2022 ASCO Insights ADC on the Frontiers of Lung Cancer

Antibody drug conjugates (ADCs) are a class of targeted biological agents that conjugate monoclonal antibodies to cytotoxic drugs through specific connectors, which have both antibody drug targeting and chemotherapy drug tumor killing, and can accurately and efficiently destroy cancer cells

At the 2022 ASCO conference, the power of the "biological missile" ADC drug was highlighted and once again became the focus of

Expert Profiles

Professor Wu Yilong

• Professor of Oncology, Doctoral Supervisor

• Winner of the IASLC Distinguished Science Award

• President of Guangdong Medical Doctor Association (GDMDA).

  
  

• Chief Expert, Guangdong Provincial People's Hospital (GDPH).

  
  

• Honorary Director of Guangdong Lung Cancer Research Institute (GLCI).

  
  

• Chairman of the China Thoracic Tumor Research Collaborative Group (CTONG).

  
  

• 2018-2021 Globally Cited Scientist in the Field of Clinical Medicine

• President of the World Congress on Lung Cancer (WCLC) 2020

• Chairman of the Pulmonary Oncology Society of Guangdong Medical Association

• Former Chairman of the Chinese Society of Clinical Oncology and Chairman of the Steering Committee

Expert Profiles

Professor Wang Zhen

• Chief Physician of Guangdong Provincial People's Hospital/Guangdong Lung Cancer Research Institute

• Master tutor

• In 2014, ASCO funded a visiting scholar in the Department of Oncology at Ohio University

• Participated in internationally renowned multi-center clinical trials such as IPASS, FASTACT-II, OPTIMAL, SATURN, LUX-LUNG6, AURA3, FALURA, CheckMate078 and so on

Targeted CEACAM5 ADC:SAR-408701 treatment NSQ NSCLC shines

Carcinoembryonic antigen-associated cell adhesion molecule 5 (CEACAM5) is a cell surface glycoprotein of the immunoglobulin superfamily

The study found that about 20% of patients with non-squamous non-small cell lung cancer (NSQ NSCLC) overexpressed CEACAM52, making CEACAM5 a potentially attractive therapeutic target.

Fig.

SAR-408701 on ASCO 2022 is once again brilliant! Data on the safety and efficacy of long-term patients in the SAR-408701 Phase I.

Figure 2 Clinical study design for SAR-408701

Figure 3 History of SAR-408701 treatment and duration of PR

Figure 4 Clinical response and CEACAM5 expression distribution of SAR-408701 treatment time ≥ 12 months

In terms of safety, SAR-408701 has been safe and controllable for a long time, and no new or unexpected safety signals
have been observed.

Patients with a treatment time ≥ 12 months experienced intratreatmental adverse events (TEAE) mostly keratitis/keratosis, 8 patients (72.
7%) developed corneal lesions, and 4 patients (36.
4%) developed ≥ 3 grade keratitis adverse reactions
.

Patients can reverse corneal lesions by dose adjustment, and 7 patients undergo subsequent treatment adjustments (delay or delay/dose reduction).


There were no patients who stopped treatment because of corneal lesions, and 1 patient discontinued the drug
due to TEAE (breast cancer).

The antitumor activity and good safety profile of SAR-408701 as an ADC targeting CEACAM5 have been reported
in the early stages.

The results of preclinical trials showed SAR-408701 showing antitumor activity in a variety of CEACAM5-positive xenotumor transplant mouse models (colon, lung, gastric) and a significant dose-response ^{relationship4}
.

Clinical findings evaluating the safety, pharmacokinetics, and antitumor activity of SAR-408701 in patients with NSQ NSCLC presented at the 2020 ASCO Annual Meeting showed that the primary endpoint objective response rate (ORR) of SAR-408701 in patients with advanced CEACAM5 high expression of CEACAM5 in advanced NSCLC patients who had previously received excessive line therapy was 20.
3%.


Sar-408701 is well tolerated and less
hematologically toxic compared to conventional chemotherapy drugs.

The results showed that the proportion of patients with leukopenia, neutropenia and thrombocytopenia treated with SAR-408701 was 14.
4%, 4.
4% and 13.
3% ^{respectively5}
.

Figure 5 Results of the SAR-408701 preclinical (left) and clinical Phase I/II( right) studies

Overall, the long-term clinical benefits and safety benefits and safety of SAR-408701 support its further clinical development, and there is currently a Phase III study (CARMEN-LC03; NCT04154956) is underway to evaluate SAR-408701 monotherapy for patients with previously treated CEACAM5 high-expression NSQ NSCLC, looking forward to the follow-up clinical manifestations of SAR-408701!

Targeting HER3 ADC: HER3-DXd, a new hope after widespread drug resistance

Human epidermal growth factor receptor 3 (HER3) is expressed in 83% NSCLC6, and overexpression of HER3 is associated with poor clinical outcomes.


Currently, patients with advanced NSCLC without EGFR-driven mutations have limited treatment options after failure with or without platinum-containing chemotherapy (PBC) plus or without immunotherapy (IO)^7,8
.

Patritumab-deruxtecan (HER3-DXd) is a novel ADC consisting of a humanized anti-HER3 monoclonal antibody covalently bound
by a stable, lysable tetrapeptide linker to a highly efficiently loaded totopisomerase I inhibitor DXd.

Figure 6 HER3-DXd structure

The HER3-DXd study disclosed at asCO included 47 patients with advanced non-small cell carcinoma who had previously received PBC ±IO and did not have EGFR activation mutations, aiming to evaluate the efficacy and safety of HER3-DXd in advanced NSCLC without EGFR activation mutations
.

The results showed that the OVERALL POPULATION assessed by BICR had an ORR of 28% (95% Cl, 16% to 43%), a median duration of sustained response (DOR) of 5.
7 months (95% CI, 3.
7 to 10.
7 months), and a median progression-free survival (PFS) of 5.
4 months (95% CI, 3.
9 to 12.
7 months).


Subgroup analysis of patients with driver gene mutations (3 patients with KRAS/NRAS mutations, 2 patients carrying ALK fusion mutations) orr was 35% and patients without driver gene mutations orr was 23%⁹
.

Figure 7 Evaluation of the clinical efficacy of HER3-DXd

HER3-DXd is safe and the adverse reactions are controllable, and the most common ≥ grade 3 TEAEs are neutropenia (26%), thrombocytopenia (15%), and fatigue (15%)
.

The incidence of drug-associated interstitial lung disease was 4 (9%), and there were 4 (9%) cases of TEAE associated with interruption of treatment, and no drug-related deaths occurred
.

The data presented this time show that HER3-DXd has good clinical activity
in NSCLC patients without EGFR mutations and mutations in other driver genes.

The overall safety profile was also similar
to previous reports in patients without EGFR mutation NSCLC.

In fact, the ability of HER3-DXd to treat widely drug-resistant cancer has long been highlighted in its Phase I clinical studies
.

The Phase I clinical study of HER3-DXd included 57 patients with advanced NSCLC who had received EGFR-TKI treatment, and the results showed an ORR of 39%, a median DOR of 6.
9 months, and a median PFS of 8.
2 ^months10, indicating that HER3-DXd had good clinical activity
after EGFR-TKI resistance.

Figure 8 Results of the HER3-DXd Phase I clinical study

Targeted c-MET ADC: Teliso-V treatment of c-MET overexpression of NSCLC is sharp

MET is a receptor tyrosine kinase encoded by the MET proto-oncogene, and the amplification or overexpression of the c-MET gene may be one of the mechanisms by which tumor cells develop resistance to EGFR-TKI11
.

Telisotuzumab vedotin (Teliso-V) is an ADC drug composed of c-MET antibody (ABT-700) and microtubule inhibitor (MMAE), which can target Teliso-V to c-MET-expressed tumor cells with high affinity specificity, and exert its role in inhibiting tumor cell mitotic and other functions by inhibiting tubulin polymerization, resulting in tumor
。

Figure 9 Teliso-V structure

In a previous Phase I.
/I.
b study, Teliso-V alone or in combination with erlotinib in patients with NSCLC overexpression of c-MET had surprising efficacy and safety, providing new possibilities for posterior therapy for patients with ^NSCLC12
.

The interim results of the safety and efficacy of the Teliso-V + osimitinib cohort of the trial published at asCO showed ¹³: The Teliso-V + oshitinib cohort was well tolerated in patients with c-MET overexpression of NSCLC who had progressed in osiminib treatment, with an ORR of 58%, of which the ORR at a Teliso-V dose of 1.
9 mg/kg was 67%.


There were 22 (88%) patients with any grade of TEAE during treatment, mainly manifested as neuropathy, nausea, and peripheral edema; There were 8 (32%) patients with ≥ grade 3 TEAE, mainly presenting with anemia and peripheral motor neuropathy
.

Figure 10 Teliso-V + oscitinib cohort efficacy data

Subsequently, Teliso-V took a steady step to open the Phase II study, the M14-239 study
.

The study aimed to identify the dominant population of c-MET overexpression of NSCLC in Teliso-V treatment and to expand the selected group to further evaluate efficacy (Phase 2
).

In Stage 1, patients are included in cohorts defined by tumor histopathology (non-squamous NSQ or squamous Squamous Squamous) and EGFR mutation status (mutant MU or wild-type WT); Non-squamous cohorts are further grouped
according to c-MET expression (high or medium).

This year ASCO updated the data
for the fourth interim analysis (IA4).

Figure 11 M14-239 study design

A total of 136 patients in the study received Teliso-V treatment, and 122 patients had an ORR that could be evaluated
.

The ORR of the NSQ EGFR WT cohort was 36.
5% (52.
2% in the c-Met high expression group and 24.
1% in the c-Met intermediate expression group).


Consistent with the third interim analysis, any of the most common TEAes in treatment were peripheral sensory neuropathy (25.
0%), nausea (22.
1%), and hypoproteinemia (20.
6%)
.

Two patients developed grade 5 TEAE (sudden death and pneumonia in 1 each of the patients in the SQ cohort) that were thought to be possibly associated with Teliso-V14
.

Figure 12 ORR results for each group

Figure 13 DOR results by group

Other target ADCs

With the emergence of ADC drugs in the field of lung cancer treatment, the competition to study ADC drug targets has intensified
.

In recent years, research on NSCLC's HER2, TROP2 targets and SCLC's DLL3 target drugs has been in full swing, these ADC drugs bind to target antigens through monoclonal antibodies, undergo internalization, linker decomposition, and finally release cytotoxin loads to achieve the purpose of killing tumor ^cells15
.

These ADC drugs have a good performance in lung cancer treatment, driving the development of ADC drugs in the field of lung cancer!

Figure 14 Study on the mechanism of action of various ADC drugs in lung cancer

Figure 15 Clinical studies of various ADC drugs in lung cancer

Challenges and outlook

Over the past decade, ADC drugs have made unprecedented breakthroughs, and the development of new ADC drugs has not only brought new treatment options, but also ushered in new challenges
.

As access to ADC drugs expands rapidly, some research data suggest that the continuous use of different ADC drugs for the same antigen may be a proven clinical treatment model, but determining the optimal treatment sequence for different drugs requires clinical exploration
.

In fact, targeted chemotherapy is still chemotherapy, so managing ADC drug payload toxicity is also one of the major challenges facing clinical ^{applications16}
.

With the vigorous development of the industry and the iterative innovation of technology, it is expected that the most reasonable target antigens will be predicted through RNA sequencing and protein expression data in the future to refine the tumor antigen profile and determine the histology that is most likely to benefit from specific ADC drugs; Or design radionuclide-binding ADCs, immunostimulatory molecularly binding ADCs, binding ADCs with different chemotherapy drug loads, etc.
to further enhance the specificity and anti-tumor activity of drugs; As well as in-depth research on the combined application of ADC and other anti-tumor drugs to greatly expand the ability to treat tumors, bringing benefits to all types of cancer patients!

References:

1.
Han ZW, et al.
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2.
Melissa Lynne Johnson, et al.
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Abstract TPS9625.

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Charles Ricordel, et al.
2022 ASCO.
Abstract 9039.

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Decary S, et al.
Clin Cancer Res.
2020; 26(24):6589-6599.

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Gazzah A, et al.
2020 ASCO.
Abstract 9505.

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ScharpenseeI H, et al.
Sci Rep.
2019; 9(1):7406.

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Brueckl WM, et al.
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Santos ES.
Expert Rev Anticancer Ther.
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Conor Ernst Steuer, et al.
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Abstract 9017.

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Jänne PA, et al.
Cancer Discov.
2022; 12(1):74-89.

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Wang Q, et al.
J Hematol Oncol, 2019, 12(1): 63.

12.
Camidge DR, et al.
J clin oncol.
2019; 37(15 suppl):abstract 3011.

13.
Jonathan W.
Goldman, et al.
2022 ASCO.
Abstract 9013.

14.
D.
Ross Camidge, et al.
2022 ASCO.
Abstract 9016.

15.
Desai A, et al.
Lung Cancer.
2022; 163:96-106.

16.
Tarantino P, et al.
CA Cancer J Clin.
2022; 72(2):165-182.