- The phase 2 I-SPY2 trial:
- Is the first to study combination therapy with:
- Oral paclitaxel, carboplatin, and the PD-1 inhibitor dostarlimab in early triple-negative breast cancer
- Among 56 patients with triple-negative breast cancer:
- This combination therapy was found to be safe and moderately effective:
- Demonstrating an estimated pathologic complete response rate of 48%
- This combination therapy was found to be safe and moderately effective:
- Results are preliminary:
- Further investigation is needed before implementing in clinical practice
- Is the first to study combination therapy with:
- The phase 2 I-SPY2 trial found that patients with triple-negative breast cancer:
- Who received the novel combination of oral paclitaxel, carboplatin, and the PD-1 inhibitor dostarlimab:
- Demonstrated a higher predicted pathologic complete response (pCR) than control participants
- Furthermore, drug-related adverse events from the novel combination treatment were manageable
- I-SPY2 is the first trial to study combination therapy with oral paclitaxel, carboplatin, and the PD-1 inhibitor dostarlimab in early triple-negative breast cancer
- Who received the novel combination of oral paclitaxel, carboplatin, and the PD-1 inhibitor dostarlimab:
- The findings show that oral paclitaxel, carboplatin, and dostarlimab:
- Can be effective in triple-negative breast cancer:
- Although the estimated pCR rate of 48% is not as high as we anticipated for a triplet-therapy combination that includes a taxane, platinum chemotherapy, and an immune checkpoint inhibitor in this subgroup:
- It may not be ideal to use these as a combination in this setting until further investigation into a larger cohort of patients
- Although the estimated pCR rate of 48% is not as high as we anticipated for a triplet-therapy combination that includes a taxane, platinum chemotherapy, and an immune checkpoint inhibitor in this subgroup:
- Can be effective in triple-negative breast cancer:
- Optimizing Oral Chemotherap:
- Intravenous (IV) taxane therapy, including with paclitaxel:
- Is highly effective in high-risk breast cancer
- To date, oral paclitaxel in combination with other treatments, such as immunotherapy:
- Has yet to demonstrate similar benefits as the IV formulation but could represent a desirable treatment option that allows patients to use at-home administration and avoid needle sticks:
- There are also some favorable side-effect profiles of oral paclitaxel compared to IV paclitaxel:
- Less peripheral neuropathy and alopecia:
- Which can impact quality of life
- Less peripheral neuropathy and alopecia:
- Intravenous (IV) taxane therapy, including with paclitaxel:
- Findings from a recent phase 3, head-to-head comparison of oral paclitaxel with IV paclitaxel have opened the door to new questions about whether an oral formulation can be optimized in combination with other treatments:
- In that study, investigators observed a higher confirmed tumor response with oral paclitaxel and a numerically (although not statistically) higher progression-free and overall survival than with IV paclitaxel
- In the phase 3 trial that compared oral paclitaxel to IV paclitaxel:
- The overall risk–benefit ratio of oral paclitaxel over IV paclitaxel was questionable:
- The U.S. Food and Drug Administration [FDA] did not approve oral paclitaxel due to concerns regarding 19-week objective response rate per blinded independent central review, where a reread of data may have brought on unmeasured bias
- In addition, FDA cited febrile neutropenia as a safety concern
- The overall risk–benefit ratio of oral paclitaxel over IV paclitaxel was questionable:
- In the I-SPY2 study, compared with IV paclitaxel:
- Oral paclitaxel caused less peripheral neuropathy;
- But led to increased rates of nausea, diarrhea, neutropenia, anemia, and urinary tract infections
- Oral paclitaxel caused less peripheral neuropathy;
- In an effort to identify optimal treatment options, the ongoing I-SPY2 trial is investigating the efficacy of several experimental therapies for early-stage breast cancer with a high risk of recurrence, including a combination treatment featuring oral paclitaxel
- Multiple investigational arms are assessed in parallel, using neoadjuvant chemotherapy plus an investigational drug (the treatment arm) versus neoadjuvant chemotherapy alone (the control arm):
- The primary endpoint is pCR
- Biomarker assessments performed at baseline are used to classify patients into 1 of 10 predefined signature subtypes:
- Based on hormone receptor (HR), erbB-2 receptor, and MammaPrint status
- Adaptative randomization in I-SPY2 preferentially assigns patients to new or standard regimens based on Bayesian predictive probabilities of rates of pCR for each subtype
- Regimens that demonstrate a high predictive probability of being statistically superior to standard treatment in at least 1 of 10 predefined signatures in a hypothetical phase 3 confirmatory trial “graduate” from the study
- In the analysis women with early-stage breast cancer:
- Considered high risk based on HR, erbB-2 receptor, and MammaPrint status were randomly assigned to the control group or experimental treatment
- The experimental arm received oral paclitaxel plus encequidar (which is required for the body to absorb oral paclitaxel) followed by carboplatin and dostarlimab and then chemotherapy with doxorubicin / cyclophosphamide
- The control arm received paclitaxel plus doxorubicin /cyclophosphamide
- Patients with HER2-positive disease also received trastuzumab during the first 12 weeks of the study
- In the 106 randomly assigned patients, 44 had HR-positive/HER2-negative disease, 56 had triple-negative breast cancer, and 6 had HER2-positive breast cancer
- Among the 10 predefined biomarker signatures in which the treatment regimen was assessed, it was most successful in the triple-negative signature:
- In this group, the treatment had a predicted pCR of 48% versus 29% in the control arm, causing the experimental treatment to “graduate” from the study:
- This is the first study to combine an oral taxane with an immune checkpoint inhibitor
- It demonstrated that the combination of oral chemotherapy and dostarlimab is safe and feasible
- The combination of chemotherapy and dostarlimab can be potentially effective in triple-negative breast cancer
- The effectiveness of oral paclitaxel plus encequidar was comparable to that of IV paclitaxel and with lower rates of neuropathy and alopecia than with the IV treatment:
- Suggesting this oral agent may be an attractive alternative to IV paclitaxel to be used as single agent
- In this group, the treatment had a predicted pCR of 48% versus 29% in the control arm, causing the experimental treatment to “graduate” from the study:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 