As ADCs continue to get incorporated in the treatment landscape across several tumors, data emerging from the next wave of ADCs add to the excitement.

Antibody Drug Conjugates – Shaping the Future Treatment Paradigms in Solid Tumors

Antibody Drug Conjugates: Shaping the Future Treatment Paradigms in Solid Tumors

As ADCs continue to get incorporated in the treatment landscape across several solid tumors, data emerging from the next wave of ADCs add to the excitement.

DECEMBER 2020

Syed Meheboob Ahmed, PhD, Research Manager; Shweta Srivastava, MBA, Therapy Area Group Manager and Nick Turner, PhD, Senior Director

Chemotherapy with conventional cytotoxic drugs has been established as standard of care for the treatment of solid tumors and hematological malignancies for several decades; however, they lack selectivity for cancer cells and have severe off-target toxicities, which limits their tolerability. Conversely, antibody therapeutics have high selectivity and specificity, and consequently fewer adverse events, but lack the cytotoxic potential of chemotherapeutic agents. Whilst naked therapeutic antibodies acting through immune-mediated mechanisms (ADCC/ADCP), blocking growth factors or promoting apoptosis have revolutionized the treatment of many cancers, coupling the target selectivity of the antibody with the direct cell-killing potential of a cytotoxic payload has clear attractions, provided off-target toxicity can be minimized.

Antibody-drug conjugates (ADC), coupling a targeting monoclonal antibody with a cytotoxic payload covalently joined by a molecular linker, are currently the subject of dynamic growth in R&D activity. Whilst toxicity was an early issue in ADC development, technological advancements including affinity-attenuated binders; more potent membrane-permeable payloads; improved linker conjugation chemistry, conveying greater stability; and higher drug-to-antibody ratios, yielding greater potency have greatly improved the therapeutic index of the latest generation of ADCs.

Currently ten ADCs have regulatory approval and more than 150 are in clinical trials.

Despite being overshadowed by anti-PD-1/L1 inhibitors, ADCs have blockbuster potential. Q3 2020 sales of the trastuzumab-based ADC Kadcyla annualize at almost $2 billion, and with monoclonal antibodies generating sales in excess of $150 billion, in 2019, the commercial potential of ADCs as the next generation of antibody therapeutics is considerable.

Unsurprisingly, the burgeoning ADC pipeline, recent approvals and promising data emerging from pivotal trials have attracted commercial interest from large biopharma players.

This is reflected in recent industry deal making. Over the last two years, AstraZeneca paid $6.9 billion to gain access to Daiichi Sankyo’s ADC trastuzumab deruxtecan (Enhertu) for HER2-positive breast and gastric cancer and a further $6bn in upfront cash and milestones for Daiichi’s TROP2 ADC, DS-1062. Gilead paid $21 billion to acquire Immunomedics, attracted by its ADC pipeline and Merck paid $2.75 billion to acquire VelosBio for its ROR1-targeting ADC VLS-101, currently in a Phase II trial for the treatment of patients with solid tumors, including triple-negative breast cancer (TNBC), HR-positive or HER2-positive breast cancer and non-small cell lung cancer (NSCLC). Merck also signed a $1.6 billion licensing deal with Seagen to co-develop and co-commercialize ladiratuzumab vedotin in mTNBC, HR-positive breast cancer and other LIV-1-expressing tumors.

As large pharma jostle to get a foothold in what is a fast-developing and commercially attractive market it is likely the above represents just the first wave of a continuing deal flow.

In this thought piece, we discuss the impact of ADCs on the treatment landscape across solid tumors and the developments that may determine their clinical and commercial potential.  

ADCs targeting novel antigens address significant unmet medical needs

Locally advanced or metastatic urothelial cancer (mUC) patients progressing on platinum-based chemotherapy and anti-PD-1/L1 checkpoint inhibitors (CPIs) represent an area of high unmet need. Astellas-Seagen’s enfortumab vedotin (Padcev), a first in-class Nectin-4-targeting ADC, demonstrated promising clinical activity (ORR: 44%, CR: 12%, mDoR: 7.6 months) in locally advanced or mUC previously treated with platinum chemotherapy and anti-PD-1/L1 (EV-201, cohort 1).1 The FDA granted Padcev Accelerated Approval in December 2019. The 30% reduction in the risk of death (HR: 0.70) compared to single-agent chemotherapy in a Phase III confirmatory trial (EV-301) in the same patient population2 confirms Padcev’s single-agent clinical potential in this setting.

Astellas and Seagen also have a registrational study exploring Padcev’s monotherapy potential in platinum-naïve/cisplatin-ineligible patients post anti-PD-1/L1 (EV-201, cohort 2). Other registrational studies are evaluating Padcev with Merck’s Keytruda for frontline locally advanced or mUC (EV-302) and muscle-invasive bladder cancer (EV-303/KeyNote-905).

Currently, there is no approved therapy for cervical cancer patients progressing on frontline combination chemotherapy and bevacizumab. Seagen and Genmab are exploring the potential of tisotumab vedotin, a first-in-class tissue factor (TF)-targeting ADC, in a pivotal trial (innovaTV 204) in previously treated recurrent or metastatic cervical cancer. A recent study (ESMO 2020) showed tisotumab vedotin had promising clinical activity (ORR: 24%, mDoR: 8.3 months, mOS: 12.1 months, mPFS: 4.2 months) and a manageable safety profile in this setting.3 By way of comparison single-agent chemotherapy results in response rates ranging between 5% and 15%. A Biologics License Application (BLA) seeking Accelerated Approval in the US is planned.

mTNBC is associated with poor prognosis compared to other breast cancer sub-types and considered difficult to treat. In a recent data readout (ESMO 2020), Immunomedics’ sacituzumab govitecan (Trodelvy), a first in-class TROP2-targeting ADC, reported significant improvement in progression-free survival, overall survival and overall response rates compared to single-agent chemotherapy in mTNBC patients previously treated with at least two prior lines of therapy. In the Phase III ASCENT trial, Trodelvy reduced the risk of disease progression and death over chemotherapy by 59% (mPFS: 5.6 months vs. 1.7 months; HR: 0.41) and 52% (mOS: 12.1 months vs. 6.7 months; HR: 0.48), respectively.4 The data are expected to support full approval of Trodelvy, which was granted Accelerated Approval for mTNBC patients in April 2020. A pivotal trial is evaluating Trodelvy monotherapy in HR-positive metastatic breast cancer treated with at least two prior lines of therapy (TROPiCS-02), broadening its breast cancer indications.

Trodelvy also showed encouraging activity in the Phase II TROPHY-U-01 trial in mUC patients progressing on platinum-based chemotherapy and anti-PD-1/L1 CPIs (mOS: 10.5 months, mPFS: 5.4 month, ORR: 27%, CR: 6%, mDoR: 5.6 months).5 Although the data do not compare favorably with Padcev, the company is hopeful that responses in the 30% of patients previously treated with Padcev may position Trodelvy as a viable option for Padcev progressors. A Phase III confirmatory trial (TROPiCS-04) is currently evaluating Trodelvy monotherapy in this patient population.

However, with most ADCs currently positioned as salvage therapy, questions remain on their potential in earlier lines of therapy.  

ADCs mitigating resistance to HER2-directed therapies and beyond

The Phase III EMILIA and TH3RESA trials supported approval of Roche/Genentech’s trastuzumab emtansine (Kadcyla) in HER2-positive metastatic breast cancer progressed after first-line trastuzumab. More recently, the Phase III KATHRINE trial established Kadcyla’s role as adjuvant therapy for HER2-positive early breast cancer with residual invasive disease after completion of neoadjuvant taxane and trastuzumab, providing a boost to sales.

Daiichi Sankyo-AstraZeneca’s trastuzumab deruxtecan (Enhertu), a HER2-targeting ADC with a topoisomerase-1 cytotoxic payload, was developed to improve on the clinical efficacy of Kadcyla, particularly in patients with moderate-to-low HER2 expression levels.

Enhertu is differentiated from Kadcyla by having greater cytotoxic potential via a higher drug-to-antibody ratio and a potent bystander killing effect due to the high membrane permeability of its payload. These properties extend Enhertu’s clinical benefit to patients with low or heterogenous HER2 expression, in whom currently available HER2-targeting agents are ineffective.

Promising clinical activity in the Phase II study DESTINY-Breast01 led to Enhurtu’s approval for HER2-positive metastatic breast cancer after two or more prior lines of anti-HER2-based regimens. In earlier lines of therapy, Enhertu is being evaluated in pivotal trials in second-line HER2-positive breast cancer (DESTINY Breast-03), and as adjuvant therapy for HER2-positive early breast cancer (DESTINY Breast-05) and in patients with low HER2 expression (DESTINY Breast-04).

Based on results of the Phase II DESTINY-Gastric01 in gastric cancer with high (ICH3+) or moderate (ICH2+) HER2 expression Enhertu was approved in Japan as second-line therapy after prior trastuzumab and has priority review in the US. Enhertu has also shown activity in heavily pre-treated HER2-mutant metastatic NSCLC (mPFS: 14 months, ORR: 61.9%; DESTINY-Lung01),6 and HER2-positive metastatic colorectal cancer (mPFS: 6.9 months, ORR: 45.3%; DESTINY-CRC01)7, broadening Enhurtu’s therapeutic potential beyond that of the parent antibody (trastuzumab)

Nonetheless, there are concerns around its toxicity profile, with black box warnings for interstitial lung disease (ILD) and embryo-fetal toxicity. 

Next wave of ADCs holds potential to revolutionize treatment practices across solid tumors

As ADCs continue to be incorporated in the treatment landscape across several solid tumors, data emerging from the next wave of ADCs add to the excitement around this class.

Recent data on Daiichi Sankyo’s patritumab deruxtecan, a HER3-targeting ADC, in heavily pre-treated EGFR-mutant, TKI-resistant NSCLC suggest this MoA has potential as a salvage therapy beyond EGFR-TKIs (ORR: 25%, mDoR: 6.9 months).8 Daiichi Sankyo has announced a clinical collaboration with AstraZeneca to explore the potential of patritumab deruxtecan in combination with AstraZeneca’s EGFR-TKI osimertinib (Tagrisso) as an option for NSCLC patients progressing on Tagrisso.

Ongoing studies could also open the door for ADC + PD-1/L1 inhibitor combinations to change standard of care (SoC) in solid tumors. For example, registrational studies are evaluating Padcev with Merck’s Keytruda for frontline locally advanced or mUC (EV-302) and muscle-invasive bladder cancer (EV-303/KeyNote-905). Merck is also evaluating ladiratuzumab vedotin in combination with Keytruda in frontline TNBC as well as in LIV-1-expressing solid tumors; preliminary data from a Phase I/II trial reported encouraging responses with the combination in frontline mTNBC.   

Future direction for ADCs

So far, ADCs have primarily been evaluated in the salvage setting after two or more lines of prior treatment; however, in our opinion, releasing their full commercial potential will require targeting earlier lines of therapy. This means ADCs will need to compete directly against current frontline or second-line SoCs. However, despite improvements in potency and therapeutic index it remains unclear whether ADC’s outperform naked antibodies on efficacy and tolerability, in earlier lines of therapy.

In the metastatic setting, there have been few, if any, head-to-head comparisons to suggest ADCs are superior to the naked antibody in terms of hard survival endpoints. Indeed, when Kadcyla was pitched against trastuzumab in the 1L HER2-positive metastatic breast cancer setting (Phase III MARIANNE), the ADC failed to show superiority to trastuzumab.

Some encouragement, however, can be drawn from the Phase III KATHERINE trial, which compared Kadcyla with trastuzumab as adjuvant therapy for HER2-positive breast cancer. The 50% lower risk of disease recurrence in a sub-group of patients with residual disease after neoadjuvant taxane and trastuzumab indicates that ADCs have the potential to move out of the salvage shadows to the more commercially attractive earlier lines of therapy. It should be noted, however, that the superiority of the ADC came with higher treatment related adverse event rates (12.7% vs. 8.1%) and greater discontinuation rates (18% vs. 2.1%) compared to trastuzumab.9

It is also not completely clear whether ADCs targeting solid tumors have the appreciably better safety profile expected from targeted payload delivery. The greater discontinuation rates on Kadcyla vs. trastuzumab in KATHERINE suggest systemic toxicity remains an issue. Moreover, Enhertu carries a boxed warning on interstitial lung disease (ILD) and showed evidence of bone marrow suppression (anemia, thrombocytopenia and neutropenia) in clinical trials, suggestive of off-target toxicity. Kadcyla also carries a boxed warning on hepatotoxicity that is not shared by the naked antibody, trastuzumab.

There are obvious clinical opportunities for ADCs outside of the 3L+ or salvage setting: as 1L therapy, 2L in patients with disease progression and in the neoadjuvant/adjuvant maintenance settings. However, to achieve competitive positioning in earlier lines of therapy developers will need to demonstrate not only a significant improvement in efficacy, but also a non-inferior safety profile to the current SoC or other emerging regimens. Nevertheless, there is preliminary evidence that ADCs possess properties which augment their clinical potential compared to the naked antibody, particularly in tumors with low target expression.

We eagerly await the data that will clarify their commercial potential.

References
  1. Rosenberg, Jonathan E, et al. “Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy.” Journal of Clinical Oncology, Vol. 37 (2019): 2592-2600.
  2. “Astellas and Seattle Genetics Announce PADCEV® (enfortumab vedotin-ejfv) Significantly Improved Overall Survival in Phase 3 Trial in Previously Treated Locally Advanced or Metastatic Urothelial Cancer.” Astellas Press Release September 18, 2020. https://www.astellas.com/us/news/5176 (accessed on November 09, 2020)
  3. Coleman, Robert. “Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: Results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study.” ESMO Oncology-PRO. https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/tisotumab-vedotin-in-previously-treated-recurrent-or-metastatic-cervical-cancer-results-from-the-phase-ii-innovatv-204-gog-3023-engot-cx6-study (accessed on November 09, 2020)
  4. Bardia, Aditya. “ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC).” ESMO Oncology-PRO. https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/ascent-a-randomized-phase-iii-study-of-sacituzumab-govitecan-sg-vs-treatment-of-physician-s-choice-tpc-in-patients-pts-with-previously-treat (accessed on November 09, 2020)
  5. Loriot, Yohann. “TROPHY-U-01 cohort 1 final results: A phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI).” ESMO Oncology-PRO. https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/trophy-u-01-cohort-1-final-results-a-phase-ii-study-of-sacituzumab-govitecan-sg-in-metastatic-urothelial-cancer-muc-that-has-progressed-after (accessed on November 09, 2020)
  6. Smit, Egbert F, et al. “Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01.” ASCO Meeting Library. https://meetinglibrary.asco.org/record/184803/slide (accessed on November 09, 2020)
  7. Siena, Salvatore, et al. “A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01.” ASCO Meeting Library. https://meetinglibrary.asco.org/record/185482/slide (accessed on November 09, 2020)
  8. Yu, Helena. “Efficacy and safety of patritumab deruxtecan (U3-1402), a novel HER3 directed antibody drug conjugate, in patients (pts) with EGFR-mutated (EGFRm) NSCLC.” ESMO Oncology-PRO. https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/efficacy-and-safety-of-patritumab-deruxtecan-u3-1402-a-novel-her3-directed-antibody-drug-conjugate-in-patients-pts-with-egfr-mutated-egfrm (accessed on November 09, 2020)
  9. Minckwitz, Gunter von, et al. “Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.” New England Journal of Medicine, Vol. 380 (2019): 617-628 

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