Initial results from the TROPION-Lung02 Phase Ib trial demonstrated that that datopotamab deruxtecan (Dato-DXd), a specifically designed TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca, in combination with pembrolizumab (Keytruda®; Merck & Co) with or without platinum chemotherapy demonstrated promising clinical activity and a tolerable safety profile in patients with previously untreated or pretreated, advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations.

These results were presented during a late-breaking presentation (#MA13.07) at the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer (WCLC).

Targeted therapy
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of the most advanced programmes in AstraZeneca’s ADC scientific platform, and one of the three leading ADCs in the oncology pipeline of Daiichi Sankyo.

The drug is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers.

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Advanced stage
NSCLC is diagnosed at an advanced stage in nearly 50% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy.[1][2][3]

While 1st-line treatment consisting of immunotherapy with or without chemotherapy has improved outcomes for patients diagnosed with NSCLC without actionable genomic alterations, disease progression still occurs in majority of patients and additional treatment strategies in this setting are needed. [4][5]

Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide. [6]

While the introduction of targeted therapies and checkpoint inhibitors in recent years have improved outcomes for patients with advanced NSCLC, the majority of tumours do not have known actionable genomic alterations. [7][8][9][10]

Current standard of care in the first-line treatment of patients with advanced NSCLC without actionable genomic alterations is immunotherapy with or without platinum-based chemotherapy, based upon PD-L1 expression. While these therapies may improve survival, at least 40 to 60% of tumours do not respond to initial treatment and disease progression occurs, underscoring the need for new therapeutic approaches and options. [11][12][13][14]

Trophoblast cell-surface antigen 2 in NSCLC
Trophoblast cell-surface antigen 2, also known as TROP2, is a transmembrane glycoprotein that is widely expressed in several types of solid tumors, including NSCLC.[15][16[17][18] While TROP2 is expressed across all lung cancer subtypes, the highest expression is seen in adenocarcinoma (64%) and squamous cell carcinoma (75%) cases (the most common forms of NSCLC).[17][19]

Today, there are no TROP2-directed therapies are currently approved for the treatment of patients with NSCLC.[14][20][21]

Unmet medical need
“Many patients with advanced non-small cell lung cancer still experience disease progression following initial treatment, underscoring the need for new therapeutic approaches,” said Benjamin Philip Levy, MD, Clinical Director of Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, Associate Professor of Oncology at Johns Hopkins University School of Medicine and investigator in the TROPION-Lung02 trial.

“The initial results from the TROPION-Lung02 trial show encouraging efficacy and safety results when combining datopotamab deruxtecan and pembrolizumab with or without platinum chemotherapy and warrant further study in the 1st-line metastatic setting,” Levy added.

A broader promise
“Building on preliminary findings of datopotamab deruxtecan combination therapy in triple-negative breast cancer shared earlier this year, these initial results from TROPION-Lung02 reflect the broader promise of combining existing treatments with antibody drug conjugates. We look forward to continuing this important research with the goal of providing a new, effective treatment option for patients with advanced non-small cell lung cancer,” said Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca

“These early findings from TROPION-Lung02 are promising and represent the first lung cancer trial to report results combining a TROP2-directed ADC with an immune checkpoint inhibitor with or without platinum chemotherapy in patients with advanced or metastatic non-small cell lung cancer,” noted Gilles Gallant, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo.

“These data support the initiation of the TROPION-Lung08 Phase III trial to further evaluate datopotamab deruxtecan in combination with pembrolizumab as a 1st-line combination treatment in patients with advanced non-small cell lung cancer without actionable genomic alterations,” Gallant further noted.

Interim Analysis
An interim analysis of the ongoing TROPION-Lung02 trial in patients with previously untreated or pretreated, advanced or metastatic NSCLC without actionable genomic alterations demonstrated a promising overall response rate (ORR) in the overall population of 37% (median follow-up of 6.5 months) in patients treated with datopotamab deruxtecan and pembrolizumab (doublet therapy) and an ORR of 41% (median follow-up of 4.4 months) in patients receiving datopotamab deruxtecan, pembrolizumab and platinum chemotherapy (triplet therapy). A disease control rate (DCR) of 84% was seen with both the doublet and triplet combination therapy in the overall population that comprised both 1st-line and 2nd-line settings.

In previously untreated patients, ORRs of 62% (eight of the 13 patients receiving doublet therapy) and 50% (10 of 20 patients receiving triplet therapy) were observed. Eight partial responses (PRs) were seen in patients receiving doublet therapy and 10 PRs (three pending confirmation) were seen in patients receiving triplet therapy. A DCR of 100% was observed with doublet therapy and a DCR of 90% was observed with triplet therapy.

Combination therapies
Combinations with datopotamab deruxtecan demonstrated a tolerable safety profile, which supports further evaluation in ongoing studies. Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 40% and 60% of patients in the doublet and triplet cohorts, respectively. The most frequent TEAEs of any Grade in the doublet and triplet cohorts respectively were stomatitis (56% and 29%), nausea (41% and 48%), decreased appetite (28% and 38%), fatigue (25% and 36%) and anaemia (16% and 36%). There were four interstitial lung disease (ILD) events determined as drug-related by an independent adjudication committee across both cohorts; two were adjudicated as Grade 1/2 events and two were adjudicated as Grade 3 events. No Grade 4 or Grade 5 ILD events were adjudicated as drug-related. At the time of the data cut-off, there were three potential ILD events pending adjudication.

Three deaths occurred (two within the doublet cohort, one in the triplet cohort), none of which were determined as drug-related. Treatment discontinuations due to adverse events occurred in less than 22% of patients and datopotamab deruxtecan dose discontinuation occurred in 13% of patients.

Study program
A comprehensive global development program called TROPION is underway with trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple solid tumors, including triple negative breast cancer, HR-positive/HER2-negative breast cancer, NSCLC, small cell lung cancer, urothelial, gastric and esophageal cancer. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

TROPION-Lung02 is an ongoing global, open-label, Phase Ib trial evaluating the safety and efficacy of datopotamab deruxtecan at two dose levels (4mg/kg and 6mg/kg) in combination with pembrolizumab (200mg) with or without platinum chemotherapy (carboplatin or cisplatin), in both previously untreated and pretreated patients with advanced or metastatic NSCLC without actionable genomic alterations (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET, MET or other known actionable alterations).

The primary endpoints of TROPION-Lung02 are dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include ORR, duration of response, progression-free survival, overall survival, pharmacokinetics and anti-drug antibodies for datopotamab deruxtecan and pembrolizumab.

Patients in TROPION-Lung02 receiving doublet therapy were previously treated with one median line of therapy, including platinum chemotherapy (60%) and immunotherapy (30%). In the triplet cohort, patients previously received platinum chemotherapy (35%) and immunotherapy (38%). Datopotamab deruxtecan-based combination as a 1st-line of therapy accounted for 33% and 63% of patients in doublet and triplet cohorts, respectively. As of the 2 May 2022 data cut-off, 53% and 77% of patients remained on the doublet and triplet therapy, respectively.

Summary of TROPION-Lung02 results

Overall Population
 Doublet (n=40)Triplet (n=48)
Median Follow-Up6.5 months4.4 months
Efficacy MeasureDoublet (n=38)Triplet (n=37)
ORR, % (confirmed and pending)a37%41%
DCR, %b84%84%
As 1st-Line Therapy
Efficacy MeasureDoublet (n=13)Triplet (n=20)
ORR, %a62%50%
PR, % (confirmed)62%35%
PR, % (pending confirmation)0%15%
DCR, %b100%90%
As 2nd- or Later-Line Therapy
Efficacy MeasureDoublet (n=25)Triplet (n=17)
ORR, % (confirmed and pending)a24%29%

DCR, disease control rate; ORR, overall response rate; PR, partial response; CR, complete response; SD, stable disease
aORR is CR + PR
bDCR is CR + PR + SD

Clinical trials
Datopotamab Deruxtecan (Dato-DXd) in Combination With Pembrolizumab With or Without Platinum Chemotherapy in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung02) – NCT04526691
Study of Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in the First-line Treatment of Subjects With Advanced or Metastatic NSCLC Without Actionable Genomic Alterations (TROPION-Lung08) – NCT05215340

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]

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Featured image: WCLC 2022. Photo courtesy: © 2022 International Association for the Study of Lung Cancer – IASLC WCLC 2022. Used with permission.

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