Multi-targeted TKIs such as afatinib and dacominitib have been studied in RM SCCHN. one area that has helped improve results with this disease. Anti-EGFR centered therapies have been shown to improve overall survival and mitigate the significant toxicities incurred from standard radiation, chemotherapy, and/or medical options. Cetuximab, probably the most well-studied anti-EGFR monoclonal antibody, offers shown a positive impact on results for RM and LA SCCHN. However, the development of early resistance to cetuximab shows the need for any wider arsenal of therapy for RM and LA diseases. The use of immune checkpoint inhibitors has recently transformed the treatment of recurrent SCCHN. Drugs such as pembrolizumab and nivolumab have demonstrated success in recent medical trials and have been authorized for the treatment of advanced disease. Given the positive results of both EGFR targeted providers and immune checkpoint inhibitors, ongoing tests are studying their synergistic effects. encodes for cyclin-D1 and preclinical data have linked EGFR inhibition resistance in SCCHN with the overexpression of . This connection suggests CDK4/CDK6 inhibitors in conjunction with monoclonal S-8921 antibodies such as cetuximab, may be of significance in SCCHN. Despite motivating results reported in one arm phase II trial of palbociclib and cetuximab, a recent confirmatory randomized phase II trial assessing palbociclib with cetuximab vs. solitary agent cetuximab in platinum-resistant, cetuximab-na?ve SCCHN carcinoma failed to statement a significant benefit in median OS or PFS [34,35]. S-8921 5. Overcoming Resistance in EGFR Therapy in SCCHN Given the numerous mechanisms for the development of treatment resistance against monoclonal antibodies and TKIs in SCCHN, it is crucial to find strategies to overcome these resistance patterns. Much of the data surrounding resistance patterns in anti-EGFR treatment modalities are currently under investigation. Some treatment modalities have reached phase II or III in development and aim to inhibit multiple aspects of the EGFR signaling pathway. These therapies can target additional users of the RTK family through multitargeted TKIs or mAbs, inhibition of parallel Rabbit Polyclonal to MIPT3 pathways, or impact downstream signaling cascades. Lapatinib, afatinib, and S-8921 dacomitinib are solitary agent TKIs that target both EGFR and additional ErbB family receptors . Lapatinib is definitely a dual inhibitor of EGFR and HER2, and it has been studied in conjunction with chemoradiotherapy (CRT) in either LA or S-8921 RM SCCHN. A phase II study in therapy-na?ve LA SCCHN suggested lapatinib had an ORR of 17% when used prior to CRT . However, more recent studies shown no response, no matter prior EGFR inhibition with stable disease as the best response . A phase II study assessed capecitabine and lapatinib as 1st collection therapies for RM SCCHN. Although the study met the primary endpoint of an OS of 9.3 months, the S-8921 authors did not believe this response rate was due to lapatinib as only two individuals overexpressed HER2, and progression free survival (PFS) curves matched previously reported data of capecitabine alone . A phase III trial with adjuvant lapatinib and concurrent CRT followed by maintenance lapatinib in stage II to IVA SCCHN in high-risk surgically resected individuals failed to display additional survival benefits and was associated with higher toxicity compared to placebo . Afatinib is an irreversible inhibitor of EGFR, HER2, and HER4 therefore inhibiting most homo-heterodimerization of the ErbB family receptors. In preclinical data, afatinib offers shown a dose-dependent antiproliferative effect, a slight improvement of radiosensitivity in in-vitro cells, and significant tumor growth delay with daily administration . It has shown similar activity to cetuximab in RM SCCHN, with continued benefit after crossover suggesting minimal cross-resistance . To further assess this the LUX-Head and Neck 2 study examined adjuvant afatinib after total response from CRT and found no benefit in disease-free survival compared to placebo in individuals with unresected, intermediate to high risk SCCHN . Ongoing studies in LA SCCHN include dual inhibition such as afatinib and cetuximab or afatinib with pembrolizumab (Table 1). Table 1 Current ongoing tests for EGFR inhibition in definitive disease. = 0.08) and no improvement in PFS demonstrating the need for further investigation in this area . Table 1 lists current ongoing or unpublished tests with EGFR inhibition in locally advanced disease. 7. Part of EGFR Inhibition in Recurrent Metastatic Disease in SCCHN Despite the vast number of completed and ongoing studies aiming to target EGFR and additional downstream signaling pathways, cetuximab remains the only FDA authorized EGFR targeted mAb for the treatment of SCCHN..