HCC represents one of the most challenging cancers. The rationale for this study was based on the demonstration of a role for EGFR and HER2/NEU signaling pathways in the carcinogenesis of HCC.
Results from this study revealed minimal activity of lapatinib as a single agent in treating patients with advanced HCC based on the lack of objective responses, the primary endpoint of the study. The choice of this primary endpoint may not have been optimal given the difficulty in assessing disease response by RECIST criteria38
. However, the lack of activity of lapatinib is also supported by the short mPFS and relatively modest proportion of patients with stable disease. Sorafenib had a reported ORR of 2.3%39
. However, the median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group. Other studies examining the role of EGFR inhibitors reported ORR ranges of 0–9% (16,27
). In our study, we reported a mPFS of 1.9 months consistent with that reported from another study with lapatinib in HCC41
. This uninteresting mPFS could be confounded by factors such as inclusion of patients with Child’s Pugh score B (27%) and prior therapy in 19 % of patients. mOS with lapatinib was one of the highest reported in the literature. This may be partly explained by the use of sorafenib following progression in 40% of our patients, an agent with a known survival advantage in HCC39
. Also noted, and similar to an effect which has been observed with EGFR inhibitors in a variety of other malignancies 15,43,44
, was that survival was significantly improved in the subgroup of patients who developed a rash. This improvement in survival does not seem to be confounded by therapy beyond progression since 38% of patients who developed a rash received sorafenib vs. 54% in those who did not have a rash. This finding suggests a potential benefit from EGFR inhibition but development of rash may also be prognostic (i.e. patients able to develop rash may have a more favorable outcome regardless of the activity of the agent).
Phase II Trials of EGFR Targeted Agents in HCC
Another interesting observation from our study is that 3 out of the 4 patients with AFP lower than ULN (AFP-negative) had stable disease longer than 4 months including the only 2 patients with disease control longer than 12 months. Improved survival has been previously reported in patients with HCC whose AFP was normal when compared to those with elevated serum marker levels 45,46
. This prognostic finding may be related to the background liver disease for most patients with HCC and the prevalence of Child’s Pugh score A seems to be higher in AFP-negative tumors45
. Indeed, our AFP-negative patients were all found to have more favorable Child’s Pugh scores (All 4 had a CP score of 5). It is unclear whether there is any added benefit in those patients from EGFR inhibition, and this question should be addressed in future randomized studies.
Interestingly, mPFS trended to be higher in patients with HCV although the differences in PFS and OS curves were not statistically significant with lapatinib when compared to the general population unlike what was noted in patients receiving sorafenib37,47
The drug was overall well tolerated with only 12% of patients requiring a dose reduction. The toxicity to lapatinib was predominantly gastrointestinal followed by cutaneous similar to other drugs that target EGFR/HER1. Of note, patients with Child’s Pugh B (7) did not have any worse toxicity than those with Child’s Pugh A (5 and 6).
We also performed a set of accompanying correlative studies of relevance to the targeted pathways. A strength of our study is the acquisition of tissue in > 90% of all patients enrolled. Similar to our previous findings24
, we found no activating EGFR
mutations on this study. However, unlike our previous published findings24
, we found no activating somatic mutations in HER2/NEU
. In addition, HER2/NEU
copy number was not found to be elevated in our analysis using FISH (nor protein expression by IHC staining). Based on these observations, therefore, dual-specificity EGFR-TKIs may in fact be predicted to not be more efficacious than EGFR-TKI. We chose to examine PTEN and the AKT signaling pathway as there has been ample evidence in other solid tumors that loss of normal PTEN function or activation of the AKT pathway would predict for resistance to EGFR-TKIs even in the context of EGRF
. However, levels of PTEN, P-AKT and P70S6K, did not correlate with progression free survival or overall survival in the current study. As part of prioritizing the correlative studies we performed, we decided not to include EGFR expression levels or to look for KRAS
mutations. EGFR expression has been documented in multiple studies to occur at high levels in HCC and did not seem to correlate with response14–16
. Somatic mutations in the genes encoding the molecules in the KRAS pathway are rarely seen in HCC47
and do not seem to have a predictive role for EGFR inhibition in this disease49
In conclusion, dual EGFR inhibition with lapatinib has minimal activity in HCC, although certain subgroups of patients (such as those who developed a rash, an effect attributable to EGFR/HER1 inhibition) had a more favorable outcome when compared to the overall study population. As such, results from this trial and others () encourage the continued development of a strategy to target EGFR-TK blockade as a single modality or preferably in combination (with VEGF or mTOR inhibitors) for treating HCC. Although our attempt to identify molecular or genetic predictors of a more favorable outcome was unsuccessful, enrichment strategies must continue to be investigated to achieve similar results to those in lung and colon cancer. Two possible mechanisms for EGFR inhibitor-related skin toxicity have been previously postulated. The first (likely) is more straightforward and relates to direct inhibition of cutaneous EGFR. The other (unlikely) relates the development of a rash as a manifestation to a systemic immunologic reaction50
. Since HCC is a heterogeneous disease with multiple redundant signaling pathways and etiologies, the role of certain pathways may be different in various subgroups (HCV, for example). Future studies should consider a randomized approach with appropriate stratifications (by Child’s Pugh score, AFP levels, presumed etiology of HCC etc…).
Statement of Translational Relevance
The rationale for this study was based on the demonstration of a role for EGFR and HER2/NEU signaling pathways in the carcinogenesis of HCC. Lapatinib appears to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully characterized. For example, we found that although dual EGFR inhibition has minimal activity in HCC, certain subgroups of patients such as those who developed a rash, an effect attributable to EGFR/HER1 inhibition, had a significantly more favorable outcome when compared to the overall study population. This finding suggests a potential benefit from EGFR inhibition.. Other considerations from our results include findings that suggest that future studies should consider a randomized approach with appropriate stratifications (AFP levels, etiology etc…). Final results of accompanying correlative studies are also presented.