Lung Cancer: ADC will play the strong role In the post PD-L1 era

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Lung Cancer: ADC will play the strong role In the post PD-L1 era

Lung Cancer: ADC will play the strong role In the post PD-L1 era.

Standard treatments for advanced non-small cell lung cancer (NSCLC) include targeted therapy, immune checkpoint inhibitors (ICIs), and systemic chemotherapy.

Antibody-drug conjugate (ADC) is an anti-tumor therapy that can directly deliver cytotoxic drugs to tumor cells, so it has both “targeted” and “cytotoxic chemotherapy”.

This article retrospectively analyzes the design, mode of action and drug resistance mechanism of ADC drugs in the field of NSCLC.

Background

ADCs started clinical trials as early as the 1980s, and in 2000 Gemtuzumab-ozogamicin, an ADC for the treatment of acute myeloid leukemia, was granted Fast Track by the FDA.

First-generation ADCs for CD33-positive relapsed acute myeloid leukemia (AML) based on surrogate endpoints of response rate in 3 early-stage clinical trials (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA) . However, the results of the phase 3 comparative clinical study SWOG-S0106 launched in 2004 showed that patients who received ADC combination therapy had worse overall survival (OS).

In fact, this study also confirmed: compared with chemotherapy alone, patients receiving combination therapy More serious adverse reactions occurred because gemtuzumab-ozogamicin carried traditional cytotoxic drugs such as doxorubicin as the payload.

At the same time, the efficacy of first-generation ADC drugs is more complicated due to the low efficacy of the payload, the instability of the ADC linker due to non-cleavable/acid-intolerant, and excessive losses in the systemic circulation.

Second-generation ADCs (eg, trastuzumab, TDM1) use 100-1000-fold more potent tubulin-targeting drugs as payloads.

Third-generation ADCs are improved by increasing the heterogeneity of ADC molecules with a high drug-to-antibody ratio (DAR).

At present, the efficacy of the new generation of ADCs has been clinically verified in the form of single drug/combination drug.

Mechanism of action and drug design of ADCs

1. Design ideas of ADC: ADC consists of three parts:

cytotoxic drug (termed as ‘payload’, payload), monoclonal antibody (mAb) and linker (Linker).

The main mechanism of ADC is antibody binding to target antigen, linker cleavage after internalization, and release of cytotoxic payload.

The ultimate meaning of ADC is to maximize tumor killing and minimize systemic toxicity.

Lung Cancer: ADC will play the strong role In the post PD-L1 era

Figure 1. Ideal Characteristics of ADC Drugs

An ideal antibody needs not only a high affinity for the target antigen, but also a certain affinity. The target antigen needs to be highly expressed in tumor cells and low or not expressed in normal cells.

For example, ADCs in hematological malignancies tend to be lineage-specific for malignant precursor cells. ADCs targeting CD22 (eg, inotuzumab oxomicin and pinatuzumab-vedotin) are ADCs targeting specific B-cell precursors approved for the treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma, respectively .

In hematological malignancies, the target antigen should ideally have little or no shedding into the circulation.

The antibody is linked to the cytotoxic payload through a molecular linker that has a major impact on the overall potency, efficacy, safety, and eventual success of the ADC.

The linker molecule itself is composed of linker, spacer, and release (or “trigger”) components (Figure 2), which must be considered separately in their design, where the attachment site in general plays an important role in overall ADC effectiveness and the most important role in toxicity.

Complementary target attachment sites need to be sufficiently internalized to achieve the desired load of cytotoxic payload.

Linkers can be broadly classified into cleavable (such as Brentuximab-Vedotin) and non-cleavable (such as T-DM1).

To release the payload, the former requires biochemical signals, such as the presence of certain enzymes, while the latter requires spontaneous degradation of the linker.

If the linker is cleavable, it needs to be effectively cleaved in all tumor cells to avoid occurrence in healthy tissues.

Lung Cancer: ADC will play the strong role In the post PD-L1 era

Figure 2 Structure of Bicycle Drug Conjugates

Ideally, the payload capable of efficiently killing tumor tissue would be released from the antigen-ADC complex in tumor cells.

If ADC transport to tumor cells is blocked, high surface expression of antigen on tumor cells alone may not guarantee efficient payload delivery.

This may be influenced by factors such as larger ADC molecules, poorer extravascular matrix distribution of the drug, and poor antigen docking due to local TME effects such as low pH.

Regardless, high antigen affinity tends to correlate with more efficient overall ADC transport in the molecule.

Ideally, the payload should remain stable in the circulation after release from the ADC complex to exert a local antitumor (or “bystander effect”) effect in the surrounding TME (even if independent of the internalization of the ADC receptor complex). , can also exert drug efficacy).

The average value of chemotherapeutic molecules attached to each antibody molecule, known as the drug-to-antibody ratio (DAR), is one of the important properties of ADCs.

High DAR is ideal for maximizing payload delivery. However, excess DAR also affects overall ADC stability in the circulation, affects antigen binding, increases toxicity, and reduces efficacy.

ADCs have a broad spectrum of dose-limiting toxicities, including hepatic, neurological, and ocular-related events.

These toxicities arise primarily from off-target effects caused by the premature release of ADC payloads in circulation, but may also result from ADC binding to noncancerous expressors of target antigens.

Most of the payloads used in ADCs are highly potent and have cytotoxicity in the picomolar range, which is fundamental to the efficacy of ADCs, and only <1% of injected ADCs localize to tumor tissue in the systemic circulation. In addition, antibody binding activity as part of ADC transport may also lead to adverse ADC reactions.

In the field of non-small cell lung cancer, a variety of ADC drugs are currently under development, and this article summarizes ADCs currently being evaluated in phase II/III clinical trials.

These trials explored emerging oncogenic targets (eg, HER2, TROP2) in advanced NSCLC. There are currently no registration trials evaluating the efficacy and safety of early-stage NSCLC ADCs.

1. Trastuzumab (T-DM1)

Currently, a new generation of HER2 inhibitors are used to treat HER2-positive breast cancer, such as monoclonal antibodies (eg, trastuzumab, pertuzumab), TKIs (eg, neratinib, tucatinib), and ADCs.

T-DM1 is an ADC composed of a humanized, monoclonal, anti-HER2-targeting drug, trastuzumab, and a cytotoxic payload, the microtubule inhibitor maytansine (DM1), linked by a thioether linker. HER2 gene overexpression (with or without amplification) is a biomarker for targeted therapy in advanced breast cancer.

T-DM1 is the first ADC drug approved for the treatment of breast cancer, and its pivotal phase III EMILIA clinical trial recruited a total of 991 patients with HER2-positive advanced breast cancer and were randomly assigned to the T-DM1 group and the lapatinib + capecitabine group , the results showed that the median progression-free survival (mPFS) and median overall survival (mOS) in the T-DM1 group were longer than those in the lapatinib + capecitabine group (mPFS: 9.6 months vs 6.4 months) , HR=0.65, P<0.001; mOS: 30.9 months vs 25.1 months, HR=0.68, P<0.001).

In a phase 2 basket trial, patients with HER2-mutant lung cancer achieved a clinical benefit of 44% ORR, with an mPFS of 5 months.

After enrolling additional patients with HER-mutated and/or amplified lung cancer, the updated ORR and mPFS were 51% and 5 months.

Based on the KAMILLA Phase 3 study, in 2013, the FDA approved T-DM1 for the treatment of HER2-positive metastatic breast cancer who had previously received taxane and trastuzumab (TH regimen), and this indication was approved in China in June 2021.

New research data now suggest that TDM1 may have additional antitumor effects in addition to its cytotoxic payload.

TDM1 stimulates ADCC by blocking HER2-HER2 homodimerization and attenuating downstream PI3K/AMT/mTOR and Ras/Raf/MAPK signaling.

This led the researchers to hypothesize that overcoming such resistance mechanisms might resensitize cancers to TDM1 and other ADCs and improve efficacy.

For example, the upregulation of EGFR by tumor cells after TDM1 treatment led directly to the initiation of a phase 2 trial (TRAEMOS) evaluating the efficacy and safety of TDM1 in combination with osimertinib in advanced EGFR-mutant NSCLC.

2. Trastuzumab Deruxtecan (T-DXd; DS-8201)

Trastuzumab Deruxtecan is an emerging, HER2-targeting ADC inhibitor composed of a humanized anti-HER2 IgG1 mAb (trastuzumab) linked to the topoisomerase I inhibitor DXd via a cleavable tetrapeptide linker made.

Compared to TDM1, DXd has a higher DAR (DAR of approximately 8 Deruxtecan molecules/trastuzumab mAb compared to 3.5 molecules/trastuzumab mAb for TDM1).

The Phase 2 DESTINY-Breast01 trial has demonstrated its efficacy as a third-line systemic treatment for patients with advanced HER2-overexpressing or HER2-amplified breast cancer.

Trastuzumab Deruxtecan showed activity even in low-to-moderate HER-overexpressing breast cancer with an immunohistochemical score of 1+ to 2+.

T-DXd was recently approved by the FDA for unresectable or metastatic HER2-positive breast cancer after 2 or more lines of anti-HER2 therapy, and locally advanced or metastatic HER2-positive gastric cancer relapsed after trastuzumab therapy.

The DESTINY-Lung01 study included 2 cohorts of HER2-overexpressing and HER2-mutated advanced NSCLC. The ORR of the HER2-mutant cohort was 61.9% (95% CI, 45.6–76.4%); mPFS was 14.0 months (95% CI, 6.4–14.0 months) ), the mDOR was not reached at the interim analysis, which is encouraging.

However, it is worth noting that about 45% of patients had central nervous system (CNS) metastases at enrollment, and this subgroup was consistent with the overall population in terms of final ORR, PFS, and DOR results.

Based on this data, both TDM1 and TDXd were granted Breakthrough Therapy Designation by the FDA for HER2-mutant advanced NSCLC.

Another point of concern is the safety issue, the significant dose-limiting toxicity of TDXd treatment – interstitial lung disease (ILD).

The incidence in these patients enrolled was 10% (any grade). Up to 10% of patients permanently discontinue treatment due to ILD.

Nonetheless, there are still numerous early clinical trials evaluating TDXs in combination with pembrolizumab/durvalumab + chemotherapy (DESTINY-Lung03).

3. Patritumab Deruxtecan (HER3-DXd; U3-1402)

In fact, HER3 expression is upregulated in advanced EGFR-mutant NSCLC cells (especially when they become resistant to EGFR-TKIs), which is considered to be one of the factors of EGFR/HER2-mediated resistance.

And this part of patients is often in a difficult situation after the failure of EGFR TKI and platinum-based chemotherapy.

Patritumab Deruxtecan is a novel ADC targeting HER3, which is composed of monoclonal antibody Patritumab, a tetrapeptide linker, and the topoisomerase I inhibitor Deruxtecan (Dxd).

Although Patritumab uses the same linker-payload system as T-DXd, Patritumab has a higher DAR than anti-HER2 mAbs.

Its first-in-class formulation is currently in a Phase I/II study in repeatedly-treated EGFR 19 deletion/L858R-mutant NSCLC patients who developed a HER3 mutation during disease progression (HERTHENA-Lung01 study). ).

Its Phase I study, reported at ESMO 2020, showed an ORR of 39% in 57 osimertinib-treated patients with advanced EGFR-mutant NSCLC treated with U3-1402 (HER3 overexpression/mutation is not required) (95% CI, 26.0% – 52.4%), DCR was 72% (95% CI, 58.5–83.0%), median DOR was 6.9 months (95% CI, 58.5 – 83.0%), median PFS was 8.2 months (95CI, 4.4 – 8.3 months).

Likewise, this benefit was seen after resistance to other different EGFR TKIs, including C797S, MET, HER2 amplification, and BRAF mutations.

Eighty-six percent of patients had received prior osimertinib, 96% had received platinum-based chemotherapy, and patients who had received prior chemotherapy had a lower ORR (37%), and an additional 7% developed ILD (any grade).

4. Datopotamab-Deruxtecan (Dato-DXd; DS-1062a)

Datopotamab-Deruxtecan is a ‘first in class’ ADC targeting trophoblast cell surface antigen 2 (TROP2). TROP2 is a ubiquitously expressed transmembrane glycoprotein and is overexpressed in many tumors (eg breast cancer, lung cancer, …) and is of great concern as a poor prognostic feature.

Dato-DXd consists of a humanized anti-TROP2 mAb linked to the cytotoxic drug Deruxtecan payload via a cleavable tetrapeptide linker.

Preliminary data from the open-label TROPION-PanTumor01 study showed that the ORR of Dato-DXd in NSCLC was 21%, the DCR was 67%, and the median PFS was 8.2 months. (TEAEs were dose-dependent between the 8 mg/kg, 6 mg/kg, and 4 mg/kg dose cohorts; included vomiting (34% vs 18% vs 12%), anemia (28% vs 16% vs 6%) , diarrhea (20% vs 11% vs 6%), and mucositis (29% vs 13% vs 6%). The incidence of serious TEAEs in the 8 mg/kg cohort (34%) was that of the 4 mg/kg cohort (10%) 3 times.

Based on these results, 6 mg/kg was selected as the registration randomized Phase 3 TROPION-Lung01 study dose.

In addition, in the TROPION-PanTumor01 study, antitumor activity was also observed with Dato-DXd treatment, with an ORR of 35% and a mDOR of 9.5 months.

5. Sacituzumab Govitecan (IMMU-132, SG)

IMMU-132 is a novel ADC formed by combining a TROP2-targeting mAb with the hinge of SN-38, the active metabolite of irinotecan.

In the phase 1/2 IMMU-132-01 study, patients with refractory metastatic epithelial cancer received different doses of SG treatment (8, 10, 12 mg/kg), among which, the ORR of NSCLC patients was 16.7%, mDOR 6 months, mOS 7.3 months, mPFS 4.4 months.

Another single-arm, multicenter study of previously treated NSCLC patients treated with SG 8 or 10 mg/kg resulted in an ORR of 19% in the efficacy-evaluable population, mDOR 6 months, mOS 9.5 months, and mPFS 5.2 months. >90% of evaluable tumor specimens were highly positive for TROP2 (IHC2+/3+), suggesting that TROP2 cannot be used as a predictive biomarker for efficacy.

Other early-stage trials of novel targeted ADCs in NSCLC

Lung Cancer: ADC will play the strong role In the post PD-L1 era

Lung Cancer: ADC will play the strong role In the post PD-L1 era

References:
1. Marks S, Naidoo J. Antibody drug conjugates in non-small cell lung cancer: An emerging therapeutic approach. Lung Cancer. 2021 Dec 2;163:59-68.

2. EL Sievers, RA Larson, EA Stadtmauer, E. Estey, B. L¨owenberg, H. Dombret, C. Karanes, M. Theobald, JM Bennett, ML Sherman, MS Berger, CB Eten, MR Loken, JJM van Dongen, ID Bernstein, FR Appelbaum, Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse, J Clin Oncol. 19 (13) (2001) 3244–3254.

Lung Cancer: ADC will play the strong role In the post PD-L1 era

(source:internet, reference only)

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