Bunn Breaks Down the Latest With Antibody-Drug Conjugates in Lung Cancer

Paul Bunn, MD

Although antibody-drug conjugates (ADCs) have yet to receive regulatory approval in the lung cancer space, several emerging agents are showing early promise in clinical trials, Paul Bunn, MD, said in a virtual presentation during the 21st Annual International Lung Cancer Congress^®, a program developed by Physicians’ Education Resource^® (PER^®), LLC.

Several parts of ADCs call for consideration, according to Bunn. “We have the antibody, and attached to the antibody is the linker, and then a drug or toxin is attached to that. Each of these [components] is extremely important with regard to both efficacy and toxicity,” said Bunn, a distinguished professor of medicine–medical oncology and James Dudley Chair in Cancer Research at the University of Colorado School of Medicine.

“That being said, the selection of the antibody is important. It’s obviously good to have an antibody that would be expressed on almost all tumor cells, and it would be good to have one that is internalized upon binding,” Bunn added. “With respect to the linker, it’s very important that the linker be stable, because if it isn’t stable in the circulation, then the toxin won’t come off and that can cause considerable toxicity.”

In the presentation, Bunn highlighted several novel antibodies with different conjugates that are under examination in the lung cancer space, the early efficacy and safety data reported with these agents, and how they might compare with the approaches that are already widely utilized in patients with this disease.

Trastuzumab Deruxtecan Takes the Stage

Fam-trastuzumab deruxtecan-nxki (Enhertu) is an ADC comprised of 3 components: a humanized anti-HER2 IgG1 monoclonal antibody that possesses the same amino acid sequence as trastuzumab (Herceptin); a topoisomerase I inhibitor payload, which is a derivative of exatecan; and a tetrapeptide-based cleavable linker.

“One of the things that distinguishes this particular ADC from others is that if you count up the number of toxins attached to each antibody molecule, you can see that with the linker, there are 8 drug molecules per every antibody molecule; that is much more than many ADCs,” said Bunn. “Whether that’s the cause of the very high response rate or whether HER2 is just such a great target is unknown at the present time.”

Cohort data from the phase 2 DESTINY-Lung01 trial (NCT03505710) presented during the 2020 ASCO Virtual Scientific Program showed that the novel ADC had favorable clinical activity with a high objective response rate (ORR) and responses that proved to be durable in patients with HER2-mutated non–small cell lung cancer (NSCLC).²

To be eligible for the open-label, multicenter study, patients had to have unresectable/metastatic nonsquamous NSCLC, had to be relapsed/refractory to standard treatment, have HER2-expressing or HER2-activating mutations, and have not received previous treatment with HER2-targeted therapy with the exception of pan-HER TKIs. Patients with HER2-expressing disease (IHC 3+ or IHC 2+) were placed into cohort 1 (n = 42), and those with HER2-mutated disease comprised cohort 2 (n = 42). The ADC was administered at a dose of 6.4 mg/kg every 3 weeks. The primary end point of the trial is confirmed ORR per independent central review (ICR).

Results from cohort 2 showed that the ADC induced a confirmed ORR by ICR of 61.9% (n = 26; 95% CI, 45.6%-76.4%); this included a 2.4% complete response rate and a 59.9% partial response (PR) rate. Furthermore, 28.6% of patients achieved stable disease with trastuzumab deruxtecan, while 4.8% experienced disease progression. Approximately 5% of patients were determined to be unevaluable.

The median duration of response had not yet been reached at the time of the presentation (95% CI, 5.3 months–not evaluable). The disease control rate with the ADC was 90.5% (95% CI, 77.4%-97.3%). Notably, the median progression-free survival (PFS) was 14.0 months (95% CI, 6.4 -14.0).

“The [ORR] was almost as high, or as high as what we see with TKIs, and the PFS was almost as good as a TKI, as well,” said Bunn. “These data are very exciting in my experience; this is the highest response rate and the longest PFS for any ADC presented to date, and it’s likely that the number of drug molecules has something to do with that because other ADCs targeting this [mutation] have not done as well.”

With regard to safety, any treatment-emergent adverse effects (TEAEs) were reported in all patients in the cohort, and grade 3 or high drug-related TEAEs were reported in 52.4% of patients. Serious TEAEs determined to be drug-related were reported in 16.7% of participants.

The most commonly reported TEAEs that were associated with dose reduction included fatigue (11.9%) and nausea (9.5%), and the most common toxicities that led to dose interruptions were decreased neutrophil count (19.0%) and lung infection (7.1%). Although 5 patients had TEAEs that were associated with death, none of these events were determined to be associated with the study drug.

“How does this compare with other agents, including TKIs? TKIs have not had very good activity in insertion 20 HER2 mutations,” said Bunn. For example, afatinib (Gilotrif), dacomitinib (Vizimpro), poziotinib, and pyrotinib have induced response rates of 7.7%, 11.5%, 50%, and 53.3%, respectively—all lower than the 61% response rate observed with trastuzumab deruxtecan. The PFS observed with these agents were 4 months, 3 months, 5.6 months, and 6.4 months, respectively, compared with the 14 months reported with the ADC.

Ado-trastuzumab emtansine (T-DM1; Kadcyla), another ADC in the breast cancer space, was shown to induce a 44% response rate with a PFS of just 5 months. “With trastuzumab deruxtecan, the response rate was 62% with a median PFS of 14 months, way higher than anything else,” stressed Bunn. “These are only phase 2 data, but they are very exciting thus far.”

Novel HER3-Targeted ADC U3-1402 Shows Preliminary Promise

U3-1402 is a potential first-in-class HER3-targeting ADC; it is comprised of a human anti-HER3 antibody that is attached to a novel topoisomerase I inhibitor payload via a tetrapeptide-based linker.³ The agent was developed to both target and deliver chemotherapy into cancer cells while decreasing systemic exposure to the cytotoxic payload.

Preliminary results from a phase 1 trial (NCT03260491) examining U3-1402 in patients with locally advanced or metastatic EGFR TKI–resistant, EGFR-mutant NSCLC showed that the ADC had tolerable safety and antitumor activity.⁴ Of 26 efficacy-evaluable patients, 6 had a confirmed PR, including a patient whose tumor harbored a EGFR C797S mutation.

“This agent has a very similar linker and payload [to that of trastuzumab deruxtecan],” noted Bunn. “This agent showed a response rate of 31% in EGFR TKI-resistant, EGFR-mutant NSCLC. The question is, since the response rate is only about half [of that seen with trastuzumab deruxtecan], is it because the antigen is not so good or because the antibody is not internalized as well? Either way, it’s important to remember that most chemotherapy drugs have a response rate of 10% in this setting, so 31% is still worth pursuing.”

Longer follow-up is needed to validate the early efficacy observed with U3-1402 as well as to elucidate potential biomarkers of response to the ADC, added Bunn. Future directions for research might include examining the agent in combination with EGFR TKIs or with PD-1 blockade.

TROP2 DS-1062a Enters the Picture

DS-1062, a TROP-targeting ADC developed by Daiichi Sankyo Company Limited, is comprised of a humanized anti-TROP2 monoclonal antibody which is attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker.

Updated data with DS-1062 from a phase 1 trial presented during the 2019 World Conference on Lung Cancer demonstrated antitumor activity in unselected patients with unresectable, advanced, NSCLC who are refractory to or relapsed following standard therapy or for whom no standard treatment is available.⁵ 

Specifically, dose-escalation data showed that the ADC induced 12 PRs observed in a dose-dependent manner, which also included 5 confirmed PRs in 7 patients who received the 8 mg/kg dose of the agent. A trend toward response in patients whose tumors expressed Trop-2 and the ADC was observed.

SAR408701 in CEACAM5-Expressing Nonsquamous NSCLC

In a first-in-human study, the ADC SAR408701, which consists of anti-CEACAM5 antibody conjugated to the cytotoxic agent maytansinoid DM4, demonstrated promising antitumor activity in heavily pretreated patients with nonsquamous NSCLC and high CEACAM5 expression.

As of January 2020, a total of 92 patients had been treated with the agent; 28 patients had moderate CEACAM5 expression, while 64 were classified as high expressors. In the moderate expressors, the ADC was found to elicit 2 confirmed PRs, with an ORR of 7.1%.⁶ In the subgroup of high expressors, the ORR was 20.3%, with 13 patients experiencing confirmed PRs. Forty-two percent of patients achieved stable disease. Moreover, in 45 patients who had received prior anti–PD-1/PD-L1 therapy, the ORR with the ADC was 17.8%.

The agent was also found to be well tolerated, with minimal hematologic toxicity versus what is typically observed with conventional chemotherapy. Cases of keratopathy were found to be reversible and manageable when doses of the agent were modified.

“The agent has a response rate of 20%, which is obviously not as high as some of the other ADCs that I discussed, but it’s high enough for the company to undertake a phase 3 trial comparing this agent with docetaxel, which really has a response rate that is presumably less than 20%; this trial is ongoing,” noted Bunn.

Looking Toward the Future

“We don’t have any approved ADCs yet, but I believe that trastuzumab deruxtecan in HER2-mutant and HER2-expressing NSCLC [shows potential]. We need to see more data but the preliminary data look good enough to obtain approval, almost as good as with TKIs, although there seems to be a little more toxicity,” said Bunn. “With these other agents, we will need to see comparator trials with standard chemotherapy to understand what their ultimate role will be in the treatment paradigm.”

References

1. Bunn P. Update on antibody-drug conjugates. Presented at: 21st Annual International Lung Cancer Congress®; July 23-25, 2020. Virtual.
2. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung 01. J Clin Oncol. 2020;38(suppl; abstr 9504). doi:10.1200/JCO.2020.38.15_suppl.9504
3. Updated phase 1 data for Daiichi Sankyo’s U3-1402 in patients with EGFR mutated NSCLC presented at 2019 World Conference on Lung Cancer. News release. Daiichi Sankyo Company, Limited. September 10, 2019. Accessed July 24, 2020. https://bit.ly/30IoO59.
4. Yu HA, Johnson M, Steuer CE, et al. Preliminary phase 1 results of U2-1402—a novel HER3-targeted antibody-drug conjugate—in EGFR TKI-resistant, EGFR-mutant NSCLC. Presented at: 2019 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7-10, 2019. Barcelona, Spain. https://bit.ly/2OU3Pqk.
5. Heist RS, Sands J, Shimizu, et al. First-in-human phase 1 study of DS-1062a (TROP2 antibody-drug conjugate) in patients with advanced non-small cell lung cancer. Presented at: 2019 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7 to 10, 2019; Barcelona, Spain. Abstract MA25.10.
6. Gazzah A, Ricordel C, Cousin S, et al. Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell-adhesion molecule 5 (CEACAM5). J Clin Oncol. 2020;38(suppl 15):9505. doi:10.1200/JCO.2020.38.15_suppl.9505