Allosteric AKT Inhibitor and Trastuzumab in HER2+ Tumors
Trastuzumab is effective therapy for HER2+ breast cancers and gastric cancers. However, relative resistance to trastuzumab is common via multiple mechanisms. Through unbiased RNA interference screening analyses, activation of the PI3K pathway has been implicated as a major mediator of trastuzumab resistance. Based on these data and preclinical findings that HER2 signaling is highly dependent on PI3K/AKT signaling, we hypothesized that tumors could have compensatory activation of this pathway, thereby avoiding the impact of HER2 inhibitors. To begin clinical exploration of combined HER2 and AKT signaling blockade, we evaluated treatment with trastuzumab and the allosteric AKT inhibitor MK-2206 in this phase 1 study. Previously, monotherapy with MK-2206 given either QOD or QW was tolerable, leading us to examine both dosing schedules combined with trastuzumab. The majority of patients enrolled in the study had exposure to trastuzumab and had progressed on treatment. Our study demonstrated that the combination of trastuzumab and MK-2206 was as tolerable as the same dosing schedule using MK-2206 monotherapy, with no evidence of enhanced toxicities with combined therapy. A true MTD for MK-2206 in combination with trastuzumab was not established, but the 60 mg QOD and 135 mg QW doses are reasonable doses for future evaluation in phase 2 trials. The pharmacokinetic profile of MK-2206 in this study was similar to that observed when MK-2206 was administered as monotherapy. In addition, the DLT of the combination therapy was skin rash, which was the same as the DLT of MK-2206 given as monotherapy. Other observed AEs were also consistent with those of MK-2206 single-agent therapy.
The combination of MK-2206 and trastuzumab also demonstrated preliminary evidence of therapeutic efficacy in patients with HER2+ breast cancer or gastroesophageal cancer, with a clinical benefit response rate of approximately 24% and a median time to progression of 72 days. One patient with metastatic breast cancer, whose disease progressed on the right chest wall around the previous mastectomy scar while on maintenance therapy with trastuzumab, achieved CR following combination therapy with MK-2206. Her erythematous chest wall skin lesion showed a dramatic improvement after receiving two cycles of study treatment and by 6 months the skin lesion had completely resolved. There was one additional patient with breast cancer treated for over a year experiencing a total reduction in tumor size of 68% who was confirmed as having PR. Five more patients had SD for more than 4 months. These preliminary efficacy results suggest that the combination of MK-2206 with trastuzumab may offer patients an effective salvage regimen following progression on trastuzumab, or may prevent or delay clinical resistance if used earlier in the disease.
The efficacy observed in this phase 1 study supports the hypothesis that a mechanism of resistance to trastuzumab may be mediated by activation of the PI3K/AKT pathway in vivo. The mechanisms through which the PI3K/AKT pathway may be activated in trastuzumab-refractory HER2+ tumors is currently unknown. Leading candidates include activating mutations of the PIK3CA gene or deletion or mutations in PTEN, an inhibitor of the PI3K/AKT pathway. We collected circulating nucleic acid to explore this possibility, based on reports that correlated findings in circulating nucleic acid with DNA from tumor specimens. Only three patients were found to have mutations in the PIK3CA gene in circulating DNA and none had notably long SD or response to treatment. No PIK3CA mutation was detected in the circulating nucleic acid samples from patients who responded to treatment. Studies have estimated that between 13 and 31% of HER2+ breast cancers harbor mutations in PIK3CA. Results of PIK3CA mutation status from circulating DNA in this study (two of 27 HER2+ breast cancer patients who received treatment) are at the lower limit of these estimations. One of the limitations of this analysis is that our PIK3CA mutation assessment was restricted to circulating DNA analysis. Tumor biopsies for biomarker analysis prior to treatment were not mandated and intratumor heterogeneity in PIK3CA mutation status or limitations of detection inherent to circulating DNA mutational analysis may be responsible for the lower than expected PIK3CA mutational frequency observed. The possibility therefore remains that tumor samples at primary or metastatic sites might demonstrate mutations that do not appear in circulating nucleic acid.
Despite these caveats, our analysis of the circulating DNA PIK3CA somatic mutation status does not support the hypothesis that tumors with PIK3CA mutations have improved responsiveness to MK-2206. Conceivably, other molecular aberrations such as p95HER2, PTEN loss of function events or alternative signaling cascades mediated by HER3, and insulin growth factor-1 receptors or epidermal growth factor receptors that were not assessed in our study, may also be predicted to render tumors resistant to trastuzumab but sensitive to combined AKT inhibition. Therefore, in an attempt to predict preferential benefit from combined AKT inhibitor/trastuzumab therapy, exploratory biomarker analyses may need to consider the polygenic nature of trastuzumab resistance and assess multiple aberrations in the HER2 signaling pathway in each tumor. This finding is consistent with the recent report of the combination of trastuzumab and everolimus, a mammalian target of rapamycin inhibitor. In that study, tumors demonstrating loss of PTEN were associated with poorer overall survival, although loss of PTEN and/or PI3KCA mutations did not seem to affect progression-free survival, compared with those without genetic alterations. Additional studies are needed to generate more data to fully determine the potential role of circulating DNA mutations as predictors of drug sensitivity in this population.
Numerous agents specifically targeting dysregulated molecular pathways, believed to be key tumorigenic drivers, have recently been approved or are being evaluated as potential treatment options in patients with breast cancer or other tumor types. Combined antibody therapy, using both trastuzumab and chemotherapy with or without pertuzumab, was recently shown to be effective. However, nonchemotherapeutic approaches are attractive because they promise reduced toxicity. For example, a phase 3 trial evaluated the combination of trastuzumab and the small molecule, reversible inhibitor of epidermal growth factor receptor and HER2, lapatinib, in HER2+ metastatic breast cancer patients refractory to trastuzumab administered in the absence of chemotherapy. Results from this trial, which enrolled 296 patients, demonstrated improvements in overall survival, progression-free survival and clinical benefit response in the combination arm compared with treatment with lapatinib alone. However, the difference in median progression-free survival – specifically between the two treatment arms – was only 4 weeks (12.0 weeks in the combination group vs. 8.1 weeks in the lapatinib monotherapy group), and the majority of patients did not achieve a dramatic improvement in tumor response rate or survival, suggesting that the combined blockade of HER2 signaling is active even without chemotherapy, but may not be sufficient to overcome downstream PI3K/AKT pathways responsible for resistance to trastuzumab.
Based on results from our phase 1 study, we believe that additional translational studies of MK-2206 with trastuzumab and possibly other agents including pan-HER kinase inhibitors (for example, lapatinib or neratinib) or broad cytotoxic agents (for example, paclitaxel) are warranted. Treatment with MK-2206 has been shown to upregulate HER3 via feedback mechanisms limiting antitumor effects, which could be rescued by the addition of lapatinib. Early phase clinical trials are already underway investigating the combination of MK-2206 and lapatinib in patients with advanced or metastatic solid tumors or breast cancer.
Discussion
Trastuzumab is effective therapy for HER2+ breast cancers and gastric cancers. However, relative resistance to trastuzumab is common via multiple mechanisms. Through unbiased RNA interference screening analyses, activation of the PI3K pathway has been implicated as a major mediator of trastuzumab resistance. Based on these data and preclinical findings that HER2 signaling is highly dependent on PI3K/AKT signaling, we hypothesized that tumors could have compensatory activation of this pathway, thereby avoiding the impact of HER2 inhibitors. To begin clinical exploration of combined HER2 and AKT signaling blockade, we evaluated treatment with trastuzumab and the allosteric AKT inhibitor MK-2206 in this phase 1 study. Previously, monotherapy with MK-2206 given either QOD or QW was tolerable, leading us to examine both dosing schedules combined with trastuzumab. The majority of patients enrolled in the study had exposure to trastuzumab and had progressed on treatment. Our study demonstrated that the combination of trastuzumab and MK-2206 was as tolerable as the same dosing schedule using MK-2206 monotherapy, with no evidence of enhanced toxicities with combined therapy. A true MTD for MK-2206 in combination with trastuzumab was not established, but the 60 mg QOD and 135 mg QW doses are reasonable doses for future evaluation in phase 2 trials. The pharmacokinetic profile of MK-2206 in this study was similar to that observed when MK-2206 was administered as monotherapy. In addition, the DLT of the combination therapy was skin rash, which was the same as the DLT of MK-2206 given as monotherapy. Other observed AEs were also consistent with those of MK-2206 single-agent therapy.
The combination of MK-2206 and trastuzumab also demonstrated preliminary evidence of therapeutic efficacy in patients with HER2+ breast cancer or gastroesophageal cancer, with a clinical benefit response rate of approximately 24% and a median time to progression of 72 days. One patient with metastatic breast cancer, whose disease progressed on the right chest wall around the previous mastectomy scar while on maintenance therapy with trastuzumab, achieved CR following combination therapy with MK-2206. Her erythematous chest wall skin lesion showed a dramatic improvement after receiving two cycles of study treatment and by 6 months the skin lesion had completely resolved. There was one additional patient with breast cancer treated for over a year experiencing a total reduction in tumor size of 68% who was confirmed as having PR. Five more patients had SD for more than 4 months. These preliminary efficacy results suggest that the combination of MK-2206 with trastuzumab may offer patients an effective salvage regimen following progression on trastuzumab, or may prevent or delay clinical resistance if used earlier in the disease.
The efficacy observed in this phase 1 study supports the hypothesis that a mechanism of resistance to trastuzumab may be mediated by activation of the PI3K/AKT pathway in vivo. The mechanisms through which the PI3K/AKT pathway may be activated in trastuzumab-refractory HER2+ tumors is currently unknown. Leading candidates include activating mutations of the PIK3CA gene or deletion or mutations in PTEN, an inhibitor of the PI3K/AKT pathway. We collected circulating nucleic acid to explore this possibility, based on reports that correlated findings in circulating nucleic acid with DNA from tumor specimens. Only three patients were found to have mutations in the PIK3CA gene in circulating DNA and none had notably long SD or response to treatment. No PIK3CA mutation was detected in the circulating nucleic acid samples from patients who responded to treatment. Studies have estimated that between 13 and 31% of HER2+ breast cancers harbor mutations in PIK3CA. Results of PIK3CA mutation status from circulating DNA in this study (two of 27 HER2+ breast cancer patients who received treatment) are at the lower limit of these estimations. One of the limitations of this analysis is that our PIK3CA mutation assessment was restricted to circulating DNA analysis. Tumor biopsies for biomarker analysis prior to treatment were not mandated and intratumor heterogeneity in PIK3CA mutation status or limitations of detection inherent to circulating DNA mutational analysis may be responsible for the lower than expected PIK3CA mutational frequency observed. The possibility therefore remains that tumor samples at primary or metastatic sites might demonstrate mutations that do not appear in circulating nucleic acid.
Despite these caveats, our analysis of the circulating DNA PIK3CA somatic mutation status does not support the hypothesis that tumors with PIK3CA mutations have improved responsiveness to MK-2206. Conceivably, other molecular aberrations such as p95HER2, PTEN loss of function events or alternative signaling cascades mediated by HER3, and insulin growth factor-1 receptors or epidermal growth factor receptors that were not assessed in our study, may also be predicted to render tumors resistant to trastuzumab but sensitive to combined AKT inhibition. Therefore, in an attempt to predict preferential benefit from combined AKT inhibitor/trastuzumab therapy, exploratory biomarker analyses may need to consider the polygenic nature of trastuzumab resistance and assess multiple aberrations in the HER2 signaling pathway in each tumor. This finding is consistent with the recent report of the combination of trastuzumab and everolimus, a mammalian target of rapamycin inhibitor. In that study, tumors demonstrating loss of PTEN were associated with poorer overall survival, although loss of PTEN and/or PI3KCA mutations did not seem to affect progression-free survival, compared with those without genetic alterations. Additional studies are needed to generate more data to fully determine the potential role of circulating DNA mutations as predictors of drug sensitivity in this population.
Numerous agents specifically targeting dysregulated molecular pathways, believed to be key tumorigenic drivers, have recently been approved or are being evaluated as potential treatment options in patients with breast cancer or other tumor types. Combined antibody therapy, using both trastuzumab and chemotherapy with or without pertuzumab, was recently shown to be effective. However, nonchemotherapeutic approaches are attractive because they promise reduced toxicity. For example, a phase 3 trial evaluated the combination of trastuzumab and the small molecule, reversible inhibitor of epidermal growth factor receptor and HER2, lapatinib, in HER2+ metastatic breast cancer patients refractory to trastuzumab administered in the absence of chemotherapy. Results from this trial, which enrolled 296 patients, demonstrated improvements in overall survival, progression-free survival and clinical benefit response in the combination arm compared with treatment with lapatinib alone. However, the difference in median progression-free survival – specifically between the two treatment arms – was only 4 weeks (12.0 weeks in the combination group vs. 8.1 weeks in the lapatinib monotherapy group), and the majority of patients did not achieve a dramatic improvement in tumor response rate or survival, suggesting that the combined blockade of HER2 signaling is active even without chemotherapy, but may not be sufficient to overcome downstream PI3K/AKT pathways responsible for resistance to trastuzumab.
Based on results from our phase 1 study, we believe that additional translational studies of MK-2206 with trastuzumab and possibly other agents including pan-HER kinase inhibitors (for example, lapatinib or neratinib) or broad cytotoxic agents (for example, paclitaxel) are warranted. Treatment with MK-2206 has been shown to upregulate HER3 via feedback mechanisms limiting antitumor effects, which could be rescued by the addition of lapatinib. Early phase clinical trials are already underway investigating the combination of MK-2206 and lapatinib in patients with advanced or metastatic solid tumors or breast cancer.
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