Blogs

FROM JUNE 7, 2022

Neoadjuvant pembrolizumab is associated with lower residual cancer burden and extended event-free survival

Lajos Pusztai (Yale School of Medicine) presented an exploratory study of event free survival (EFS) by residual cancer burden (RCB) in patients from the KEYNOTE-522 study. The KEYNOTE-522 study consisted of 1174 patients with previously untreated, nonmetastatic, stage T1c/N1-2 or T2-4/N0-2 triple negative breast cancer (TNBC) randomized 2:1 to pembrolizumab (pembro) or placebo (pbo) given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. RCB was assessed by the local pathologist at the time of surgery. A Cox regression model was used to assess association between RCB categories [RCB-0, -1, -2, -3; RCB-0 corresponds to pathologic complete response (pCR) and increasing numbers correspond to increasingly larger residual cancer] and EFS, with treatment as a covariate. Median follow-up was 39.1 months. Increased RCB consistently corresponded with worse EFS across the entire spectrum. Pembro shifted RCB to lower categories across the entire spectrum. Pembro was associated with increased pCR; 63.4% of the pembro arm (n=401) was classified as RCB-0, compared to 56.2% of pbo arm (n=201). Pembro resulted in fewer EFS events for most RCB categories and was most pronounced in the RCB-2 category. The HRs for EFS were 0.70 for RCB-0 (equivalent to pCR), 0.92 for RCB-1, 0.52 for RCB-2, and 1.24 for RCB-3. The RCB-3 sample size was smaller than the other categories, as it represented only 5% of all patients. The most common EFS event in both arms was distant recurrence, which occurred in fewer patients in the pembro arm in all RCB categories. These data indicate that benefit from pembro applies to patients who do not achieve a pCR, suggesting adjuvant pembro treatment in the pembro arm may provide some clinical benefit.

Identifying clinical and molecular characteristics of patients with HR+/HER2- breast cancer who respond to neoadjuvant therapy

504. Pathologic complete response (pCR) rates for HR+/HER2- breast cancer by molecular subtype in the I-SPY2 Trial.

Laura Ann Huppert (UCSF Helen Diller Comprehensive Cancer Center) presented a study of clinical and molecular characteristics associated with pathologic complete response (pCR) in patients with HR+/HER2- breast cancer. The study analyzed data from I-SPY2, a multicenter, phase II, randomized, adaptive study evaluating multiple agents as neoadjuvant therapy against early-stage breast cancer. Estimated pathologic complete response (pCR) rates were analyzed for seven agents with control weekly paclitaxel for 12 doses followed by doxorubicin/cyclophosphamide for 4 cycles in the HR+/HER- subset of patients. 38% (379/387) patients had HR+/HER2- disease, and patients were subdivided by clinical characteristics (stage and histology) and molecular characteristics [Mammaprint (MP) high risk score, BluePrint (BP), and Response Predictive Subtype (RPS) immune signature]. pCR rates were higher in patients with stage II disease (21.9%) compared to Stage III disease (8.7%). With regards to histology, pCR was highest for invasive ductal carcinomas (18.6%), followed by invasive lobular carcinomas (10.5%), then mixed ductal/lobular carcinomas (5.6%). pCR rates were higher in patients with MP High2 scores (-0.57 to –1.0; pCR=31%) compared to patients with MP High1 scores (0 to -0.56; pCR=11%). BP Basal pCR rate was 34%, and BP Luminal pCR rate was 10%. The third molecular subdivision, RPS, are newly developed predictive subtypes derived from gene expression, protein phosphorylation, and clinical data from the I-SPY2 trial. The pCR rate in patients with the Immune+ RPS signature was 32%, compared to 7% in patients with the Immune- signature. In the subgroup of HR+/HER2- patients treated with pembrolizumab, pCR for Immune+ patients was 69%, compared to 4% for Immune- patients treated. These data suggest that Mammaprint and Blueprint signatures have potential to identify patients with high-risk HR+/HER2- disease who are more likely to respond to neoadjuvant treatment. The RPS immune signature shows promise in identifying patients with HR+/HER2- disease who are more likely to respond to neoadjuvant therapy with pembrolizumab. The I-SPY-2.2 trial, a fully adaptive trial to develop tailored therapies based on patients’ individual histology and molecular characteristics and clinical responses, is in development.

Safety and efficacy of a fatty acid oxidation inhibitor against advanced solid tumors

3005. A phase 1 study of TPST-1120 as a single agent and in combination with nivolumab in subjects with advanced solid tumors.

Mark Yarchoan (Johns Hopkins Sidney Kimmel Comprehensive Cancer Center) reported on a phase I study investigating oral therapy TPST-1120 monotherapy and in combination with nivolumab for advanced solid tumors. TPST-1120 inhibits PPARalpha, a transcription factor that regulates fatty acid oxidation.Preclinical studies indicate that TPST-1120 inhibits tumor proliferation, reduces T cell exhaustion, and promotes anti-tumor activity of PD-1 blockade. In the dose-escalation phase of the study, the monotherapy cohort (n=20), which consisted of multiple solid tumor types, received dose escalation of TPST-1120. The combination cohort (n=18), which consisted of hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and cholangiocarcinoma (CCA), received dose escalation of TPST-1120 in combination with nivolumab. The recommended phase 2 dose for TPST-1120 was determined to be 600 mg for both cohorts. Treatment-related adverse events (TRAEs) were observed in 50% (n=10) of patients in the monotherapy cohort, and 1 patient experienced grade 3 hypertension. TRAEs were observed in 83.3% (n=15) of patients in the combination cohort, with 3 patients experiencing grade 3 events. Disease control rate in the monotherapy cohort was 53%, and 4 patients experienced some tumor reduction that did not qualify as a partial response. 2 patients with advanced cholangiocarcinoma (CCA) in the monotherapy cohort exhibited long-term stable disease for up to 10 months after the start of the study. These patients had experienced 3 and 4 prior systemic therapies, and both had disease refractory to anti-PD-1. In the combination cohort, the objective response rate (ORR) was 23% across all dose levels and 38% among patients who had received the highest dose of TPST-1120. 3 patients experienced partial responses: 1 responder had heavily pre-treated CCA, and 2 responding patients had late-line RCC that had progressed on anti-PD-1 therapy. One of these patients has maintained their response for over 12 months. Results from this study indicate that TPST-1120 is safe and tolerated by patients as monotherapy and in combination with nivolumab. TPST-1120 demonstrated disease control as monotherapy and promising anti-tumor activity in combination with nivolumab, even in patients with disease refractory to anti-PD-(L)1 therapy. A randomized phase 1b/2 trial investigating TPST-1120 in combination with atezolizumab and bevacizumab for first line HCC is ongoing.