New options for combination therapy for advanced non-squamous NSCLC

ABSTRACT

Introduction: Nonsquamous non-small-cell lung cancer (NSCLC) is divided in oncogene-addicted subgroups, highly expressed programmed death ligand-1 (PD-L1 ≥ 50%) subgroup, and ‘negative’ subgroup. The latter represents the most common group comprising about 50% of all new diagnoses of nonsquamous NSCLC. For this group, chemotherapy was the standard approach with pemetrexed- and/or bevacizumab-based regimens reaching an overall survival of about 12–17 months.

Areas covered: This review will focus on the new options for combination therapies, which have already recently arrived or are going to arrive in the clinical practice, mainly through registrative trials, for the management of advanced nonsquamous non oncogene-addicted NSCLC. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken in order to discuss this topic.

Expert opinion: In the ‘negative’ nonsquamous NSCLC patients, first-line combinations of pembrolizumab, an anti-PD-1, or atezolizumab, an anti-PD-L1, plus chemotherapy are already available in the clinical practice, regardless of PD-L1 expression. In this group of patients, the combinations of antiangiogenic agents, such as ramucirumab and nintedanib, in combination with docetaxel, become new options for second-line treatment. More studies are needed to investigate new combinations for the treatment of these patients.

KEYWORDS:

• Antiangiogenic
• checkpoint inhibitors
• immunotherapy
• nintedanib
• NSCLC
• nonsquamous
• ramucirumab
• regimen
• resistance

Article highlights

• Nonsquamous non-small-cell lung cancer (NSCLC) can be divided in oncogene-addicted subgroups, highly expressed programmed death ligand-1 (PD-L1 - ≥ 50%) subgroup, and ‘negative’ subgroup.

• For the ‘negative’ subgroup, accounting for about 50% of all new diagnoses of nonsquamous NSCLC, chemotherapy was the standard approach with pemetrexed- and/or bevacizumab-based regimens reaching an overall survival of about 12–17 months.

• Combinations of pembrolizumab plus platinum/pemetrexed and atezolizumab plus bevacizumab plus carboplatin/paclitaxel scored much better than chemotherapy alone and they are already available in the clinical practice for the treatment of non oncogene-addicted nonsquamous NSCLC patients, regardless of PD-L1 expression.

• Atezolizumab plus bevacizumab plus carboplatin/paclitaxel regimen showed activity also in the group of oncogene-addicted NSCLC progressing to previous corresponding TKIs, and baseline liver metastases nonsquamous NSCLC patients, reaching the clinical practice also in these subgroups of patients.

• Considering that the checkpoint inhibitors in combination with chemotherapy are going to become the standard-of-care for first-line therapy, the combination of antiangiogenic drugs, such as nintedanib or ramucirumab, plus docetaxel, may become the new options for second-line therapy of nonsquamous NSCLC patients.

• Ongoing and future studies should clarify the rationale of the resistance to these new regimens characterizing the patterns of such resistance in order to determine the best management strategies.

Overall, the next few years will be very exciting due to the understanding of the mechanisms for regulating the response to checkpoint inhibitors, the discovery of new targets for optimizing treatments, the investigation of new combinations to prevent and/or overcome resistance, the design of new algorithms for cancer treatment guidance including nonsquamous NSCLC.

Declaration of interest

A Rossi has been an advisory board member and received honoraria as speaker bureau for MSD, Eli-Lilly, Roche, Boehringer Ingelheim and AstraZeneca.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.