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WCLC 2020: Novel ADCs
WCLC 2020: What’s New With Novel Antibody–Drug Conjugates in Non-Small-Cell Lung Cancer

Released: March 08, 2021

Expiration: March 07, 2022

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Antibody–drug conjugates (ADCs) are well known to medical oncologists, but no ADC is currently approved in the United States or the European Union for patients with lung cancer. Earlier trials with the ADC trastuzumab emtansine (T-DM1, which is approved for breast cancer) in patients with HER2-overexpressing non-small-cell lung cancer (NSCLC) showed objective responses in IHC3+ tumors. Today, increasing numbers of novel ADCs are currently in clinical trials with a wide range of targets on cancer cells including the HER family proteins and more generally expressed proteins like TROP-2, c-MET, CEACAM5, or Nectin-4. In this commentary, I discuss new efficacy and safety data in NSCLC for 3 ADCs presented at the 2020 World Conference on Lung Cancer (WCLC).

Trastuzumab Deruxtecan
The DESTINY-Lung01 study is a multicenter, open-label, phase II study where patients with advanced nonsquamous NSCLC that were refractory or relapsed on standard-of-care treatment received trastuzumab deruxtecan, a novel ADC that couples a humanized anti-HER2 IgG1 antibody, trastuzumab, to a topoisomerase I inhibitor, deruxtecan. The trial enrolled patients with either HER2-overexpression (cohort 1: IHC 3+ or IHC 2+) or HER2-mutated disease (cohort 2) who were treated with trastuzumab deruxtecan at a dose of 6.4 mg/kg.

The interim analysis of the HER2-overexpressing cohort 1 presented at WCLC included 49 patients at the May 2020 data cutoff—11 patients remaining on treatment and 38 discontinuing treatment due to progressive disease (n = 22), adverse events (n = 9), or for other reasons (n = 7) with the median duration of treatment of 18 weeks. ORR was the primary endpoint. PFS, duration of response (DoR), OS, and safety and tolerability were secondary endpoints.

The efficacy analysis showed an ORR of 24.5% in the overall HER2-overexpressing patient population and a response rate of 20% in IHC 3+ patients (n = 10) and 25.6% in IHC 2+ patients (n = 39). In the overall population, 1 CR and 11 PRs were achieved with a disease control rate of 69.4%, which is notable. The median DoR was approximately 6 months in both of the IHC 3+ and IHC 2+ patient groups.

The waterfall plot analysis revealed that few patients actually had progressive disease as their best response to treatment. PFS was 5.4 months and the median OS was 11.3 months. Of note, these results were obtained in a fairly heavily pretreated population with a median of 3 previous treatments.

All patients experienced treatment emergent adverse events (TEAEs) and 55% of patients experienced grade ≥ 3 drug-related TEAEs—in 8 patients, it was serious, and in 6 patients, the drug was discontinued because of an adverse event. Dose interruptions occurred in 53.1% of patients and 34.4% were drug related.

The most frequently occurring grade ≥ 3 TEAE was decreased neutrophil count. Drug-related interstitial lung disease (ILD) was an adverse event of special interest affecting 8 patients (16%), 3 of whom died, with the primary cause of death being progressive disease in 2 patients and pneumonitis in 1 patient. This adverse event seems to be a class-related event of all 3 deruxtecan-containing ADCs presented at WCLC 2020.

Although drug discontinuation and steroids are important in the handling of drug-related ILD events, there are no identified risk factors for the occurrence of drug-related pneumonitis. Many patients have previously received immune checkpoint inhibitors, many patients have received thoracic radiotherapy, and most patients were smokers.

The DESTINY-Lung01 trial enrolled a second cohort of patients with HER2-mutated NSCLC (n = 42) who were treated as described above, and the data cutoff was November 2019 when the median treatment duration was 7.8 months. The primary endpoint was ORR and secondary endpoints included PFS, OS, DoR, and safety.

The waterfall plot analysis showed that most patients had a decrease in their tumor size with an ORR of 62% including 1 CR and 25 PRs. The median PFS for the whole population was 14 months, and the median DoR and OS were not yet reached in this population, with a median of 2 previous treatments—so a little bit less heavily pretreated than the HER2-overexpressing cohort, but still a fairly heavily pretreated cohort of patients, with an encouraging response rate.

Most TEAEs were gastrointestinal including nausea, vomiting, and decreased appetite. Some patients had decreased neutrophil counts (grade ≥ 3 in 26%) with febrile neutropenia observed in 2 patients. Grade 2 ILD occurred in 5 patients and was easily treated with protocol steroids. No treatment-related deaths were reported by investigators.

Patritumab Deruxtecan
Another ADC that attracted attention at WCLC is patritumab deruxtecan. This ADC, like trastuzumab deruxtecan, consists of the topoisomerase I inhibitor deruxtecan but instead coupled to a monoclonal antibody targeting HER3. At ESMO 2020, this ADC showed significant activity in patients with EGFR-mutated advanced NSCLC previously treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy. At WCLC 2020, Dr. Yu and colleagues presented the current analysis of the dose-expansion cohort in the phase I study (N = 57) that received 5.6 mg/kg patritumab deruxtecan.

In 56 efficacy-evaluable patients, 1 patient (2%) had a CR and 13 patients (23%) had a PR for a confirmed ORR 25%. Regardless of which TKI resistance mechanism was the underlying reason for the nonresponsiveness to EGFR TKIs, this ADC induced responses in patients with known resistance mechanisms to first-line and third-line EGFR TKIs.

Most patients had TEAEs including 67% having grade ≥ 3 severity with thrombocytopenia (28%) and neutropenia (19%) being the most common. Five patients experienced a TEAE that led to treatment discontinuation. There were 3 cases of treatment-related ILD. Three TEAEs were associated with death, but none was treatment related.

In addition, Jänne and colleagues showed that clearance of circulating tumor DNA of EGFR-activating mutations correlated with patritumab deruxtecan responses, and I think this is a useful biomarker to follow patritumab deruxtecan effects in patients with EGFR-mutated NSCLC.

I also think that this agent may emerge as a very useful drug in our armamentarium for the treatment of patients with EGFR-mutated NSCLC. How patritumab deruxtecan will tie in with existing treatments for these patients will be the object of future clinical studies.

Datopotamab Deruxtecan
Datopotamab deruxtecan comprises an antibody-directed against TROP2—a protein that is frequently expressed in NSCLC tumors. In TROPION-PanTumor01, a first-in-human phase I study, Spira and colleagues treated 159 patients with relapsed/refractory, advanced NSCLC with datopotamab deruxtecan at a dose of 4, 6, or 8 mg/kg every 3 weeks. An ORR of 23%, 21%, and 25% was achieved by the 4-, 6-, and 8-mg/kg dose cohorts, respectively. A disease control rate of 73%, 67%, and 80% was observed for the 4-, 6-, and 8-mg/kg doses, respectively. A median PFS of 4.3 months was attained with the 4-mg/kg dose, 8.2 months with the 6-mg/kg dose, and 5.4 months with the 8-mg/kg dose, but the 95% CI for all of the median PFS values overlapped, suggesting no difference.

Regarding OS, I think that ILD is the noteworthy TEAE with an incidence of 8% of treatment-related ILD. ILD was observed in 4 patients with respiratory failure, and an independent adjudication committee judged that 3 of these patients indeed had ILD. Again, this appears to be a class effect of ADCs with the deruxtecan payload that I think we need to be aware of, particularly in patients with NSCLC.

Summary
Various ADCs against different cancer cell epitopes with different linkers and payloads are being developed, and I expect that we will hear about their activity in NSCLC at future conferences. Common adverse events of ADCs currently in clinical trials include nausea, vomiting, cytopenias, and neutropenias, depending on the drug payload. Pneumonitis and ILD are adverse events of this class of drugs. In my own experience, ADCs are very well tolerated over time by the majority of the patients, but I think pneumonitis is the most noteworthy adverse event to watch followed by nausea, vomiting, and cytopenias.

I expect to see initial approvals of ADCs in NSCLC in the coming year, particularly for patients with HER2-mutated disease. In addition, clinical trials are in development to combine ADCs with current standards of care including immune checkpoint inhibitors and combination chemotherapy plus immune checkpoint inhibitors.

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