E-Newsletter - July 2019
Spotlight on Alliance Trials

Patients with Advanced Cutaneous Squamous Cell Carcinoma of the Skin May Benefit from New Alliance Trial Teaming Immunotherapy and Monoclonal Antibodies

Alliance A091802 - Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma of the Skin (cSCC)

The Alliance trial looks at how well avelumab with or without cetuximab work in treating patients with skin squamous cell cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as avelumab and cetuximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Study Rationale
Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers with an estimated 700,000 new cases diagnosed each year in the United States.[1,2] More than 12,500 patients per year have nodal metastasis and the number of deaths from cSCC per year is upwards of 8,700. Despite the approval of anti-PD-1 mAb cemiplimab, there is still a need for better systemic therapy options for locally advanced cSCC without a surgical option or metastatic disease. IgG1 mAbs can induce the innate immune system through NK cell mediated antibody dependent cellular cytotoxicity (ADCC) and can additionally stimulate adaptive immunity, with pre-clinical synergy observed when combined with anti-PD-1/PD-L1 blockade [3,4]. This forms the basis for this trial which evaluates cetuximab, an IgG1 mAb targeting EGFR with independent activity against advanced cSCC, in combination with anti-PD-L1 mAb avelumab compared to avelumab alone in patients with advanced cSCC. Patients that are randomized to the avelumab alone arm and progress can continue on trial and be treated with combination cetuximab and avelumab.

Study Outcomes
The primary, secondary, and exploratory objectives are described below.

Primary objective:
To evaluate whether treatment with avelumab plus cetuximab prolongs progression free survival (PFS) compared to avelumab alone.

Secondary objectives:

1.    To evaluate the confirmed objective response rate of each treatment arm.

2.    To evaluate the clinical benefit rate of each treatment arm.

3.    To evaluate the PFS of cetuximab plus avelumab in patients that have progressed on single agent avelumab.

4.    To evaluate the overall survival (OS) for each treatment arm.

5.    To evaluate toxicity across treatment arms of avelumab plus cetuximab and avelumab alone.

Key Eligibility Criteria
Some of the eligibility criteria include:

Pre-registration eligibility criteria:
Available sample for PD-L1 testing. Patients will be stratified by PD-L1 status but PD-L1 expression is not required to go on trial.

Registration Eligibility Criteria
-- Biopsy proven advanced cutaneous squamous cell carcinoma. Advanced disease is defined as either metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma not amendable to curative surgical resection, or the patient declines surgical resecton.

-- Measurable lesions by RECIST 1.1

Prior Treatment

-- Patients who received prior treatment with cetuximab as palliative treatment for advanced cSCC are excluded. Patients that received cetuximab based chemoradiation as prior treatment for locally advanced disease are eligible as long as the last dosage was given >6 months prior to registration.

-- Patients who received cetuximab as part of definitive therapy in the adjuvant setting are eligible as long as the last dosage was given > 6 months prior to registration.

-- Patients who received prior cetuximab and had a severe infusion reaction requiring discontinuation of cetuximab are excluded.

-- No prior treatment with anti-PD-1 or anti PD-L1 mAbs

-- Patients cannot have received treatment with radiation or chemotherapy including another investigational agent within 2 weeks of registration. Other than as stated above for cetuximab there are no limits on the number of lines of other therapies given for advanced cSCC. If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

Prior Surgery

-- If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

-- Not pregnant and not nursing

-- Age 18

-- ECOG Performance status 0-2

-- No active second malignancy with the exception of other non-melanoma skin cancers or cervical carcinoma in situ

-- If HIV positive the CD4 count mustbe >200, andHIV viral load <200 copies/mL. If an HIV positive patient is on HAART the patient must have been so for > 4 weeks.

No history of the following:

--Autoimmune disease (including inflammatory bowel disease) with the exception of patients with diabetes type I, vitiligo, psoriasis, or hypo-or hyperthyroid diseases not requiring immunosuppressive treatment.

--Non-infectious pneumonitis that required steroids within 5 years.

--Organ transplant including prior stem cell transplant.

--Receipt of a live vaccine 4 weeks

--No active infection requiring systemic treatment

--No currently active non-infectious pneumonitis

--No use of immunosuppressive medication 7 days of registration

--Chronic concomitant treatment that are strong inhibitors of CYP3A4 are not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study.

Description of Treatment
Patients will be randomized into one of two groups. Those in Group 1 will receive avelumab intravenously once every two weeks (days 1 and 15) in 28-day cycles up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients who fail avelumab will crossover to Group 2. Those patients in Group 2 will receive cetuximab intravenously once a week (days 1, 8,15 and 22) in 28-day cycles up to 12 cycles in combination with avelumab intravenously every two weeks (days 1 and 15) in 28-day cycles up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients will be followed every three months until disease progression, then every six months for up to two years.

Refer to the study protocol, which can be found on the Alliance website at www.AllianceNCTN.org, for complete information on the trial design, treatment plan and patient eligibility.

Study chair: Dan P. Zandberg, MD, University of Pittsburgh Medical Center Hillman Cancer Center
E-mail: zandbergdp@upmc.edu
Activated: 5/17/19
Ststus: Now accepting patients
ClinicalTrials.gov Identifier: NCT03944941


  1. Rogers HW, Weinstock MA, Harris AR et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010; 146: 283-287.
  2. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 2013; 68: 957-966.
  3. Ferris RL, Lenz HJ, Trotta AM et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev 2017; 63: 48-60.
  4. Stagg J, Loi S, Divisekera U et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci U S A 2011; 108: 7142-7147.


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