Inroads to Targeting HER2-Mutant Lung Cancer Begin Taking Shape

Targeted treatment options for patients with HER2-mutant non–small cell lung cancer (NSCLC) have been slow to reach benchmarks for approval given the limited patient populations harboring this disease characteristic. Three classes of agents have demonstrated efficacy in patients with HER2-mutant disease: tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody-drug conjugates (ADCs).¹ As the pool of available data grows for targeted treatments in this molecular subtype, investigators must stay informed about treatment options to optimize patient care, according to Edward S. Kim, MD, MBA.

“There [are] multiple alterations in HER2 we’ve found over the years,” Kim said in an OncLive^® Molecular Targets Workshop. “It’s not just overexpression, we can also have gene amplification mutations. We see this in 1% to 5% of patients with lung cancer and data have showed that this is more frequent in women and never-smokers. We’re seeing more of these EGFR family mutations and most of these HER2 mutations occur in exon 20.”² Kim is physician in chief at City of Hope Orange County and vice physician in chief at City of Hope National Medical Center, both in California.

Limited progress has been demonstrated with standard NSCLC treatments for patients such as chemotherapy and immunotherapy among patients with HER2-mutant tumors. “Chemotherapy [had] some limited degrees of efficacy [and] immunotherapies have been looked at,” Kim said. “Multiple TKIs have been developed that have a wider range of target nonspecificity.” For example, afatinib (Gilotrif) is approved for patients with NSCLC whose tumors have nonresistant EGFR mutations.³ Despite early efficacy supporting a new drug application for the pan-HER TKI poziotinib for previously treated patients with locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations, a recent meeting the FDA’s Oncologic Drugs Advisory Committee voted 9-4 that poziotinib’s benefit do not outweigh its risks.⁴

“We’re seeing some activity with TKIs, especially in the mutation side, but there is also activity with monoclonal antibodies such as trastuzumab [Herceptin] in combinations, and ADCs. They’ve been around for some time; however, they have been accelerating as far as the number of indications and drugs that have been coming to market,” Kim said.

HER2-Directed ADCs Enter the NSCLC Space

Investigators have attempted to translate the success of HER2-directed ADCs from breast cancer to NSCLC. “ADCs focus on using the overexpression of a receptor that the antibody portion [of the agent] binds to,” Kim explained. “Once you use that antibody to link that receptor, the drug and the payload are distributed when that drug that gets into the cell. It will cause liposomal degradation and the cleaver releases the payload inside, [resulting in] damage to the cell and then eventually cell death.”

The bystander effect is also a feature of the ADC, Kim added. “[The ADC is] delivering this cytotoxic drug intracellular, but there is also a bystander effect to nearby cells. That’s where we can see some of the toxicities that can occur.”

Kim discussed results of a single-arm multicenter phase 2 study (NCT02289833) of ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive advanced or metastatic NSCLC who had received prior platinum-based chemotherapy. If patients had EGFR- or ALK-positive disease, they would have received prior targeted therapy prior to enrollment.⁵

Patients were divided into 2 cohorts based on baseline immunohistochemistry (IHC) intensity: IHC 2+ (n = 29) or IHC 3+ (n = 20). T-DM1 was administered at a dose of 3.6 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The primary end point of overall response rate (ORR) was evaluated among 49 treated patients. The median age was 61 years (range, 36-80), 29 patients were prior smokers, 10 were current smokers, and 10 never smoked. Most patients received 2 or more prior lines of therapy (n = 34).⁵

In the IHC 2+ cohort, the median follow-up was 23.1 months, and no patients responded to treatment. Eight patients (28%) had stable disease (SD). In the IHC 3+ cohort, the ORR was 20% (95% CI, 5.7%-43.7%), with all responders reporting a partial response (PR) and 4 patients reporting stable disease. The clinical benefit rate was 7% and 30% in the IHC 2+ and 3+ cohorts, respectively.⁵

“These responses are typical of what we saw in the old chemotherapy days—these balanced waterfall plots,” Kim said. “But certainly 20% response in a heavily pretreated population with a targeted therapy offered some hope that there might be some efficacy in this particular tumor aspects.”

The median progression-free survival (PFS) was 2.6 months (95% CI, 1.4-2.8) and 2.7 months (95% CI, 1.4-8.3) in the IHC 2+ and 3+ cohorts, respectively. The median overall survival (OS) was 12.2 months (95% CI, 3.8-23.3) and 15.3 months (95% CI, 4.1-not estimable [NE]), respectively.5 A safety analysis of the agent showed that the median duration of treatment was 3.6 months (range, 0-24.8). Adverse effects (AEs) of grade 3 or 4 higher were reported among 10 and 1 patients, respectively.

“There were some grade 3 and not too many grade 4 toxicities, with fatigue being the only grade 3 AE reported in more than 1 patient,” Kim said. “Ten patients withdrew from study treatment because of AEs. [This treatment was] not without some toxicity, but overall, pretty well tolerated from a grade 3 and higher AE perspective.”

An Approval Set a Course for ADCs in HER2-Mutant Disease

In August 2022, the FDA granted accelerated approval to the first HER2-targeted treatment for patients with NSCLC. Fam-trastuzumab deruxtecan-nxki (Enhertu) was approved for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy based on data from the phase 2 DESTINY-Lung02 trial (NCT04644237).⁶

Trastuzumab deruxtecan was examined at a dose of 6.4 mg/kg (n = 152) across several trials, as well as at a dose of 5.4 mg/kg (n = 102) in a randomized dose-finding trial. Response rates achieved with the agent were consistent across the dose levels evaluated. However, increased rates of interstitial lung disease/pneumonitis were noted at the higher dose. The recommended dose of the agent is 5.4 mg/kg every 3 weeks.

Kim highlighted data from the DESTINYLung01 study (NCT03505710) were presented in which patients were treated with trastuzumab deruxtecan at a dose of 6.4 kg/mg in the expansion cohort of the trial (n = 91) to demonstrate the efficacy of the agent.⁷

The ORR was 54.8% with 1 patient having a complete response and 49 having a PR. The disease control rate was 92% and the median duration of response (DOR) was 9.3 months (95% CI, 5.7-14.7). The median PFS was 8.2 months (95% CI, 6.0-11.9) and the median OS was 17.8 months (95% CI, 13.8-22.1).⁷

“When looking at HER2 mutations, 86% of them were in exon 20,” Kim said. “There’s also HER2 protein expression [83%], as well as a very low number of HER2 gene amplifications [4.4%]. [That’s] a very impressive waterfall plot in this patient population, and this is what we like to see especially in our era of precision medicine—these types of waterfall plots.”

At the time of data cutoff, 16.5% of patients remained on treatment and 25% discontinued because of drug-related AEs. Adjudicated drug- related interstitial lung disease, a known associated effect of treatment, was reported in 24 patients—grade 1/2 (n = 18), grade 3 (n = 4), and grade 5 (n = 2).⁷ Thirteen cases were fully resolved at data cutoff. “This is something that can sneak up on clinicians—asymptomatic cough, other respiratory aspects, there could be pneumonitis [as well],” Kim said.

For the basis of the approval, the FDA reviewed data from patients treated in DESTINY-Lung02. Participants were selected for treatment with trastuzumab deruxtecan if an activating HER2 mutation was present in their tumor specimen; they were administered the ADC at 5.4 mg/kg every 3 weeks until progressive disease or intolerable toxicity.⁶

The primary efficacy population comprised 52 patients. The median age was 58 years (range, 30-78) and most patients were women (69%) and Asian (79%). Data showed that trastuzumab deruxtecan elicited a confirmed ORR of 58% (95% CI, 43%-71%) with a median DOR of 8.7 months (95% CI, 7.1-NE). Response was assessed by blinded independent central review and RECIST 1.1 criteria.⁶

The most common toxicities experienced by 20% or more of patients included decreased white blood cell count, hemoglobin level, neutrophil count, lymphocyte count, platelet count, and albumin level. Other common AEs included increased aspartate aminotransferase and alanine aminotransferase levels, as well as nausea, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase level, and alopecia.

Bringing New Therapies Into Practoce

Although trastuzumab deruxtecan is only approved in the second-line or later settings, moderator Paul A. Bunn, MD, asked Kim what these data mean in the treatment landscape for patients with HER2-mutant disease. Kim replied, “A lot of us have a bias [to use a targeted therapy] if we see a driver mutation or a biomarker approach and it can result in less total therapy being delivered to the patient, especially when balanced with an efficacy that we ‘find acceptable.’ Sometimes we’re a little disappointed with response rates of single agents in biomarker populations when they’re less than 50%. But when they start hitting 50% or higher, you get a little more positive. I would be very comfortable treating patients in the first-line setting with drugs like trastuzumab deruxtecan, especially if I could delay the use of different type of cytotoxic chemotherapy or other base [therapy].”

He added that lung cancer is not thought of in lines of therapy. “We try to think of how much therapy we can give patients in totality, and we know that there will be resistance that comes up. But now we have biologics, we have different mutations, drivers, and [treatment] is about trying to get in the most therapy we can in total and expand disease control over the longest period.”

First and foremost to implementing these new therapies is identification of the markers: “We don’t routinely test every individual [for HER2 expression] right now. I think it’s something that we can do, it can be done very quickly and easily,” Kim said.

He added that HER2 expression does not change much across lines of therapy and thus is something to capture at baseline. “We’ve got different approaches now to attack this biomarker, whether it’s through mutations, through expression. And I think something that looked very small and something we’ve been lingering about for quite some time is now becoming a very relevant marker,” Kim said.

References

1. Cooper AJ, Gainor JF. Human epidermal growth factor receptor 2–mutant non–small-cell lung cancer: continued progress but challenges remain. J Clin Oncol. 2022;40(7):693-697. doi:10.1200/ JCO.21.02550
2. Jebbink M, de Langen AJ, Boelens MC, Monkhorst K, Smit EF. The force of HER2 - a druggable target in NSCLC? Cancer Treat Rev. 2020;86:101996. doi:10.1016/j.ctrv.2020.101996
3. Gilotrif. Prescribing information. Boehringer Ingelheim Pharmaceuticals Inc; 2022. Accessed September 26, 2022. bit.ly/3raV8eA
4. September 22-23, 2022 meeting of the Oncologic Drugs Advisory Committee (ODAC) – Day 1. FDA YouTube page. Accessed September 22, 2022. bit.ly/3dFRtlU
5. Peters S, Stahel R, Bubendorf L, et al. Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: efficacy, safety, and biomarkers. Clin Cancer Res. 2019;25(1):64-72. doi:10.1158/1078-0432. CCR-18-1590 FDA grants accelerated approval to fam-trastuzumab deruxtecan- nxki for HER2-mutant non-small cell lung cancer.
6. FDA. Updated August 16, 2022. Accessed September 26, 2022. bit.ly/3bVts9g
7. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431