Table 1.
Overcoming primary and secondary resistance:
| Drug combination |
Target |
Mechanism/Rational |
Outcomes |
Indications |
Reference |
|---|---|---|---|---|---|
|
Pembrolizumab
Pemetrexed-Platinum chemotherapy |
PD-1 Key proteins that are abundant in cancer cells |
Platinum compounds recruit dendritic cells, induce their maturation, and enhance antigen presentation within the TME | Improved OS and PFS compared with placebo plus pemetrexed-platinum | NSCLC | 43, 44 |
|
Pembrolizumab
carboplatin and paclitaxel/nab-paclitaxel |
PD-1 DNA, Tubulin beta-1 chain |
carboplatin and paclitaxel/nab-paclitaxel can lead to depletion of myeloid-derived suppressor cells | Significantly improved OS and PFS in comparison to chemotherapy alone | NSCLC | 44 |
|
Pembrolizumab
Datopotamab deruxtecan |
PD-1 Trophoblast cell surface protein 2 |
ADCs combine the potency of strong chemotherapy drugs with the specificity of mAbs | Phase Ib trial (TROPION-Lung02) showed promising clinical activity in patients with advanced or metastatic NSCLC | NSCLC |
48, 49 |
|
Atezolizumab
Vemurafenib with Cobimetinib |
PD-L1 BRAF MEK1 |
Vemurafenib can enhance antigen processing and increase the expression of major MHC molecules | Improved PFS | Unresectable or metastatic melanoma | 51, 52 |
|
Pembrolizumab
Lenvatinib |
PD-1 VEGFR |
Antiangiogenic drugs can increase intra-tumoral effector cells, decrease PDL1 expression, and reduce infiltration of MDSCs and regulatory T cells | Increase in PFS compared to sunitinib alone | Renal cell carcinoma, Endometrial carcinoma |
53, 54, 55, 56 |
|
Ipilimumab
Rituximab |
CTLA-4 CD20 |
Depletion of tumor-associated B cells that have been implicated in drug resistance and the secretion of pro-tumorigenic factors | Median survival exceeding 1 year in patients with multi-treated metastatic melanoma | Metastatic melanoma | 57 |
Abbreviations: PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, CTLA-4 cytotoxic-T-lymphocyte-associated protein 4, TME tumor microenvironment, MDSC myeloid-derived suppressor cells, OS overall survival, PFS progression-free survival, MHC major histocompatibility complex, NSCLC non-small cell lung cancer.