38.5 | Consensus | |
2 | 0 | 7.7 | 19.2 | 73.1 | 92.3 | |||
11. Upon progression to first-line immunotherapy (pembrolizumab or nivolumab + ipilimumab) followed by progression to second-line platinum-based chemotherapy, there currently is no evidence that reintroduction of immunotherapy is effective. It is reasonable to only offer immunotherapy in the clinical study setting | 1 | 0 | 0 | 7.7 | 19.2 | 73.1 | 92.3 | Consensus |
2 | NA | NA | NA | NA |
Treatment after platinum-based chemotherapy without immunotherapy in advanced wild-type lung adenocarcinoma: options and optimal therapeutic sequencing
Round | Range of responses (N = 26) | % of panela | Final consensus | |||||
---|---|---|---|---|---|---|---|---|
1 (%) | 2 (%) | 3 (%) | 4 (%) | 5 (%) | ||||
1. Tumour PD-L1 expression is a fundamental criterion to help therapeutic decision making in a patient previously treated with first-line platinum-based chemotherapy | 1 | 0 | 23.1 | 23.1 | 30.8 | 23.1 | Reformulated | |
2 | NA | NA | NA | NA | ||||
1′. Tumour PD-L1 expression is a criterion to help therapeutic decision making in a patient previously treated with first-line platinum-based chemotherapy | 1 | NA | NA | NA | NA | NA | Consensus | |
2 | 0 | 11.5 | 34.6 | 53.8 | 88.4 | |||
2. When selecting second-line treatment options following progression to first-line platinum-based chemotherapy, another criterion to consider is tumour aggressiveness | 1 | 0 | 0 | 23.1 | 53.8 | 23.1 | Unanimity | |
2 | 0 | 0 | 23.1 | 76.9 | 100 | |||
3. When selecting second-line treatment options following progression to first-line platinum-based chemotherapy, tumour PD-L1 expression, tumour aggressiveness, and accumulated toxicity from previous treatments should be assessed | 1 | 3.8 | 0 | 19.2 | 38.5 | 38.5 | Unanimity | |
2 | 0 | 0 | 19.2 | 80.8 | 100 | |||
4. When selecting second-line treatment options following progression to first-line platinum-based chemotherapy, the aggressiveness of the tumour could favour choosing docetaxel and nintedanib if tumour PD-L1 expression is negative | 1 | 3.8 | 3.8 | 11.5 | 38.5 | 42.3 | Consensus | |
2 | 0 | 3.8 | 19.2 | 76.9 | 96.2 | |||
5. When selecting second-line treatment options following progression to first-line platinum-based chemotherapy, the aggressiveness of the tumour could favour choosing docetaxel and nintedanib if tumour PD-L1 expression is low | 1 | 3.8 | 3.8 | 26.9 | 46.2 | 19.2 | Consensus | |
2 | 0 | 3.8 | 42.3 | 53.8 | 96.2 | |||
6. In a patient with unknown tumour PD-L1 expression and slow progression to first-line platinum-based chemotherapy, second-line immunotherapy could be a reasonable therapeutic option | 1 | 0 | 0 | 3.8 | 61.5 | 34.6 | Unanimity | |
2 | 0 | 0 | 19.2 | 80.8 | 100 | |||
7. In a patient with negative tumour PD-L1 expression and slow progression to first-line platinum-based chemotherapy, second-line immunotherapy could be a reasonable therapeutic option | 1 | 0 | 11.5 | 7.7 | 61.5 | 19.2 | Unanimity | |
2 | 0 | 0 | 19.2 | 80.8 | 100 | |||
8. Upon progression to second-line immunotherapy, one could consider administering docetaxel and nintedanib as third-line treatment (second-line chemotherapy) | 1 | 0 | 0 | 7.7 | 46.2 | 46.2 | Consensus | |
2 | 0 | 7.7 | 19.2 | 73.1 | 92.3 | |||
9. Upon progression to second-line chemotherapy (docetaxel and nintedanib, docetaxel alone or pemetrexed alone), one could consider administering immunotherapy as third-line treatment, but exclusively in patients with positive tumour PD-L1 expression | 1 | 7.7 | 42.3 | 30.8 | 11.5 | 7.7 | Majority disagreement | |
2 | 7.7 | 53.8 | 23.1 | 15.4 | 61.5 | |||
10. Upon progression to second-line chemotherapy (docetaxel and nintedanib, docetaxel alone or pemetrexed alone), one could consider administering immunotherapy as third-line treatment, independently of the tumour PD-L1 expression | 1 | 0 | 11.5 | 23.1 | 46.2 | 19.2 | Consensus | |
2 | 0 | 11.5 | 38.5 | 50.0 | 88.4 | |||
11. When considering administering third-line immunotherapy treatment, one should assess the aggressiveness of the disease progression to previous second-line chemotherapy as well as tumour PD-L1 expression | 1 | 3.8 | 0 | 23.1 | 53.8 | 19.2 | Consensus | |
2 | 3.8 | 0 | 46.2 | 50.0 | 96.2 | |||
12. In a patient with negative tumour PD-L1 expression treated with first-line platinum-based chemotherapy plus bevacizumab attaining a disease control greater than 18 months, one could consider administering a second-line anti-angiogenic therapy (docetaxel and nintedanib) because of the benefit from the previous anti-angiogenic therapy | 1 | 7.7 | 23.1 | 38.5 | 23.1 | 7.7 | Dissent | |
2 | 3.8 | 38.5 | 42.3 | 15.4 | 57.7 |
Discussion
Variables | Clinical scenarios | ||
---|---|---|---|
After durvalumab as post-chemoradiotherapy consolidation therapy in Stage III disease | After first-line immunotherapy ± chemotherapy in advanced disease | After treatment with platinum-based chemotherapy without immunotherapy in advanced disease | |
Clinical aggressiveness of the progression | |||
High symptomatic tumour load | × | × | × |
Early progression | × | × | × |
Previous treatment | × | × | |
Accumulated toxicity from previous treatments | × | × | × |
Progression-free interval with immunotherapy | × | ||
PD-L1 expression | × | × | |
Tumour mutational burden | × |