ADCs on the Horizon Offer Hope for Challenging Cancers

DNA helix enlarged model in bright colors and spots, generative AI: © Radomir Jovanovic - stock.adobe.com

Several FDA-approved antibody-drug conjugates (ADCs) have paved a new treatment course for the treatment of solid tumors and hematologic malignancies. Given the promising responses and survival results that these agents elicit, the field is full of new ADCs with unique targets. Some agents are still in early phases of research, while others have been added to, withdrawn from the market, and undergo continued evaluation.

Part 1: Antibody-Drug Conjugates Continue to Transform the Oncology Landscape

Part 2: ADCs Change the Game for Cancer Treatment

Belantamab Mafodotin

In 2020, the FDA granted accelerated approval to belanatamab mafodotin (Blenrep), the BCMA-targeted ADC, for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

The phase 2 DREAMM-2 study (NCT03525678) supported this approval, and the surrogate end point of overall response rate (ORR) was used. The ORR for belantamab mafodotin was 31% (97.5% CI, 21%-43%), and 73% of responders had a response duration that was at least 6 months.¹

However, in November 2022, GSK announced that it had begun the process to withdraw the marketing authorization for belantamab mafodotin. This followed a request from the FDA after the confirmatory phase 3 DREAMM-3 study (NCT04162210) failed to meet the accelerated approval regulations. The median PFS for belanatmab mafodotin was 11.2 months vs 7 months with pomalidomide and dexamethasone (PomDex), and the PFS hazard ratio was 1.03 (95% CI, 0.72-1.47). Moreover, the ORR was 41% with belantamab mafodotin vs 36% with PomDex.² By March 2023, the agent was withdrawn from the market.³

Other DREAMM trials are investigating belantamab mafodotin alone and in combination with other agents in various lines of myeloma treatment, including the phase 3 DREAMM-8 trial (NCT04484623) which is evaluating belantamab mafodotin in combination with PomDex (BPd) in the second line or later. In March 2024, it was announced that this study met its primary end point of progression-free survival (PFS).⁴

Data from DREAMM-8 were presented at the 2024 American Society for Clinical Oncology (ASCO) Annual Meeting. The triplet showed a median PFS that was not reached (NR; 95% CI, 20.6 months-NR) in the BPd arm compared with 12.7 months (95% CI, 9.1-18.5) in the PomDex plus bortezomib arm (HR, 0.52; 95% CI, 0.37-0.73; P <.001). At 12 months, the PFS rate was 71% and 51% in each respective arm. Findings also highlighted that treatment with BPd reduced the risk of progression or death in difficult-to-treat subgroups, which included patients with cytogenic or functional high-risk disease, refractory disease following lenalidomide and previous treatment with anti-CD38 therapy.⁵

“Taken together with the results of phase 3 DREAMM-7 [NCT04246047], which combined [belantamab mafodotin] with bortezomib and dexamethasone, these data highlight the potential of [belantamab mafodotin]-containing triplets to address an unmet need for novel regimens to treat patients with myeloma and first relapse,” study investigator Suzanne Trudel, MD, MSc, a clinician scientist at Princess Margaret Cancer Centre, said in the presentation.

Moxetumomab Pasudotox

In 2018, the FDA approved moxetumomab pasudotox (Lumoxiti) for the treatment of patients with hairy cell leukemia who received at least 2 prior systemic therapies, including treatment with a purine nucleoside analog. A single-arm, open-label trial (NCT01829711) supported the approval, where 30% of patients achieved a durable complete response (CR), maintaining hematologic remission for more than 180 days, and the ORR was 75%.⁶

However, in January 2023, AstraZeneca announced plans to discontinue the agent due to poor clinical uptake, not due to any safety or efficacy issues.⁷

Cancer cells, 3D illustration: © Dr_Microbe - stock.adobe.com

Datopotamab Deruxtecan

Tanya Gupta, MD, medical oncologist in the Stanford University Department of Medicine, Division of Medical Oncology, highlighted an exciting therapy that has yet to receive FDA approval for patients with HER2- breast cancer, datopotamab deruxtecan (Dato-DXd; DS-1062a).

“Dato-DXd is a TROP2-directed antibody-drug conjugate. This was studied in the phase 3 TROPION-Breast01trial [NCT05104866], which was a global study that enrolled patients with hormone receptor-positive, HER2- advanced disease who had received 1 to 2 prior lines of chemotherapy,” said Gupta in an interview with Targeted Oncology^TM.

In this study, patients with HR+/HER2- metastatic breast cancer were treated with Dato-DXd (n = 365) or investigator’s choice of chemotherapy (n = 367). Experts sought to evaluate the coprimary end points of PFS by BICR and overall survival (OS).⁸

“Dato-DXd had a median progression-free survival of 6.9 months as compared with the median progression-free survival of 4.9 months among those treated with physicians' choice of chemotherapy,” explained Gupta.

Additional findings showed that at 6 months, the PFS rates were 53.3% vs 38.5%, respectively, and at 12 months, the PFS rates were 25.5% vs 14.6%.

“Dato-DXd is given on day 1 of a 3-week cycle. We are very excited to see what comes of Dato-DXd,” added Gupta.

“The field of ADCs in breast cancer is an exciting area. We are excited to see more about Dato-DXd. If Dato-DXd gains approval, there will be a lot of discussion about sequencing of therapies, because you can certainly imagine there will be patients who are candidates for multiple ADCs. More to come and more discussion to be had in this space of sequencing.”

Dato-DXd is also being evaluated in other spaces, specifically in the TROPION-Lung01 trial (NCT04526691). According to findings presented at the 2023 European Society for Medical Oncology (ESMO) Congress, Dato-DXd shows promise in treating non–small cell lung cancer (NSCLC) by eliciting a median PFS of 4.4 months (95% CI, 4.2-5.6) vs 3.7 months (95% CI, 2.9-4.2) with docetaxel. The ORR was higher with Dato-DXd at 26.4% (95% CI, 21.5%-31.8%) vs 12.8% (95% CI, 9.3%-17.1%) for docetaxel. Additionally, the median duration of response (DOR) was 7.1 months in the treatment arm (95% CI, 5.6-10.9) vs 5.6 months in the control arm (95% CI, 5.4-8.1).⁹

Dato-DXd also appeared to be safer than docetaxel, causing fewer severe adverse effects (AEs). Less patients needed to and frequently lower the dose or stop treatment altogether on the Dato-DXd arm.

While more studies are needed, Dato-DXd represents a promising new option for patients with nonsquamous NSCLC, offering potentially longer PFS and a better safety profile compared with docetaxel.

Disitamab Vedotin

Disitamab vedotin (formerly RC48) is an ADC composed of a HER2-targeted monoclonal antibody, hertuzumab and monomethyl auristatin E (MMAE) via an mc-val-cit-PABC linker.¹⁰

A prior phase 2 trial, RC48-C005 (NCT03507166), showed encouraging antitumor activity and safety data when RC48 was used as a monotherapy in patients with HER2+ locally advanced or metastatic urothelial carcinoma (mUC) after at least 1 systemic treatment failure.

The agent is also being studied in combination with the PD-1 inhibitor toripalimab (Loqtorzi), which demonstrated promising clinical activity with a manageable safety profile in patients with locally advanced or mUC. Another phase 2 study is evaluating disitamab vedotin alone or in combination with pembrolizumab (Keytruda).

Telisotuzumab Vedotin

This agent targets c-Met and consists of a humanized recombinant IgG1κ antibody conjugated to the microtubule inhibitor and MMAE using a valine-citrulline cleavable linker. In a phase 1 study (NCT02099058), telisotuzumab vedotin demonstrated activity as a monotherapy in a MET-positive enriched population of patients with NSCLC.¹¹

At data cutoff of January 2020, 42 patients were enrolled and 36 were deemed eligible for evaluation. The median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8-not reached). The ORR in EGFR mutation-positive patients (n = 28) was 32.1%, and 52.6% for c-Met high (n = 15) patients. The median PFS was 6.8 months for patients with non-T790M+ disease and those whose T790M status was unknown vs 3.7 months for those with T790M+ disease.

The most frequently observed AEs of any-grade included peripheral sensory neuropathy (43%), dermatitis acneiform (38%), diarrhea (33%), and hypoalbuminemia (33%). AEs deemed grade 3 or higher were seen in 27 patients (64%) and most consisted of pulmonary embolism (14%), hypokalemia (10%), and diarrhea, malignant neoplasm progression, peripheral sensory neuropathy, and hypophosphatemia (7% each).

Cancer cell or tumor illustration in high detail for medical education or science background, generative AI: © LAYHONG - stock.adobe.com

Tusamitamab Ravtansine

Tusamitamab ravtansine (SAR408701) consists of a humanized IgG1 antibody specific to CEACAM5 that has been conjugated to maytansinoid DM4, which inhibits tubular polymerization.¹²

A phase 1 dose-escalation study (NCT02187848) evaluated tusamitamab ravtansine at 2 schedules: intravenous tusamitamab ravtansine at a 120- to 170-mg/m2 loading dose followed by 100 mg/m2 every 2 weeks (n = 28) or a 120- to 190-mg/m2 fixed dose every 3 weeks (n = 15).

There is also an ongoing phase 3 trial titled CARMEN-LC03 (NCT04144956) which is currently evaluating the agent vs docetaxel in patients with nonsquamous NSCLC following chemotherapy and immunotherapy treatment in patients with CEACAM5 high expression.

Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is an anti-HER3 IgG1 antibody ADC. In a phase 1 study (NCT03260491) of patritumab deruxtecan in heavily pretreated patients with EGFR-mutated locally advanced or metastatic NSCLC, a pooled analysis of 102 patients showed an ORR of 40.2% (95% CI, 30.6-50.4). This included 1 CR, 40 patrial responses (PRs), and 39 cases of stable disease.¹³

The disease control rate (DCR) was 78.4% (95% CI, 69.2-86.0), the median DOR was 7.6 months (95% CI, 6.9-14.7), the median PFS was 6.4 months (95% CI, 5.3-8.3), and median OS was 15.8 months (95% CI, 10.8-21.5).

ABBV-011

ABBV-011 is another ADC which was studied in a phase 1, open-label, dose-escalation study. Ninety-nine patients with small cell lung cancer were included in the trial.

According to findings presented at the 2023 ASCO Annual Meeting (NCT03639194),¹⁴ the confirmed ORR with ABBV-011 was 19% among the 98 evaluable patients. The clinical benefit rate was 36% with stable disease lasting longer than 12 weeks. Forty patients were treated in the expansion phase of the study with the agent at a 1-mg/kg dose. Here, the ORR was 25%, and the DOR was 4.2 months.

ABBV-637

A phase 1 dose-escalation and dose-expansion study (NCT04721015) evaluated ABBV-637 in combination with osimertinib (Tagrisso) in the second- and third-line settings for the treatment of patients with relapsed/refractory NSCLC harboring an EGFR mutation.¹⁵ The ADC includes an EGFR-targeting antibody and a BCL-XL inhibitor.

In the study, the ORR in the second line was 10% (n = 42) vs 14% in the third line. The DCR was 65% vs 73% in the second and third lines. Among the 20 patients in the second-line cohort, 10% had a confirmed partial response (PR), and in the third-line cohort of 22 patients, 14% had a confirmed PR.

For safety, the most common treatment-emergent AEs were increases in aspartate levels (38%) and alanine aminotransferase (33%), nausea (33%), and fatigue (21%).

BL-B01D1

Another to look out for is BL-B01D1, a bispecific ADC evaluated in patients with NSCLC. Findings from a first-in-human phase 1 trial (NCT05194982) were also presented during the 2023 ESMO Congress, showing promising efficacy in heavily pretreated metastatic/locally advanced NSCLC. This was particularly true for patients with an EGFR mutation.¹⁶

In patients with EGFR wild-type, the ORR was 44.0% (95% CI, 30.0%-58.7%), with 22 patients reporting a PR, and a DCR of 94.0% (95% CI, 83.5-98.8). Among patients with EGFR mutation (n = 38), the ORR was 63.2% (95% CI, 46.0%-78.2%). Twenty-four patients reported a PR, and a DCR of 89.5% (95% CI, 75.2%-97.1%) was observed.

The most common treatment-related AEs seen in over 10% of patients or all grade/grade 3 or higher included anemia (59%/25%), leukopenia (59%/28%), neutropenia (51%/32%), thrombocytopenia (48%/23%), and nausea (36%/less than 1%). There were no cases of interstitial lung disease observed.

REFERENCES:

1. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. News release. FDA. Updated March 7, 2024. Accessed June 4, 2024. https://tinyurl.com/yvyfy86m

2. GSK provides update on DREAMM-3 phase III trial for Blenrep in relapsed/refractory multiple myeloma. News release. GSK. November 7, 2022. Accessed June 4, 2024. https://tinyurl.com/ymjy8ma8

3. Morè S, Offidani M, Corvatta L, Petrucci MT, Fazio F. Belantamab Mafodotin: From Clinical Trials Data to Real-Life Experiences. Cancers. 2023; 15(11):2948. doi:10.3390/cancers15112948

4. GSK announces positive results from DREAMM-8 phase III trial for Blenrep versus standard of care combination in relapsed/refractory multiple myeloma. News release. GSK plc. March 7, 2024. Accessed June 4, 2024. https://tinyurl.com/5n6mz3jv

5. Trudel S, Beksac M, Pour L, et al. Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;(suppl 17):LBA105.

6. FDA approves moxetumomab pasudotox-tdfk for hairy cell leukemia. News release. FDA. Updated December 3, 2018. Accessed June 4, 2024. https://tinyurl.com/2x5urfuk

7. AstraZeneca – Discontinuation of Lumoxiti® (moxetumomab pasudotox-tdfk). OptumRx. Accessed June 4, 2024. https://tinyurl.com/4ujbdurp

8. Bardia A, Jhaveri K, Kalinsky K, et al. TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Future Oncol. 2024;20(8):423-436. doi:10.2217/fon-2023-0188

9. M. Ahn, A.E. Lisberg, L. Paz-Ares, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): Results of the randomized phase III study TROPION-Lung01. Presented at: Presented at: The European Society of Medical Oncology (ESMO) Congress. October 20-24, 2023. Madrid, Spain. Abstract LBA12.

10. Sheng X, Zhou L, Yang K, et al. Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: An open-label phase 1b/2 study. J Clin Oncol. 41, 2023 (suppl 16; abstr 4566). doi: 10.1200/JCO.2023.41.16_suppl.4566

11. Camidge DR, Barlesi F, Goldman JW, et al. Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-Met protein-expressing non-small-cell lung cancer. J Clin Oncol. 2023;41(5):1105-1115. doi:10.1200/JCO.22.00739

12. Tabernero J, Bedard PL, Bang YJ, et al. Tusamitamab ravtansine in patients with advanced solid tumors: phase i study of safety, pharmacokinetics, and antitumor activity using alternative dosing regimens. Cancer Res Commun. 2023;3(8):1662-1671. doi:10.1158/2767-9764.CRC-23-0284

13. Patritumab deruxtecan continues to show encouraging clinical activity in distinct patient populations with metastatic lung and breast cancer in updated results of two early trials. News release. Daiichi Sankyo. March 20, 2023. Accessed March 20, 2023. https://bwnews.pr/42BwmFY

14. Morgensztern D, Ready NE, Johnson ML, et al. First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer. J Clin Oncol. 2023;41 (suppl 16):abstr 3002. doi:10.1200/JCO.2023.41.16_suppl.3002.

15. Rotow JK, Waqar SN, Papadopoulos KP, et al. First-in-human study of ABBV-637, an EGFR-targeting BCL-XL–inhibiting antibody-drug conjugate combined with osimertinib (OSI) in relapsed/refractory, EGFR-mutated non-small cell lung cancer (NSCLC). Presented at: The European Society of Medical Oncology (ESMO) Congress. October 20-24, 2023. Madrid, Spain. Abstract 1318MO.

16. Zhang L, Ma Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with non-small cell lung cancer: Updated results from first-in-human phase I study. Presented at: The European Society of Medical Oncology (ESMO) Congress. October 20-24, 2023. Madrid, Spain. Abstract 1316MO.