Nab-paclitaxel is an albumin-bound-stabilized nanoparticle formulation of paclitaxel designed to overcome the insolubility of the conventional solvent-based paclitaxel (sb-paclitaxel). Nab-paclitaxel has the merit that it requires a shorter infusion time (30 minutes vs. 3 hours), and can avoid hypersensitivity reactions, as it is free of Cremophor EL, a solvent for sb-paclitaxel30. While it may be less convenient in that nab-paclitaxel should be administered every week rather than every 3 weeks, it may be beneficial in terms of managing or avoiding critical adverse events.

A pivotal phase 3 trial has demonstrated significantly higher ORR and non-inferior PFS and OS of nab-paclitaxel/carboplatin compared to sb-paclitaxel combination31. Interestingly, the difference in ORR was more prominent in patients with squamous histology compared with nonsquamous histology. Moreover, the nab-paclitaxel arm was associated with a lower rate of grade ≥3 neutropenia, peripheral neuropathy, arthralgia, and myalgia, although it was associated with more grade ≥3 anemia and thrombocytopenia31. In a subsequent trial, nab-paclitaxel/carboplatin combination has shown OS benefit over sb-paclitaxel combination in elderly patients over 70 years old32. This survival benefit seen in elderly patients may be associated with less toxicity and more completion of preplanned treatment. In addition, the weekly dosing schedule of nab-paclitaxel might contribute to better treatment efficacy30. Current guidelines recommend nab-paclitaxel/carboplatin combination as a first-line regimen in both squamous and nonsquamous histology8910. In particular, the National Comprehensive Cancer Network (NCCN) guideline states that nab-paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or where premedications are contraindicated10. In Korea, nab-paclitaxel use has been approved for pancreatic, breast and lung cancer treatment; however to date, its usage for lung cancer is not reimbursed by the NHIS. Given its favorable efficacy and tolerability, nab-paclitaxel is a valuable option for a first-line treatment in patients with advanced NSCLC.

Antibody drug conjugates (ADCs) are one of the targeted drug delivery systems. ADCs are complexes of antibody linked to a biologically active cytotoxic agent to be delivered specifically to cancer cells33. Two drugs worth mentioning in lung cancer are ado-trastuzumab emtansine for NSCLC, and rovalpituzumab tesirine for small cell lung cancer (SCLC). Adotrastuzumab emtansine is the FDA-approved ADC for human epidermal growth factor receptor 2 (HER2)-positive breast cancer34. In a recent phase 2 basket trial which included heavily treated HER2-mutant NSCLC patients, ado-trastuzumab emtansine showed 44% of response rate (RR), and 5 months of median PFS35. Toxicities were manageable, and no patient stopped therapy as a result of toxicity35.

Rovalpituzumab tesirine (Rova-T) is an ADC directed against ligand delta-like protein 3 (DLL3), a novel target expressed in patients with SCLC36. The first phase 1 trial evaluating Rova-T in patients with relapsed or refractory SCLC has reported impressive data: 18% of ORR and 68% of disease control rate (DCR)37. Intriguingly, high DLL3 expression was associated with high DCR; 88% and 50% in high (>50%) and low (<50%) DLL3 groups, respectively. In addition, high DLL3 group showed a significantly longer median PFS (4.3 months) and OS (5.8 months), compared with the overall population37. Rova-T showed a unique toxicity profile, notable for thrombocytopenia, serosal effusions, and skin reactions. The mechanism of these toxic effects is not clear, but probably relates to the pyrrolobenzodiazepine dimer component of this complex37. Overall, Rova-T showed encouraging single-agent antitumor activity with a manageable safety profile in patients with relapsed or refractory SCLC. In addition, DLL3 may be a potential predictive marker in this setting. Based on these promising data, several clinical trials investigating Rova-T in SCLC are now ongoing; a phase 3 trial on Rova-T maintenance treatment after 4-cycled platinum-based doublet, and another phase 3 trial comparing Rova-T and topotecan as second-line treatment for relapsed disease38.

As a monoclonal antibody that binds vascular endothelial growth factor (VEGF)-A, bevacizumab inhibits endothelial cell proliferation and migration which are the critical steps in carcinogenesis. Clinical efficacies of bevacizumab in lung cancer have been proved in several previous trials394041. In the phase 3 ECOG4599 trial, bevacizumab (at a dose of 15 mg/kg) combined with paclitaxel/carboplatin has demonstrated significantly clinical benefit in terms of RR (35% vs. 15%, p<0.001), PFS (6.2 months vs. 4.5 months, p<0.001), and OS (12.3 months vs. 10.3 months, p=0.003), compared to paclitaxel/ carboplatin alone39. In Europe, the phase 3 AVAiL trial attempted to confirm the benefit of bevacizumab in combination with cisplatin/gemcitabine at two different doses (7.5 mg/kg and 15 mg/kg)40. Although significantly better PFS in both doses of bevacizumab was shown, the OS was not different between the two groups42. The subsequent phase 3 BEYOND trial evaluating the efficacy of the bevacizumab (15 mg/kg) plus carboplatin/paclitaxel combination in a Chinese cohort has demonstrated significant improvements in both PFS (9.2 months vs. 6.5 months; HR, 0.40; p<0.001) and OS (24.3 months vs. 17.7 months; HR, 0.68; p=0.0154)41. A metaanalysis also demonstrated significant RR, PFS, and OS benefit of bevacizumab plus platinum-doublet over platinum-doublet alone43. As bevacizumab was associated with a high rate of life-threatening hemoptysis, tumor adjunct to major blood vessels, cavitary tumors and squamous histology are contraindicated, and bevacizumab plus platinum-doublet is recommended only for nonsquamous histology813. This combinational approach has been evaluated in adjuvant setting for surgically resected, early-staged NSCLC, however, it failed to prove OS benefit44.

Ramucirumab, a monoclonal antibody to VEGF receptor 2, and nintedanib, a multiple kinase inhibitor, are another angiogenesis inhibitors with proven survival benefit in the second or later line setting in lung cancer treatment4546. The phase 3 REVEL trial compared ramucirumab plus docetaxel combination and docetaxel alone in the second-line setting45. Of note in this trial, patients who previously received bevaciuzumab and those who had squamous histology were not excluded. Modest but statistically significant improvement in OS (10.5 months vs. 9.1 months; HR, 0.86; p=0.023) and PFS (4.5 months vs. 3.0 months; HR, 0.76; p<0.0001) was shown in combination arm45. Although, the NCCN guideline recommend use of ramucirumab plus docetaxel combination10, the use of the regimen seems to have not been widely adopted, maybe due to the concern of toxicities and relatively low cost-effectiveness47. Currently, bevacizumab and platinum doublet combination regimen is approved for the treatment of advanced nonsquamous NSCLC; however, this regimen is not covered by the NHIS in Korea.

Although molecular targeted therapy has dramatically improved the survival of EGFR-mutated or ALK-rearranged NSCLC patients48, it is undeniable that OS benefit is partly attributable to the use of subsequent chemotherapy after TKI failure. From this point of view, the combination of TKI and chemotherapy as a first-line treatment for advanced NSCLC is a feasible approach. The INTACT 1 trial investigated gefitinib plus gemcitabine/cisplatin combination in advanced NSCLC49. Although there were no significant unexpected adverse events, there was also no clinical benefit in the combination group49. Another phase 3 trial testing erlotinib plus gemcitabine/cisplatin also failed to prove clinical benefit over the control group50. In this trial, in only a small never-smoker subgroup, OS and PFS were increased in combination arm50.

FASTACT-2 trial has firstly demonstrated the potential benefit of the chemotherapy plus EGFR-TKI combination in advanced NSCLC18. In this trial, an intercalated combination of chemotherapy and erlotinib (150 mg/day on days 15–28) was associated with better PFS (16.8 months vs. 6.9 months; HR, 0.25; p<0.0001) and better OS (31.4 months vs. 20.6 months; HR, 0.48; p=0.0092) over chemotherapy alone in EGFR-mutated patients18. The safety profile was similar between the two groups18. Despite these positive findings, erlotinib plus chemotherapy combination has not yet been recommended in guidelines, maybe due to the issues of dose schedule, optimal intercalation, and post-study treatments in the trial51. The clinical benefit of this kind of combinational approach seems to be validated by further trials.

Until recently, potential antagonism between chemotherapy and immunotherapy is one of the concerns when considering the chemotherapy and ICI combination. However, there have been a bunch of studies that have supported optimistic data on this kind of combinational strategy. Chemotherapy can modulate tumor to be more susceptible for ICI by releasing tumor-specific antigens, up-regulation of major histocompatibility complex expression, increasing the cytotoxic lymphocyte to regulatory T-cell ratio, and inhibiting myeloid-derived suppressor cells52535455. Preclinical studies have also shown a synergistic effect of the chemotherapy and ICI combination5657. The phase 2 KEYNOTE-021G trial is a proof-of-concept study that demonstrated the superiority of combination of chemotherapy and immunotherapy in advanced NSCLC58. In this trial, pemetrexed/carboplatin combined with pembrolizumab showed significantly better RR and longer PFS than chemotherapy alone in previously untreated patients with metastatic nonsquamous NSCLC without EGFR or ALK genomic aberrations irrespective of PD-L1 expression58. Based on those data, this combination has been granted accelerated approval by the U.S. FDA in May 2017.

The clinical benefit of chemotherapy and ICI combination in the same clinical setting were investigated in the phase 3 KEYNOTE-189 trial in which pemetrexed maintenance treatment was permitted in the control arm19. Pembrolizumab in combination with pemetrexed/carboplatin showed significant improvement in both PFS (8.8 months vs. 4.9 months; HR, 0.52; p<0.001) and OS rate at 12 months (69.2% vs. 49.4%; HR, 0.49; p<0.001)19. In addition, the clinical benefit was found in all subgroups examined, including those with PD-L1 TPS of less than 1%19. Considering 41.3% of the patients in the placebo-combination group received ICIs on progression, the HR is quite impressive. Adverse events of grade 3 or higher occurred similarly in both groups (67.2% in the pembrolizumabcombination group and 65.8% in the placebo-combination group), although discontinuation due to adverse event was higher in the pembrolizumab-combination group (13.8%) than in the placebo-combination group (7.9%)19. The addition of pembrolizumab did not appear to increase the frequency of adverse events that are commonly associated with pemetrexed/carboplatin. Similarly, the incidence of most immune-mediated adverse events was not higher with the pembrolizumab-combination group than that previously observed with pembrolizumab monotherapy4. In addition, the interim data of KEYNOTE-407 phase 3 trial (NCT02775435) also demonstrated better response and longer PFS and OS in the pembrolizumab plus carboplatin/paclitaxel (or nab-paclitaxel) combination over chemotherapy alone in patients with metastatic squamous cell carcinoma irrespective of PD-L1 expression38. Taken together, “chemoimmunotherapy” may be a new standard of care for the first-line treatment of advanced NSCLC with manageable safety profile. The results of ongoing trials on the chemoimmunotherapy for NSCLC are eagerly awaited38.