- Background: Preclinical data suggest squamous cell tumors, such as SCCHN, are driven by epidermal growth factor receptor (EGFR) overexpression. However, many patients are refractory to anti-EGFR treatment due to intrinsic and acquired resistance. PI3K/AKT/mTOR pathway activation is a potential mechanism of resistance to EGFR-directed therapy. BYL719, a selective α-isoform PI3K inhibitor, enhances cetuximab (EGFR inhibitor) activity in SCCHN cell lines. A Phase Ib/II study combining BYL719 with cetuximab in patients with recurrent/metastatic SCCHN is testing this hypothesis (Razak et al, ASCO 2014, abst 6044; NCT01602315). Here, we outline the preclinical rationale for combining BYL719 with cetuximab in the setting of cetuximab-resistant squamous cell carcinoma, highlight Phase Ib safety and efficacy data in patients with SCCHN who have received prior cetuximab, and describe the design of the Phase II portion of the study, which is assessing both cetuximab-naive and -pretreated patients. Methods: The combination of BYL719 and cetuximab was tested in vivo in two xenograft models of esophageal squamous cell carcinoma: KYSE180 (cetuximab-sensitive model) and KYSE180_CR (cetuximab-resistant, induced by long-term in vivo treatment). In the Phase Ib study, BYL719 was administered once daily (QD) in 28-day cycles with standard weekly (QW) cetuximab (400 mg/m 2 on Cycle 1 Day 1; 250 mg/m 2 QW thereafter) to adults with histologically/cytologically confirmed recurrent/metastatic SCCHN resistant/intolerant to platinum-based chemotherapy (prior cetuximab therapy was allowed). Results: In the KYSE180 model, the addition of BYL719 to cetuximab demonstrated an additive effect leading to tumor regression; furthermore, in the KYSE180_CR model, adding BYL719 to cetuximab completely restored sensitivity and led to similar activity as seen in the cetuximab-sensitive model, suggesting that inhibiting PIK3CA signaling may overcome resistance to cetuximab. In the Phase Ib study, as of March 10, 2014, 37 patients were treated with BYL719 300 mg QD (n=32) or 400 mg QD (n=5) and cetuximab. Frequent adverse events (>30%; all-grade/Grade 3/4) were hyperglycemia (54/24), stomatitis (38/5), and dermatitis acneiform (35/3). Best overall response (BOR) per RECIST v1.1 in the full population (n=37) was 4 partial responses (PRs), 16 stable disease (SD; of which 5 were unconfirmed PRs), 10 unknown (UNK) responses, and 1 non-complete response/non-progressive disease (PD) at 300 mg or 400 mg. Six patients had PD as BOR. The overall response rate (ORR) in the full population was 4/37 (11%) and the disease control rate (DCR) was 20/37 (54%). Within this population, 7 patients had received prior cetuximab therapy (6 in the metastatic/recurrent setting and 1 curative; BOR: 4 SD, 1 PR, 1 PD, and 1 UNK). Of these 7 patients, 1 had a confirmed PR, 2 had unconfirmed PRs, 2 had SD, and 1 had PD with BYL719 and cetuximab. One patient with prior cetuximab therapy had an UNK response due to death from tumor lysis syndrome after 1 week in the study. The ORR among patients with prior cetuximab was 1/7 (14%) and DCR was 5/7 (71%). Phase II tests the combination of BYL719 at the recommended Phase II dose of 300 mg QD in two second-line SCCHN patient populations. Patients who are cetuximab-naive are randomized to cetuximab alone or to BYL719 in combination with cetuximab, while patients who have received cetuximab and platinum therapy in the first-line setting are enrolled in a single arm to receive BYL719 with cetuximab. Conclusion: Combined inhibition of PI3Kα and EGFR by BYL719 and cetuximab, respectively, overcame cetuximab resistance in the preclinical setting, was well tolerated, and demonstrated encouraging antitumor activity in both cetuximab-naive and -pretreated patients with SCCHN. The Phase II part of the study in both patient populations is ongoing. Citation Format: Pamela Munster, Moshe Elkabets, Jill Gilbert, Albiruni R Abdul Razak, Myung-Ju Ahn, Chia-Jui Yen, Se-Hoon Lee, Hung-Ming Wang, Carla van Herpen, Wan-Teck Lim, David Demanse, Rupam Ranjan Pal, Alan Huang, Qing Sheng, Chiara Lambertini, Malte Peters, Christina Coughlin, Maurizio Scaltriti, Jose Baselga, George Blumenschein. Inhibition of PIK3CA with BYL719 can overcome resistance to cetuximab in squamous cell carcinoma of the head and neck (SCCHN). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A46.