ADC Drug Combination: How to Achieve 1+1>2

Antibody-drug conjugates (ADC) are a novel type of medication that couples monoclonal antibodies, which specifically recognize cancer cell surface antigens, with cytotoxic chemotherapy drugs through specific linkers, exerting a significant tumor-killing effect. Currently, 15 ADC drugs, represented by trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd, DS-8201), have been approved globally, significantly changing the treatment landscape of malignant tumors.

Figure 1

From May 12-14, 2023, the 7th Hangzhou Xianghu International Breast Cancer Summit and the 8th Hangzhou Xianghu Young Breast Cancer Forum were grandly held in Hangzhou, during which Professor Cao Wenming from Zhejiang Cancer Hospital gave an exciting presentation on how to achieve 1+1>2 with ADC drug combination strategies.

Although ADC monotherapy has shown significant survival benefits in cancer treatment, there is a desire for more. On one hand, how to maximize the anti-tumor effect of ADC; on the other hand, how to solve the resistance problem of ADC monotherapy, making ADC combination strategies a direction that researchers continuously explore. A meta-analysis pooling 16 randomized clinical trials indicated that the efficacy of ADC combination therapy is generally superior to that of ADC monotherapy.

Figure 2

Previous studies have shown that the best combination strategies with ADC drugs should produce additive or synergistic effects on tumor cells or the tumor microenvironment without overlapping toxicity profiles. A rational ADC combination strategy can enhance ADC activity, with specific mechanisms including the following four:

● Enhancing ADC delivery to tumor tissues: For example, anti-angiogenic drugs may improve ADC delivery to tumor tissues by promoting the normalization of tumor blood vessels, thereby enhancing ADC’s cytotoxic effects;

● Regulating antibody target protein expression: Drugs that increase the expression of target antigens on tumor cell surfaces may promote antibody-antigen binding; at the same time, drugs that enhance antigen conversion or degradation may facilitate ADC uptake and effective payload cleavage and release, thereby enhancing cytotoxicity;

● Enhancing effective payload activity and/or synthetic lethality: Other drugs that exert synergistic effects through complementary mechanisms or synthetic lethality can enhance effective payload activity;

● Promoting anti-tumor immunity: Immunotherapy has the potential to build on ADC-induced anti-tumor immunity, which can be enhanced through antibody-dependent cellular cytotoxicity or by enhancing T-cell mediated tumor recognition and immune effector functions.

Figure 3

The combination strategies with ADC mainly focus on chemotherapy drugs, anti-HER2 targeted drugs, anti-angiogenic inhibitors, and immune checkpoint inhibitors. Currently, multiple studies exploring ADC combination strategies have made significant progress in the field of breast cancer.

Figure 4

Exploring ADC drug combination strategies for breast cancer treatment

ADC Combination with Chemotherapy

Combination with Taxanes

The phase Ib/IIa study of T-DM1 combined with taxanes showed an objective response rate (ORR) of 47.8% and a median progression-free survival (PFS) of 7.4 months; the combination treatment significantly increased toxicity responses, the most common being neutropenia (25.0%) and peripheral neuropathy (18.2%).

Figure 5

Combination with Anthracyclines

The phase I Thelma study explored the efficacy of T-DM1 combined with anthracyclines for HER2-positive advanced breast cancer, showing an ORR of only about 40% for different dose combinations.

Figure 6

Although taxanes and anthracyclines are the backbone of breast cancer chemotherapy, both studies yielded negative results. Despite evidence of enhanced anti-tumor activity from the combination of ADC and chemotherapy, overlapping toxic effects remain a challenge, with over half of patients requiring dose reductions or discontinuation of taxanes.

Future combination chemotherapy still needs to ensure sufficient tolerability while optimizing ADC drugs and selecting appropriate tumor types and combination medications. Particularly for high-risk patients, the potential advantages of combination therapy can be anticipated, such as those who respond poorly to standard neoadjuvant therapy or non-pCR patients.

ADC Combination with Targeted Therapy

T-DM1 Combined with Pertuzumab

Previous clinical studies of T-DM1 combined with pertuzumab, namely KAITLIN, KRISTINE, and MARIANNE, all yielded negative results. Although T-DM1 combined with pertuzumab showed comparable efficacy to standard taxanes, trastuzumab, and pertuzumab (THP), the overall side effects were lower.

Figure 7

T-DXd Combined with Pertuzumab

The DESTINY-Breast 07 study compared the efficacy of single-agent T-DXd with T-DXd combined with pertuzumab, showing similar ORR between the two groups (87% vs 81.8%); however, the combination increased the endocytosis of T-DXd by pertuzumab, potentially enhancing anti-tumor effects. The DB09 study is currently exploring the efficacy of this combination strategy in first-line HER2-positive patients.

Figure 8

T-DM1 Combined with Lapatinib

The TEAL study showed that T-DM1 combined with lapatinib and albumin-bound paclitaxel significantly improved the pathological complete response rate (pCR) (62.5% vs 100%), especially in the hormone receptor-positive subgroup (pCR 25% vs 100%).

Figure 9

T-DM1 Combined with Tucatinib

The phase I study of T-DM1 combined with tucatinib showed an ORR of 47%, with an ORR of up to 36% for patients with breast cancer with brain metastases. Therefore, further phase III clinical studies of tucatinib combined with T-DM1 (HER2CLIMB-02) or T-DXd (HER2CLIMB-04) are being conducted.

Figure 10

T-DM1 Combined with Neratinib

The preliminary phase I study of T-DM1 combined with neratinib showed that out of 19 evaluable patients, 12 (63%) achieved objective response.

ADC Drug Combination: How to Achieve 1+1>2

Figure 11

T-DM1 Combined with PI3K Inhibitor Alpelisib

The phase I study of T-DM1 combined with the PI3K inhibitor alpelisib showed an ORR of 43% and a median PFS of 8.1 months.

ADC Drug Combination: How to Achieve 1+1>2

Figure 12

T-DM1 Combined with CDK4/6 Inhibitor Palbociclib

The phase I study of T-DM1 combined with the CDK4/6 inhibitor palbociclib showed an ORR of only 33% and a median PFS of 6 months; moreover, the incidence of grade 3 hematological toxicity exceeded 10%.

ADC Drug Combination: How to Achieve 1+1>2

Figure 13

Similarly, the ORR of T-DM1 combined with another CDK4/6 inhibitor ribociclib was even lower, at only 16.7%. This may be related to the CDK4/6 inhibitor preventing tumor cells from entering the S/M phase, thereby reducing the efficacy of T-DM1.

ADC Drug Combination: How to Achieve 1+1>2

Figure 14

T-DM1 Combined with Endocrine Therapy

Studies show that the pCR rate of T-DM1 combined with endocrine therapy (53.2%) is significantly higher than that of trastuzumab combined with endocrine therapy (23.4%), but there is no significant difference in the final invasive disease-free survival (iDFS) between the two groups, which may be related to the fact that hormone receptor-positive patients received more targeted or endocrine therapy postoperatively.

ADC Drug Combination: How to Achieve 1+1>2

Figure 15

Moreover, the TALENT study of T-DXd combined with endocrine therapy showed lower efficacy. Currently, studies are ongoing to explore the efficacy of T-DXd combined with fulvestrant or anastrozole in the DESTINY-Breast 08 study.

ADC Drug Combination: How to Achieve 1+1>2

Figure 16

ADC Drug Combination: How to Achieve 1+1>2

Figure 17

ADC Combination with Immunotherapy

Numerous studies indicate that ADC may enhance the efficacy of immunotherapy, with mechanisms possibly including: inducing immunogenic cell death, dendritic cell maturation, increased T lymphocyte infiltration, and enhanced expression of immune memory and immune regulatory proteins such as PD-L1 and MHC.

ADC Drug Combination: How to Achieve 1+1>2

Figure 18

Based on the potential synergistic activity of ADC with immune checkpoint inhibitors, numerous clinical studies are currently underway.

The first phase II study exploring ADC combined with immunotherapy, KATE2, showed no significant difference in median PFS between the T-DM1 combined with atezolizumab group and the control group (8.2 months vs 6.8 months, p = 0.33); however, in the PD-L1 positive subgroup, the median PFS for the two groups was 8.5 months and 4.1 months, respectively. Although there was no significant statistical difference (p = 0.099), the T-DM1 combined with atezolizumab group could reduce the risk of progression by 60%, warranting further research. Therefore, the phase III KATE3 study of T-DM1 combined with atezolizumab is currently ongoing.

ADC Drug Combination: How to Achieve 1+1>2

Figure 19

ADC Drug Combination: How to Achieve 1+1>2

Figure 20

Moreover, the phase Ib study of T-DM1 combined with pembrolizumab showed an ORR of only 20% and a median PFS of 9.6 months.

ADC Drug Combination: How to Achieve 1+1>2

Figure 21

In the BEGONIA study, cohorts 6 (T-DXd combined with durvalumab) and 7 (Data-DXd combined with durvalumab) both achieved certain efficacy, with higher efficacy observed in tumors with high and low PD-L1 expression.

ADC Drug Combination: How to Achieve 1+1>2

Figure 22

ADC Drug Combination: How to Achieve 1+1>2

Figure 23

The DS8201-A-U105 study of T-DXd combined with nivolumab showed similar efficacy between the combination treatment and T-DXd monotherapy.

Figure 24

Additionally, studies on sacituzumab govitecan (SG) combined with pembrolizumab in early and advanced breast cancer treatment are also ongoing.

ADC Drug Combination: How to Achieve 1+1>2

Figure 25

Regarding the treatment of ADC combined with immune checkpoint inhibitors, due to design limitations in published studies, the incremental benefit of combination therapy remains uncertain. However, existing clinical data seem to indicate that the combination of ADC yields higher response rates compared to monotherapy results in the same tumor type. For appropriate tumors and target populations, some combinations may be considered alternatives to chemotherapy. This is especially true for frail and elderly patients, who are at higher risk for chemotherapy toxicity. Furthermore, there is almost no publicly available clinical data on combinations of ADC with immunotherapies other than anti-PD-1/PD-L1/CTLA-4 antibodies.

Future Development Directions of ADC Combination Strategies

From the preliminary exploration of numerous ADC combination strategies, we can find many areas for improvement.

ADC Drug Combination: How to Achieve 1+1>2

Figure 26

Moreover, in future drug combination development directions, preliminary studies have pointed out more exploration directions.

ADC Drug Combination: How to Achieve 1+1>2

Figure 27

Currently, the clinical trial design principles for ADC combination therapy align with the principles published by the Clinical Trial Design Working Group of the National Cancer Institute.

ADC Drug Combination: How to Achieve 1+1>2

Figure 28

However, to date, the success of ADC combination strategies has been limited, possibly due to non-specific expression of targets leading to adverse reactions in normal tissues, overlapping toxic reactions, and newly emerging resistance mechanisms.

ADC Drug Combination: How to Achieve 1+1>2

Figure 29

Therefore, future efforts need to actively explore favorable partners for ADC drugs, deeply understand the pharmacology of ADC, and explore combinations of predictive biomarkers related to efficacy.

Currently, many studies on ADC combination therapies are underway, so let’s wait and see!

The full text is complete. If you find the content good, please give it a like or “seen”; it would be best to add a star🌟, as WeChat has recently been revamped. Thank you for reading.

ADC Drug Combination: How to Achieve 1+1>2

Organized by: Huang Yuting; Reviewed by: Professor Cao Wenming

Typesetting:Lin Shuya; Illustrations: Professor Cao Wenming’s teaching PPT

Submission: [email protected]

ADC Drug Combination: How to Achieve 1+1>2

References:

1. Nicolò E, Giugliano F, Ascione L, et al. Combining antibody-drug conjugates with immunotherapy in solid tumors: current landscape and future perspectives. Cancer Treat Rev. 2022;106:102395.

2. Fuentes-Antrás J, Genta S, Vijenthira A, Siu LL. Antibody-drug conjugates: in search of partners of choice. Trends Cancer. 2023;9(4):339-354.

3. Emens LA, Esteva FJ, Beresford M, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomized, double-blind trial. Lancet Oncol. 2020;21(10):1283-1295.

4. Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984.

5. Harbeck N, Im SA, Barrios CH, et al. Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 500-500.

6. Erika Hamilton, Charles L. Shapiro, Daniel Petrylak, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing advanced breast cancer: a 2-part, phase 1b, multicenter, open-label study. 2020 SABCS. PD3-07.

7. Peter Schmid, Seock-Ah Im, Anne Armstrong, et al. BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—Initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd). 2021 ASCO. 1023.

8. Hurvitz SA, Martin M, Jung KH, et al. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study. J Clin Oncol. 2019 Sep 1;37(25):2206-2216.

9. Modi S, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J. Clin. Oncol. 2020;38(17):1887–1896.

Related posts

Leave a Comment Cancel reply