Ziv–Aflibercept (Zaltrap ^®) is a recombinant fusion protein that binds (scavenges) to VEGF-A, VEGF-B, and placental growth factor and hence does not allow the binding of VEGF to its receptors as shown in Fig. 19.2. This relatively new agent has been randomized in one trial for NSCLC. The VITAL study is a randomized multinational double-blind trial that enrolled 913 patients with non–squamous NSCLC (adenocarcinoma making 80 % of the NSCLC) who have already failed one platinum doublet therapy. The randomization was 1:1 with one subgroup receiving docetaxel (75 mg/m²) and aflibercept (6 mg/kg) every 3 weeks, while the control subgroup received docetaxel only. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS) and overall response rate (ORR). A total of 12.3 % of the patients had already received prior bevacizumab therapy. The OS in the treatment subgroup was 10.1 months, while it was 10.4 months in the placebo group. PFS and ORR were 5.2 % versus 4.1 % and 23.3 % versus 8.9 % in the treatment and placebo subgroup, respectively [2]. This pioneering study did not show any advantage of scavenger fusion proteins in the treatment of NSCLC.

Bevacizumab or Bev is a humanized monoclonal antibody aimed against VEGF-A, developed by Genentech/Roche, and marketed as Avastin^®. VEGF-A is one of the key components in promoting de novo angiogenesis. Bev has been recommended in renal cell carcinoma, carcinoma of the breast (in some countries), glioblastoma multiforme, colonic cancer, and advanced stages of NSCLC. Recent evidence in using Bev has been counterbalanced by the unpredictable nature of the response. This is due to the neutralizing effect of another isoform of VEGF-165b which is an antiangiogenic form of VEGF-A and neutralizes the effect of Bev [3]. This has prompted the development of scavenger agents: ziv-aflibercept and VEGF-receptor inhibitors. So far, none of the VEGFR inhibitors have undergone any clinical trials in relation to pulmonary tumors.

One the first clinical trials employing Bev was E4599 (Eastern Cooperative Oncology Group) which randomized 878 patients with recurrent or advanced non-squamous NSCLC (IIIB or IV) to receive either paclitaxel or carboplatin (N = 444) versus the same therapy plus bevacizumab (N = 434). Chemotherapy was given for 3 weeks for six cycles, while Bev was given every 3 weeks until disease progression or increased toxicity. The primary endpoint was overall survival. The overall difference between the two groups was 2 months in favor of the chemotherapy+Bev group (p = 0.003). Progression-free survival was 6.2 months in the chemotherapy+Bev versus 4.5 months in chemotherapy alone [4]. This trial subsequently led to the European AVAiL trial which confirmed the positive results of adding bevacizumab (7.5 or 15 mg/kg) to gemcitabine and cisplatin in treating non-squamous NSCLC tumors. The results showed a significant benefit in progression-free survival (PFS) (6.7 months in the low-dose group vs. 6.1 for the placebo group and 6.5 months for the high-dose group vs. 6.1 months for the placebo).

Two additional complimentary trials with Bev have emerged as maintenance therapies after chemotherapy. These are AVAPERL and POINTBREAK trials. AVAPERL was a European phase III trial that randomized 362 patients previously treated with pemetrexed, cisplatin, and bevacizumab. The patients were further randomized to receive either maintenance Bev or Bev + pemetrexed every 3 weeks until progression. The trial demonstrated the superiority of maintenance therapy with combined medications (PFS of 10.2 months vs. 6.6 months) but contrasted the futility of having bevacizumab alone in any treatment modality. Finally, POINTBREAK as referred in Fig. 19.3 is a very recent North American trial which was primarily powered for overall survival and PFS as well as RR as secondary endpoints (see below). It proved to be a negative study with absolutely no difference in overall survival between the two arms of the study (13 months) and very similar progression-free survival, but it did show that maintenance therapy was tolerable with significantly higher level of thrombocytopenia in the combined arm.

The birth of the monoclonal antibody against programmed death and its ligand PD1/PD1-L was heralded as a great leap in immunotherapy. PD-1 is a member of the CD28 family. It is expressed on T cells, memory cells, and regulatory T cells. The binding of PD-1 to its corresponding ligand PD-1L downregulates the activity of the T cell and inhibits it. The expression of PD-1L heralds poor tumor prognosis. PD1/PD-1L is regarded as a secondary signal after the initial interaction of T-cell receptor with antigen and MHC—Fig. 19.4. This secondary signaling pathway acts as an inhibitor of death. Henceforth, an antibody blocking the PD1 motif will cause cell death. BMS-936558 is an IgG4 monoclonal that blocks the docking of PD-1L and PD-2L onto PD-1. The current literature demonstrates good safety and efficacy in a preliminary phase I study by Brahmer and colleagues, whereby 39 patients with advanced solid tumors were given dose-escalating infusions of 0.3, 1, 3, and 10 mg/kg. The patient pool contained melanoma, renal cell carcinoma (RCC), colorectal carcinoma, NSCLC, and castration-resistant prostatic carcinoma (CRPC). The treatment was well tolerated; however, in nine patients observed, the success of the treatment was correlated with PD-1L expression [5]. Yet, in another study, SL Topalian and colleagues recruited 296 patients with advanced solid tumors who were given anti-PD-1 antibody at doses from 0.1 mg/kg up to 10 mg/kg every 2 weeks. Response was assessed after 8 cycles, but patients were given up to 12 cycles of therapy until complete response or disease progression. Of the 236 assessed, objective responses were more common in patients with NSCLC, melanoma, and RCC; this was further reflected with the response rate of PD-1L-expressing tumors which was 36 % (9 out of 25) and totally negative in the tumors not expressing PD-1L (Fig. 19.5). Overall response rate in the NSCLC subgroup was 18 % (14 out of 76), 28 % in the melanoma subgroup, and 27 % in the RCC subgroup [6]. Although this was not a randomized trial, it did prove the principle that in tumors expressing PD-1L, it is well worth examining the option of using anti-PD1 antibodies. Another phase II multicenter trial (CA 209-063) with BMS 936558 will be looking into patients with advanced squamous cell NSCLC who have received at least two prior chemotherapy regimens. The study is still recruiting patients and should be finished by 2014. Thus, although we do not have a large well-powered randomized trial with BMS 936558, this relatively new monoclonal antibody could hold much promise in the future.

Cetuximab is a monoclonal antibody that targets epidermal growth factor receptor (EGFR), which is an extracellular receptor with complex downstream signaling. Cetuximab is an IgG1 chimeric antibody that prevents the dimerization of its receptor with five- to tenfold affinity compared to its native ligand, thus preventing further receptor action. It also mediates antibody-dependent cell-mediated cytotoxicity (ADCC) and downregulation of the extracellular receptor. The dogma of using cetuximab in NSCLC is based upon the fact that 80 % of the diagnosed patients have high expression of EGFR extracellularly on immunohistochemical analysis. However, further analysis in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck (SCCHN), whereby cetuximab and another antibody, panitumumab, are used to treat advanced stage disease, revealed that mutational variations in K-ras, a further downstream GTPase, have a significantly different outcome. Colorectal cancer and squamous cell carcinoma of the head and neck patients treated with EGFR monoclonal antibodies against wild-type K-ras have a significantly better outcome than those harboring mutations as demonstrated from the phase III CRYSTAL and EXTREME trials, respectively. In diametric contrast, analysis of K-ras mutations in NSCLC, whether wild type or mutated, this correlation has not been demonstrated, thus suggesting that further biomarkers are required in the determination of prognosis. Crucial to the use of cetuximab in NSCLC has been the FLEX trial which has shown that the addition of cetuximab to first-line chemotherapy in advanced NSCLC significantly improved survival in patients as compared to chemotherapy alone. In 1,121 patients with positive immunohistochemistry for EGFR staining that were further subdivided into high (345) and low (776), the overall survival in the high EGFR-expressing chemotherapy plus cetuximab group versus the chemotherapy alone group was significantly higher (12.0 months vs. 9.6 months), whereas the low EGFR-expressing subgroup showed no overall benefit (9.8 cetux +chemo. vs. 10.3 months for chemotherapy alone) [7]. However, there has been some reluctance in using cetuximab in some communities due to high cost and availability of oral tyrosine kinase inhibitors that act further downstream from EGFR receptor.