Targeted PI3K/AKT/mTOR therapy for metastatic carcinomas of the cervix: A phase I clinical experience

Abstract

Background: Activated PI3K/AKT/mTOR pathway frequently occurs in metastatic or recurrent cervical carcinomas. However, the clinical benefits of matched therapy, a therapeutic approach targeting a specific mutational abnormality, have not yet been established.

Methods: We analyzed the outcomes of patients with metastatic or recurrent cervical carcinomas who had a test for PIK3CA mutation and/or PTEN loss/mutation, and received ≥1 phase I therapeutic regimen between January 2006 and June 2013.

Results: Patients with adenocarcinoma had fewer PIK3CA mutations (14%), and survived longer (median, 14.2 months) than those with squamous cell carcinoma (48% and 7.2 months; p = 0.016, and 0.001, respectively). Matched therapy targeting the activated PI3K/AKT/mTOR pathway led to a favorable rate of SD ≥ 6 months/CR/PR (53%) and significantly longer progression-free survival (median, 6.0 months) than non-matched therapy (11% and 1.5 months; p = 0.08 and 0.026; respectively). In patients with squamous cell carcinoma of the cervix, the presence of PIK3CA mutations was associated with a significantly longer overall survival (median, 9.4 months) than the absence of PIK3CA mutations (median, 4.2 months; p = 0.019).

Conclusions: Matched therapy targeting the activated PI3K/AKT/mTOR pathway provided meaningful clinical benefits. Thus, further evaluation of PI3K/AKT/mTOR pathway targeted therapy is warranted, especially in metastatic or recurrent squamous cell carcinoma.

Figure 1. The waterfall plot shows the best tumor response to their initial phase I clinical trial therapy (n = 55)

Figure 2. Kaplan-Meier plots for survivals

In Figure 2A, a median OS of 9.1 months (95% CI, 7.1–11.1, in green) and a median PFS of 3.6 months (95% CI, 2.3–5.0, in blue) were observed in patients with metastatic or recurrent cervical carcinomas (n = 55). In Figure 2B, patients with adenocarcinoma (in green) showed a median OS of 14.2 months (n = 24; 95% CI, 7.8–20.6), significantly longer those with squamous cell carcinoma (in blue), 7.2 months (n = 31; 95% CI, 5.3–9.1; p = 0.001).

Figure 3. Kaplan-Meier plots for survivals

In Figure 3A, match therapy (in green) was associated with a median PFS of 6.0 months (n = 15; 95% CI, 3.2–8.8), significantly greater than non-matched therapy (in blue) with 1.5 months (n = 9; 95% CI, 1.2–1.8; p = 0.026). In Figure 3B, matched therapy (in green) was associated with a median OS of 10.1 months (n = 15; 95% CI, 5.9–14.3), compared to non-matched therapy (in blue) with 7.7 months (n = 9; 95% CI, 1.6–13.8; p = 0.427).

Figure 4. Kaplan-Meier plots for survivals

In Figure 4A for in patients with squamous cell carcinoma, PI3KCA mutations (in green) were associated with a median OS of 9.4 months (n = 14; 95% CI, 8.1–10.7), significantly longer than wild-type PI3KCA (in blue) with 4.2 months (n = 15; 95% CI, 2.2–6.2; p = 0.019). In Figure 4B for patients with adenocarcinoma, PI3KCA mutations (in green) were associated with a median OS of 19.4 months (n = 3; 95% CI, 0–43.6), compared to wild-type PI3KCA (in blue) with 14.2 months (n = 19; 95% CI, 4–24.4; p = 0.754).

Figure 5. Kaplan-Meier plots for survivals

In Figure 5A for in patients with squamous cell carcinoma, PTEN aberrations (in green) were associated with a median OS of 6 months (n=3; 95% CI, 2–10), similar to PTEN intact (in blue) with 7 months (n = 21; 95% CI, 3.1–10.9; p = 0.762). In Figure 5B for patients with adenocarcinoma, PTEN aberrations (in green) were associated with a median OS of 11.3 months (n = 4; 95% CI, 0–22.6), similar to PTEN intact (in blue) with 15.7 months (n = 16; 95% CI, 7.1–24.3; p = 0.791).