T-DXd Sequencing and Treatment Options in the Tumor-Agnostic Setting

The expert panel

HER-directed treatment approaches in the tumor-agnostic field were the highlight of the discussion for a panel of experts who convened at the IASLC World Conference on Lung Cancer. The panel was led by Misako Nagasaka, MD, PhD, associate clinical professor in the Division of Hematology/Oncology in the School of Medicine at the University of California (UC) Irvine.

Additional panelists included Rajat Thawani, MBBS, assistant professor of medicine at the University of Chicago Medicine in Illinois; Cathleen Park, MD, assistant professor in the Division of Hematology/Oncology at UC Irvine; Andreas Saltos, MD, medical oncologist and clinical research director in the Department of Thoracic Oncology at Moffitt Cancer Center in Tampa, Florida; Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutch Cancer Center in Seattle; Edward Kim, MD, MBA, physician in chief at City of Hope Orange County, vice physician in chief of City of Hope National Medical Center, professor in the Department of Medical Oncology and Therapeutics Research, and construction industries alliance City of Hope Orange County physician in chief chair, all in California; and Hatim Husain, MD, associate professor of medicine at UC San Diego Health.

The panel highlighted recent approvals and clinical trial updates in all aspects of cancer care that involve HER2 mutations. They also touched on the importance of biomarker testing and looked at the safety profiles of HER2-targeted agents in different cancer types.

Impact of HER2 Expression Across Tumor Types

The detection of HER2 expression has different definitions and different techniques of detection among cancer types. The detection of mutations depends on the ability to offer the correct FDA-approved therapies to patients and enroll them in ongoing clinical trials. Nagasaka asked how to best utilize the HER2 expression and how to incorporate that into lines of therapy.

Thawani mentioned that HER2 overexpression is available on certain panels from different vendors and having that information can be useful for subsequent lines of therapy. Regarding results from the phase 2 DESTINY-PanTumor02 trial (NCT04482309), the response rate of 51.4% allows clinicians to stain for HER2 expression and determine whether patients are eligible for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu).¹

One of Thawani’s concerns, specifically for patients with lung cancer, is for testing to become more accurate, more tissue will need to be taken, and that could lead to bronchoscopy biopsies with fine needle aspirations. He pondered how many times patients will be subjected to these biopsies.

For patients with an immunohistochemistry (IHC) score of 3+, Nagasaka asked Park if she would consider T-DXd either in the first or second line.

“When it comes to a patient with HER2 3+ IHC expression, I’m curious to see more of the data from phase 1b DESTINY-Lung03 [NCT04686305], but I would consider it in the second line if there are no other oncogenic driver mutations.² The next lines of therapy are docetaxel plus or minus ramucirumab [Cyramza], and some of the preliminary results that we’re seeing at least have a better overall response rate than docetaxel as a single agent,” said Park.

HER2-Directed Therapies for NSCLC

T-DXd is currently approved in 2 indications for non–small cell lung cancer (NSCLC). In August 2022, T-DXd was approved for patients with
unresectable or metastatic NSCLC with EGFR2/HER2 mutations detected by an FDA-approved test and who have had prior systemic therapy.³ The second approval occurred in April 2024 for patients with unresectable or metastatic HER2-positive solid tumors who have received prior systemic treatment with no other alternatives.⁴

The phase 2 DESTINY-Lung01 (NCT03505710), DESTINY-Lung02 (NCT04644237) and DESTINY-Lung03, and phase 3 DESTINY-Lung04 (NCT05048797) trials assessed the impact of T-DXd on patients with NSCLC.^5-7

In cohort 1a of DESTINY-Lung01, which led to the April 2024 approval of T-DXd, the confirmed objective response rate (ORR) was 34.1% (95% CI, 20.1%-50.6%). The median progression-free survival (PFS) was 6.7 months (95% CI, 4.2-8.4) and the median overall survival (OS) was 11.2 months (95% CI, 8.4-not estimable).

Husain asked what the prevalence of IHC 2+ was for this population.

“IHC 3+ is about 10%, and then 2+ is about 20% to 25%. It’s quite high, but if you look at the Lancet Oncology paper, there’s a very intriguing waterfall plot with coalterations. There were many patients who had EGFR and then developed HER2 overexpression. It’s possible that since we started to see the data, maybe the patients who were being enrolled were a little bit biased by the investigators because we were trying to look for HER2 2+ and 3+,” Nagasaka said.

Nagasaka explained that HER2 overexpression is a known resistance to tyrosine kinase inhibitors (TKIs), and certain patient populations, like the one in cohort 1a, may benefit from this.

The safety in this study was also something that should be highlighted. In cohort 1a at the 5.4 mg/kg dose, interstitial lung disease that was adjudicated occurred in 2% of patients at grade 4 and 5% at grade 5. Another grade 5 adverse effect (AE) included dyspnea in 2% of patients. The most common grade 1/2 AEs were nausea (68%), fatigue (63%), and decreased appetite (46%).

Nagasaka asked the panel how they would treat HER2 overexpressing NSCLC and in which lines of therapy they would consider using T-DXd. Saltos said looking at the toxicity and efficacy between T-DXd and docetaxel, he would pick T-DXd even though they are similar. Deng would consider T-DXd in the second-line setting and would prefer it over docetaxel as well.

Kim, however, worries about sequencing with immunotherapy (IO). He referred to docetaxel as the topotecan of NSCLC. Thawani pointed out the potential AE of pneumonitis from combining T-DXd with durvalumab (Imfinzi). He highlighted that these discussions always revolve around sequencing, but never the pros and cons of combining treatments.

Husain has had patients start on ado-trastuzumab emtansine (Kadcyla) and transition to T-DXd, and they were able to obtain more robust responses. Saltos has had positive experiences in using T-DXd in patients with HER2-mutated NSCLC. although he is not using RECIST criteria to assess responses.

The DESTINY-Lung04 trial assessed T-DXd as the first-line treatment vs standard of care for patients with HER2-mutated NSCLC.

“I’ve not used T-DXd first line. I’ve just used on-label indications. I have used T-DXd after platinum chemotherapy. Not necessarily all patients will get IO, and some of the considerations are is this for the mutation or the tumor agnostic indication?” pondered Husain. “I’m aware of T-DXd plus IO in these types of strategies, but if there was a strategy of carboplatin plus T-DXd without the IO, I wonder why not consider such a strategy as well?”

Kim noted that this has been the debate for this disease. Should clinicians treat this like a targeted therapy or chemotherapy? He noted that results from the phase 3 KEYNOTE-189 trial (NCT02578680) assessing pembrolizumab (Keytruda) plus pemetrexed for patients with nonsquamous NSCLC will be hard to beat.⁸ He believes in a less-is-more approach, which may not always include a TKI in the first-line setting.

Deng believes that T-DXd treatment is not in the frontline yet, but it does have the potential to beat KEYNOTE-189’s results when all patients have been treated based on its robust response rates.

Husain is interested in seeing results from DESTINY-Lung04 before he makes a decision. He believes its overall response rate at just under 60% could be a rationale for giving T-DXd up front.

“I would consider T-DXd in the first-line setting for HER2-mutant NSCLC. The response rates have been fantastic, and the question that’s already been brought up is how we sequence it,” Park said.

Impact of HER2-Directed TKIs

Nagasaka transitioned the discussion to look at results from the phase 1b BEAMION LUNG-1 trial (NCT04886804).⁹ This trial looked at the use of zongertinib in patients with HER2 NSCLC. Topline results include an ORR of 66.7% (97.5% CI, 53.8%-77.5%; P <.0001).

She also highlighted the results from cohort D of the phase 1 SOHO-01 trial (NCT05099172), which looked at BAY 2927088 for those with previously treated NSCLC. The ORR in this trial was 72.1% (95% CI, 56.3%-84.7%).¹⁰

“Both the response rates looked identical in the 2 studies and seeing a response rate north of [about] 60% is exciting in this field, and both are oral agents. The landscape is rapidly evolving, and by the time we meet again next year, we might be talking about different approvals and different sequencing,” Nagasaka said. “The things to watch out for are that both drugs can cause significant diarrhea and rash.”

Husain compared the toxicity profile of both agents to those of osimertinib (Tagrisso) or alectinib (Alecensa). He believes since clinicians are familiar with how to treat diarrhea and rash, they can be easily treatable. One unmet need he highlighted is understanding the long-term PFS with these treatments.

In response, Nagasaka wants to see more follow-up data to see how the toxicity plays out. Additionally, investigators also claim this drug have central nervous system penetration, but she would like a more robust data set to confirm as well.

Kim thinks zongertinib and BAY 2927088 may get lumped together because of their similar response rates when, in reality, they’re different from each other.

Saltos agreed with Kim and noted that zongertinib has better tolerability than BAY 2927088. Unless there are updated data to show better tolerability with BAY 2927088, Saltos would prefer to use zongertinib. He also believes this could have first-line potential.

Thawani suggested the importance of differentiating the mechanisms of resistance between these drugs and T-DXd. If patients have a resistance mechanism that would prevent them from receiving T-DXd earlier, this may impact overall survival.

“Whether they get intrinsic resistance, or extrinsic resistance will help us determine the sequencing of drugs. Short of that, what you would naturally get inclined toward is using a TKI first and then using an [antibody-drug conjugate] later to prevent the toxicity of chemotherapy. That might not be the strategy that is the most effective one,” Thawani said.

Husain emphasized this point because traditionally, oncogene-directed therapy has bypass pathways that can surface. He mentioned the use of patritumab deruxtecan (HER3-DXd) and the responses observed with the different bypasses. The reasoning behind this is if there are bypass pathways with first-line treatment of a TKI, ADCs can be held back for the second line. He hopes there will be additional information about the resistance of T-DXd, as going from T-DXd to TKI patients may experience salvage if there’s a bypass or another oncogene driver.

HER2 Tumor-Agnostic Trials

Results from the DESTINY-PanTumor02 trial were the next topic of discussion, which led to the approval of T-DXd in the tumor-agnostic disease state in 2024. The trial assessed patients with cervical (n = 40), endometrial (n = 40), ovarian (n = 40), biliary tract (n = 41), pancreatic (n = 25), bladder (n = 41), and other cancers (n = 40). The ORR in all patients was 37.1%, complete response rate was 5.6%, partial response rate was 31.5%, and stable disease was 46.1%. The disease control rate at 12 weeks was 68.2%, and the median duration of response was 68.2%.

Looking at these data across numerous cancer types, the panel wondered what other options lie in the second line outside of lung cancer. If there aren’t other options, perhaps T-DXd could be used for those with IHC 2+.

“I like the idea of sort of these pan-tumor indications. We saw them first with transfusions, which was cool… There’s certainly an unmet need, and a lot of these tumors have immunotherapy involved with them. The fact is that you can start giving some of this as well. I like that,” Kim said.

While Deng doesn’t specialize in many of the cancers from the DESTINY-PanTumor02 study, he noted that those patients who have been pretreated may not have had many options anyway. He hopes there is further investigation because there are not many alternatives.

Nagasaka asked Thawani how to best optimize predictive models to better satisfy patients who may benefit from T-DXd beyond HER2 expression levels.

Thawani, from previous experiences, believes artificial intelligence (AI) can help play a role here. AI has the ability to predict HER2 positivity through a whole-slide image or digital pathology. With the training of models, the prediction of survival may become possible.

References

1. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
2. Planchard D, Brahmer JR, Yang JCH, et al. 1507TiP Phase Ib multicenter study of trastuzumab deruxtecan (T-DXd) and immunotherapy with or without chemotherapy in first-line treatment of patients (pts) with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (OE): DESTINY-Lung03. Ann Oncol. 2023;34(suppl 2):S848-S849.
3. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. News release. FDA. August 16, 2022. Accessed October 4, 2024. https://shorturl.at/5S9S4
4. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. News release. FDA. April 5, 2024. Accessed October 4, 2024. https://shorturl.at/mdlqV
5. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol. 2024;25(4):439-454. doi:10.1016/S1470-2045(24)00064-0
6. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol. 2023;41(31):4852-4863. doi:10.1200/JCO.23.01361.
7. Li BT, Ahn MJ, Goto K, et al. Open-label, randomized, multicenter, phase 3 study evaluating trastuzumab deruxtecan (T-DXd) as first-line treatment in patients with unresectable, locally advanced, or metastatic non–small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations (DESTINY-Lung04). J Clin Oncol. 2022;40(suppl 16): TPS9137. doi.10.1200/JCO.2022.40.16_suppl.TPS9137
8. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non–small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023;41(11):1992-1998. doi.10.1200/JCO.22.01989
9. Boehringer’s zongertinib shows encouraging efficacy and tolerability profile in previously treated HER2 mutated lung cancer patients. News release. Boehringer Ingelheim. September 9, 2024. Accessed October 4, 2024. https://shorturl.at/KisIW
10. Le X, Girard N, Janne PA, et al. Safety and efficacy of BAY 2927088 in patients with HER2-mutant NSCLC: expansion cohort from the phase I/II SOHO-01 study. Presented at: 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7-10, 2024. PL04.03