Molecular Markers and Targeted Therapies in the Management of Non-Small Cell Lung Cancer
CASE 1 CONTINUED
Based on the EGFR L858R mutation status, the patient is started on erlotinib. He is quite happy that he does not need intravenous chemotherapy but wants to know what toxicities he might potentially have with erlotinib.
What are the common adverse effects (AEs) of EGFR TKIs? How are AEs of TKIs managed?
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Safety Profile
The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity. Rash is an AE specific to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab. The epidermis has a high level of expression of EGFR, which contributes to this toxicity.51 Rash usually presents as dry skin or acneiform eruption. Prophylactic treatment with oral tetracyclines and topical corticosteroids is generally recommended upon initiation of TKI therapy. Diarrhea is the most prevalent gastrointestinal toxicity. All patients starting treatment should be given prescriptions to manage diarrhea such as loperamide and be advised to call when it occurs. Hepatic toxicity is often manifested as elevated transaminases or bilirubin. Interstitial lung disease (ILD) is a rare but potentially fatal pulmonary toxicity.
Rash of any grade was reported in 49.2% of patients treated with erlotinib in clinical trials, while grade 3 rash occurred in 6% of patients and no grade 4 was reported. Diarrhea of any grade was reported in 20.3% of patients, grade 3 diarrhea occurred in 1.8%, and no grade 4 was reported. Grade 2 and 3 alanine aminotransferase (ALT) elevations were seen in 2% and 1% of patients, respectively. Grade 2 and 3 bilirubin elevations were seen in 4% and less than 1% of patients, respectively. The incidence of serious ILD-like events was less than 1%.52
Afatinib is associated with higher incidences of rash and diarrhea. Specifically, diarrhea and rash of all grades were reported in 96% and 90% of patients treated with afatinib, respectively. Paronychia of all grades occurred in 58% of patients. Elevated ALT of all grades was seen in 11% of patients. Approximately 1.5% of patients treated with afatinib across clinical trials had ILD or ILD-like AEs.53
Gefitinib, the most commonly used TKI outside United States, has a toxicity profile similar to erlotinib, except for hepatic toxicity. For instance, rash of all grades occurred in 47% of patients, diarrhea of all grades occurred in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials. In comparison, elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.54 Therefore, close monitoring of liver function is clinically warranted. In particular, patients need to be advised to avoid concomitant use of herbal supplements, a common practice in Asian countries.
CASE 1 CONTINUED
The patient does well while on erlotinib at 150 mg orally once daily for about 8 months, until he develops increasing abdominal pain. A CT scan of the abdomen and pelvis with contrast shows a new 8-cm right adrenal mass. Additionally, a repeat CT scan of the chest with contrast shows a stable lung mass but enlarging mediastinal lymphadenopathy.
How would you manage the patient at this point?
MANAGEMENT OF T790M MUTATION AFTER PROGRESSION ON FIRST-LINE EGFR TKIS
As mentioned above, the median PFS of patients with EGFR mutations treated with 1 of the 3 TKIs is around 9 to 13 months.46 Of the various resistance mechanisms that have been described, the T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.55,56 Other mechanisms, such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.56 The first- and second-generation EGFR TKIs function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways (Figure, part B) and ultimately cell death.35 The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.57,58
Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations. It has low affinity for wide-type EGFR as well as insulin receptor and insulin-like growth factor receptor.59 Osimertinib has been fully approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation. An international phase 3 trial (AURA3) randomly assigned 419 patients in a 2:1 ratio to either osimertinib or platinum/pemetrexed. Eligible patients all had the documented EGFR mutations and disease progression after first-line EGFR TKIs. Central confirmation of the T790M mutation was required. Median PFS by investigator assessment, the trial’s primary end point, was 10.1 months for osimertinib versus 4.4 months for chemotherapy (HR 0.3 [95% CI 0.23 to 0.41]; P < 0.001). ORR was 71% for osimertinib versus 31% for chemotherapy (HR 5.39 [95% CI 3.47 to 8.48], P < 0.001). A total of 144 patients with stable and asymptomatic brain metastases were also eligible. Median PFS for this subset of patients treated with osimertinib and chemotherapy was 8.5 months and 4.2 months, respectively (HR 0.32 [95% CI 0.21 to 0.49]). In the AURA3 trial, osimertinib was better tolerated than chemotherapy, with 23% of patients treated with osimertinib experiencing grade 3 or 4 AEs as compared to 47% of chemotherapy-treated patients. The most common AEs of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%).60
For the case patient, a reasonable approach would be to obtain a tissue biopsy of the adrenal mass and more importantly to check for the T790M mutation. Similar to the companion diagnostic for EGFR mutations, the cobas EGFR mutation test v2 is the FDA-approved test for T790M. However, if this resistance mutation is detected by any CLIA-certified laboratories, osimertinib should be the recommended treatment option. If tissue biopsy is not feasible, plasma-based testing should be considered. A blood-based companion diagnostic also is FDA approved.
