Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Colorectal, Non-small Cell Lung and Pancreatic Cancer

Summary: This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib; and PART B - a randomized phase II study investigating the progression free survival and safety of selumetinib/afatinib combination therapy compared to standard of care chemotherapy.

Detailed description: In a pre-clinical study, treatment of KRAS mutant (KRASm) colorectal cancer (CRC) cell lines with an inhibitor of multiple epidermal growth factor receptor (ErBb) kinases in combination with a MEK-inhibitor resulted in synthetic lethality. MEK inhibition alone in these cells resulted in a strong feedback activation of human epidermal growth factor receptors (HER)2 and HER3 after about 48 hours. This enables the formation of activating complexes with other ErbB family members such as EGFR, causing primary resistance via subsequent activation of the phosphoinositide 3-kinase (PI3K) pathway. Concomitant treatment with a MEK inhibitor and a multiple inhibitor of ErBbs completely suppressed this feedback activation and resulted in cell death. Among various combinations, the combination of afatinib, an irreversible EGFR/HER2/HER4 inhibitor, and selumetinib, a MEK inhibitor, showed the strongest response in these cell lines by synergistic induction of apoptosis. This effect was observed both after concomitant use and after intermittent exposure to afatinib starting 48 hours after start of exposure to selumetinib. In addition to these observations in KRASm CRC cell lines, the anti-tumor activity of this combination was confirmed in cell lines derived from KRASm non-small cell lung cancer (NSCLC) and in xenografts in mice with KRASm NSCLC cells.
  Because of the histology-independent activity of this concept and the similarities in cancer cells at a molecular level, the combination of afatinib and selumetinib is likely to be effective in pancreatic cancer as well. Enhanced antitumor activity of the combination of a MEK and an EGFR inhibitor has already been established in pancreatic cancer cell lines in vitro. Therefore it is plausible that the combination of a MEK inhibitor with a multiple epidermal growth factor receptor inhibitor will have enhanced efficacy in KRASm driven and PIK3CA wildtype pancreatic cancer in patients as well. Hence, there is a strong rationale for combining afatinib and selumetinib in patients with KRASm and PIK3CA wildtype (wt) CRC, NSCLC, or pancreatic cancer.

Eligibility: Inclusion Criteria:
  -  Histological or cytological proof of advanced CRC, NSCLC or pancreatic cancer; for PART B: treated with first line therapy for metastatic disease only.
  -  Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (defined as absence of mutations in exon 9 and 20)
  -  Able and willing to give written informed consent
  -  Able and willing to undergo blood sampling for PK and PD analysis
  -  Life expectancy >=3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
  -  WHO performance status of 0 or 1.
  -  Able and willing to undergo a tumor biopsies prior to start, after two weeks (part A only) and upon progression of disease
  -  Measurable disease according to RECIST 1.1
  -  Adequate organ system function measured by laboratory values
  Exclusion Criteria:
  -  Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
  -  History of another malignancy Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies are eligible. Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin. 3. Symptomatic or untreated leptomeningeal disease.
  -  Symptomatic brain metastasis.
  -  Patients previously treated with any drug combination known to interfere with EGFR, HER2, HER3, HER4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK.
  -  History of interstitial lung disease or pneumonitis
  -  Radio-, immuno- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed.
  -  Opthalmological diseases
  -  Patients with left ventricular ejection fraction (LVEF) < 55%
  -  Patients with cardiac comorbidities
  -  Concomitant or recent use (in the past 14 days) of strong inhibitors and inducers of CYP1A2, CYP2C19, CYP3A4, 3A5 and P-glycoprotein (P-gp)

Relevance to patient case: not relevant