Abstract SP122: Novel biomarkers in immune therapy response
Authors: Pusztai L 
Published: February 2021

Abstract
Four randomized trials demonstrated statistically significant increase in pCR rates when an immune checkpoint inhibitor (ICI) was added to neoadjuvant chemotherapy in triple negative breast cancer (TNBC), these include the KN-522, Impassion-031, I-SPY2 pembrolizumab, and I-SPY2 durvalumab/oleparib arms. One trial, GeparNuevo, showed a non-significant trend for higher pCR rate, and one trial (NeoTrip-aPDL1) showed no effect. In each of these randomized trials, high tumor infiltrating lymphocyte count, high expression of PD-L1 protein and a broad range of immune-related genes and immune gene signatures predicted for higher pCR rate in both chemotherapy alone and chemotherapy plus ICI treatment arms. Unexpectedly, the positive trials also consistently demonstrated that pCR rates significantly improved with ICI therapy even in PDL-1 negative TNBC. For example, in KN-522 the pCR rates were 30% vs 45% in the PDL-1 negative and 55% vs 69% in the PD-L1 positive populations. There is less data on the efficacy of neoadjuvant immune checkpoint therapy in estrogen receptor positive (ER+) cancers. However, both the pembrolizumab and durvalumab + olaparib arms of the I-SPY2 trail demonstrated improvement in pCR rates in ER+ cancers, and these improvements were also independent of PDL-1 mRNA expression or other immune markers. On the other hand, the ER+ MammaPrint ultrahigh (MP2) subset that is characterized by high proliferation, and low ER-related gene expression showed selective benefit from ICI therapy, while no benefit was seen in the MP1 group. The same MP2 group also benefited from adding carboplatin and veliparib to paclitaxel in an earlier arm of I-SPY2 suggesting that among ER+ cancers, the MP2 tumors are more chemotherapy sensitive and this sensitivity might be further enhanced by adding an immune checkpoint inhibitor.A very different biomarker picture emerged from the randomized first line trials in metastatic TNBC (mTNBC). In this clinical setting, the efficacy of immune checkpoint inhibitors (ICI) is proportional to the level of PD-L1 protein expression by immunohistochemistry, or by immune infiltration that can be quantified by tumor infiltrating lymphocyte count. In PDL-1 negative, or immune low, mTNBC no benefit is seen from ICI therapy. In immune rich metastatic TNBC (defined as CPS&gt;20 with 22C3 Assay), close to 30% response rate was seen with single agent pembrolizumab in the KN-199 trial. Two large randomized first line trials, IMpassion-130 and KN-355, demonstrated improved response rates and increased progression free survival (and overall survival in Impassion-130) when ICI was added to nab-paclitaxel (Impassion-130), or taxol or nab-paclitaxel or gemcitabine/carboplatin (KN-355) chemotherapies, respectivel. Impassion-130 also demonstrated that different immunohistochemistry assays for PDL-1 determination have different accuracy to define the atezolizumab sensitive population. The SP142 Ventana assay that defines approximately 40% of the mTNBC population as PDL-1 positive had the highest overall accuracy. A third, and smallest, randomized trial, IMPassion-131, failed to show significant benefit (HR:0.82, p=0.2) from adding atezolizumab to paclitaxel. This failure is likely due to differences in patient composition and limited sample size and power, rather than choice of chemotherapy. Pembrolizumab is also approved in the US for metastatic solid tumors, including breast cancer regardless of receptor status, that have either microsatellite instability, or high tumor mutation burden (&gt;10 mutation /MB). Few trials examined the role of ICI in ER+ metastatic breast cancer, and these studies showed low single agent activity. Due to the paucity of data, the relationship between immune therapy efficacy and PDL-1 expression, or recurrence score, or luminal A versus B subtype is unknown in ER+ metastatic disease.
Citation Format: L Pusztai. Novel biomarkers in immune therapy response [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP122.