Immune-checkpoint inhibitors are moving into first-line therapy of advanced non-small cell lung cancer (NSCLC) for tumours without driver-mutation. For high expressers of PD-L1, i.e., a tumour proportional score (TPS) of 50% or higher pembrolizumab monotherapy demonstrated in comparison to doublet chemotherapy an advantage regarding toxicity, progression-free survival and overall survival (1,2). For all-commers regarding PD-L1-expression the combination of pembrolizumab with pemetrexed and cis-/carboplatin was superior in comparison to the chemotherapy alone group in non-squamous NSCLC (3). Atezolizumab plus Paclitaxel, Carboplatin and Bevacizumab was also superior in comparison to the three-drug regimen (4). In squamous cell cancer atezolizumab plus carboplatin plus nab-paclitaxel improves progression-free and overall survival (5). This is also true for pembrolizumab plus paclitaxel or nab-paclitaxel and carboplatin (6). In NSCLC with high mutational burden the combination of PD-1- and CTLA4-inhibition showed a benefit over chemotherapy irrespective the PD-L1 expression (7)). Furthermore a consolidation therapy with durvalumab after simultaneous chemoradiotherapy had relevant advantage in survival (8,9). We have good evidence that PD-1-/PD-L1 inhibition works after first-line chemotherapy (10-13), but there are very few and almost no prospective data how we should proceed with refractory or progressive tumours having first-line therapy with immune-checkpoint inhibition. We present therefore in the following strategies according to the various first-line settings how we can treat after first-line immune check-point inhibition. These strategies have of course to be checked and confirmed with prospective data in registries and clinical trials.
Disease progression after stopping immune check-point inhibition due to toxicity or after an extended period of treatment
If there is disease progression after stopping immune check-point inhibition due to toxicity re-establishing immune check-point inhibition seems to be an option (14). After long-term application of immune check-point inhibition and durable response re-induction at progression seems to be possible (15). This topic will be elaborated in a separate manuscript in this issue of PMC.
Disease progression during PD-1 inhibition as monotherapy
In case of disease progression during PD-1 inhibition as monotherapy a classical chemotherapy doublet can be given (3) and is probably adequate. In the case of only one or few sites of progression local therapies, especially radiotherapy can be added (16,17). Radiation therapy leads to an immunological reaction, which can end in tumour destruction distant to the irradiated area (abscopal effect) (18). In a systematic review of 46 cases between 1969 and 2014 there was a wide variety in the cases and the abscopal effect was described after up to 12 months (19). The abscopal effect was also described after radiotherapy and ipilimumab (20). In a phase II trial pembrolizumab after locally ablative therapy in the oligometastatic setting demonstrated a reasonable progression-free and overall survival (21). The combination with other immune therapies is also an option for clinical trials (22,23). One principle of acquired resistance is the exhaustion of T-cells, which could be overcome by adding an alternative stimulation. One example is the addition of nivolumab after the CTLA4-antibody ipilimumab (24). Also targeting TGF-ß in addition to PD-1 may be an option (25).
Disease progression during or after immune check-point inhibition and chemotherapy (plus bevacizumab)
After the combination of immune check-point inhibition and doublet chemotherapy (plus bevacizumab) probably standard second-line mono-chemotherapy with docetaxel or pemetrexed (in non-squamous NSCLC, if not given already in first-line) is a reasonable choice. Chemotherapy may also be immunogenic and enable further immune check-point inhibition (26). In the second-line setting after doublet chemotherapy the addition of ramucirumab or nintedanib (in non-squamous NSCLC) is of benefit. This seems to be true especially for tumours who relapse or progress early (27-29). Probably this is also true after immune check-point inhibition, even in the third-line setting after chemotherapy and nivolumab (30,31). As described already above also in the setting of mono- or oligo-progression with immune check-point inhibition and chemotherapy (plus bevacizumab) locally ablative therapies can be useful. If available also further immune therapy approaches can be tested in clinical trials (32). Examples are pegilodecakin (IL-10) (33), entinostat (HDAC inhibitor) (34), toll-like receptor 9 agonists, e.g., lefitolimod (35), Adenosine-antagonists (36,37) and adoptive cell transfer using tumour infiltrating lymphocytes (38).
Disease progression during or after a combination of PD-1- and CTLA4-inhibition
If in first-line a combination of PD-1- and CTLA4-inhibition was used, classical doublet chemotherapy is probably the preferred option. Alternatively prospective clinical trials can examine further immune modulating agents. In case of mono- or oligo-progression local treatments can be evaluated—as already described above.
We have good evidence for the second-line setting in NSCLC without driver mutation after a doublet chemotherapy in first-line. As immunotherapy is moving in first-line we have no adequate evidence, how we should handle primary progression or recurrence. The situation can be improved when in all first-line clinical trial the monitoring of second- and third-line therapy is mandatory and includes the treatment regimens, their efficacy and the second and third progression-free survival. Also prospective registries of the patients which get immunotherapy in first-line would be of help. Of course it would be nevertheless necessary to use trial designs where the best approach over the several lines of therapy is tested.
As immunotherapy in NSCLC without driver mutation is moving into first-line we need strategies to treat progression and recurrence. At the moment only recommendations at the level of expert opinions can be given. Our recommendations are outlined in Figure 1. Depending on the regimen in first-line mostly chemotherapy will be applied: as doublet chemotherapy, if only immune check-point inhibition was used, as classical second-line mono chemotherapy after the combination of immune check-point inhibition and doublet chemotherapy (plus bevacizumab) and chemoradiotherapy with immune check-point inhibition. If the progress/recurrence is early the addition of an antiangiogenetic agent (nintedanib, ramucirumab) is probably useful. If there is mono- or oligo-progression only locally ablative therapies may be adequate and foster the efficacy of immune check-point inhibition. Mostly in clinical trials further immune therapy combinations can be applied. Overall we urgently need prospective data to these concepts.
Provenance and Peer Review: This article was commissioned by the Guest Editor Nir Peled for the series dedicated to the Congress on Clinical Controversies in Lung Cancer (CCLC 2018) published in Precision Cancer Medicine. The article has undergone external peer review.
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/pcm.2019.03.01). The series dedicated to the Congress on Clinical Controversies in Lung Cancer (CCLC 2018) was commissioned by the editorial office without any funding or sponsorship. RMH reports grants and personal fees from Astra Zeneca, and personal fees from Takeda, Merrimak, Chugai, Abbvie, Novartis, Bayer, BMS, Boehringer Ingelheim, Celgene, Pfizer, Roche, Lilly, Guardant Health, Mologen, MSD, outside the submitted work . The author has no other conflicts of interest to declare.
Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Cite this article as: Huber RM. Disease progression in non-small cell lung cancer on immune-checkpoint inhibition, what are the options? Precis Cancer Med 2019;2:13.