Ashling Wahner joined MJH Life Sciences in 2022. She produces 

, and helps ensure timely publication of news content and announcements from the FDA approval pipeline. She also attends conferences live and virtually to conduct video interviews and produce written coverage. Email: awahner@mjhlifesciences.com

New treatment methods in patients with small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) are on the horizon, with the introduction of combination immunotherapy, biomarker assays, and supportive oncology programs for patients and care partners, according to faculty from an 

 Institutional Perspectives in Cancer webinar on lung cancer.

, chief of the section of Thoracic Medical Oncology, Levine Cancer Institute, Atrium Health, focused on the clinical benefits of immunotherapy in the frontline setting in advanced NSCLC, the evolving management of SCLC, the role of testing aberrations to discover and treat mechanisms of resistance, and the importance of oncology departments that identify and support patients’ unmet needs.

oncologist, Levine Cancer Institute, Atrium Health

research scientist, Levine Cancer Institute, Atrium Health

dietician, Levine Cancer Institute, Atrium Health

Below, Mileham, Haggstrom, Carrizosa, Beeler, and Szafranski summarize the main points from their presentations.

: The role of immunotherapy in the frontline setting for [advanced] NSCLC continues to expand. Combination immunotherapy with ipilimumab [Yervoy] and nivolumab [Opdivo] and combination chemotherapy [and] immunotherapy are viable first-line options.

Patients that experience immune-related toxicities, now that the recognition and management protocols are in place, can still receive clinical benefit even after cessation without negatively affecting response. Patients who respond [to] or can complete 2 years of maintenance immunotherapy have a significant and durable survival benefit compared with those who cannot.

Additional comparative studies across histologic subtypes in potentially high-risk groups such as patients with active brain disease [that are] powered to compare frontline [immuno-oncology (IO) agents] with chemotherapy/IO combinations continue to be needed.

: At this point in extensive-stage SCLC, we have what we now know is a standard of care using immunotherapy either with durvalumab [Imfinzi] or atezolizumab [Tecentriq] in the first-line setting. This improves overall survival and has changed the course of SCLC.

Unfortunately, remembering the curves [from the data that led to these approvals], a bunch of patients [don’t] respond to this [approach]. We are still looking for second-line therapies.

Lurbinectedin [Zepzelca] is a new option that we’ve been able to come up with recently, and we will see in the next several years if combinations [with this agent] are necessary or where [lurbinectedin] will go in the landscape. We still have both oral and intravenous topotecan that is FDA approved, and we can try and find other ways of trying to treat our patients in the second-line setting. With studies, we’re trying to find other ways to improve maintenance or other forms of treatment that may help these patients.

Unfortunately, as we all know, [SCLC] is a very difficult disease. We have been moving that marker some, as the 2-year [overall] survival [(OS) rate] was very low, less than 10% in historical data, and the 5-year overall survival [rate] was [0%]. Looking at the data with durvalumab, we have improved [OS] significantly. At this point, we’ll have to see how things change over the next several years, but hopefully we will get newer drugs for [SCLC] that will start looking like what we have for [NSCLC].

: [Selpercatinib (Retevmo) and pralsetinib (Gavreto)] are standard first-line therapies for

 fusion–positive [NSCLC]. Additional RET inhibitors are under development, and off-target resistance appears to be a dominant mechanism in [patients] who have progressed on prior therapies for 

The overarching message for this comprehensive, and yet, still touching-the-surface discussion on targeted therapies in [NSCLC] is really that there is no mutation unless you test. Unless you test to identify the aberration, you don’t know if it exists.

Selective treatment, although beneficial, ultimately leads to progression, and, that mechanism of resistance needs to be identified. If you do not test for that mechanism of resistance, you don’t know the direction for the next selective treatment that can be utilized, whether that’s a standard of care, or [one that is] being developed and available in a clinical trial.

Development and Coordination of a Lung Cancer Supportive Oncology Program

: Myself and my colleague Michelle Szanfranski presented information regarding some collaborative work we did with [Atrium Health’s Levine Cancer Institute’s] thoracic oncology department to support the unmet needs of patients and their caregivers, or care partners. This work was presented to demonstrate the ways in which a needs assessment can support departments in supporting their patients and [introduce] the programs that were generated from that work.

[My biggest take-home message regarding this program is] an emphasis on health literacy. It’s certainly good to put these programs together, but they don’t accomplish anything if patients and care partners don’t understand the material. Also, having the support of a leading expert in the department and the section is necessary as well. Dr Mileham served that end and continues to do so.

Another take-home is to constantly reassess the program. Don’t view it as a static piece of information, but rather something that is a living, breathing entity that needs to be revised on occasion.

And, in relation to coming out of the pandemic, one of the things that we learned was to have multiple touchpoints. It’s good to see people in person, but what we also find is that as people have grown more accustomed to these virtual platforms, we can reach a wider audience now, and people can get support when and how it suits their needs.

: We’re [going to] have a continuous review of [patient] unmet needs going forward. We want to continue to engage the patients and their care partner voices. We really want to focus on health literacy. That was one of the things that really shone through in the data we got back. Patients need to be able to understand what our programs and services are about. [Our work also focused on] ease of access and self-referral—we wanted to make it very easy for patients to be able to self-refer to most of these programs.

: What we presented the other night was also a call, a soft sell, to say that what we put together is a model that can serve other departments as well outside of just thoracic [oncology]. This is something that can expand to other departments, other sections, other areas altogether. It’s a model that we hope we can expand on in other areas as a supportive oncology department so other patient bases can benefit from this approach.

Articles

New treatment methods in patients with small cell lung cancer and non–small cell lung cancer are on the horizon, with the introduction of combination immunotherapy, biomarker assays, and supportive oncology programs for patients and care partners.

Lung Cancer Management Methods Expand to Encompass Multiple Treatment Perspectives

The regulatory approvals of fam-trastuzumab deruxtecan-nxki (Enhertu), tucatinib (Tukysa), and margetuximab-cmkb (Margenza), have altered the treatment paradigm for patients with HER2-positive breast cancer. As clinical trials continue to evaluate uses for these and other novel therapies, the question of finding the optimal sequencing approach has remained at the forefront of discussion, according to Mridula George, MD.

The phase 3 CLEOPATRA study (NCT00567190) and phase 3 EMILIA study (NCT00829166) set taxane-based chemotherapy with dual anti-HER2 therapy and ado-trastuzumab emtansine (Kadcyla; T-DM1), respectively, as current standards of care for patients with HER2-positive breast cancer, George said. However, new data from DESTINY-Breast03 (NCT03529110), the first global phase 3 study to compare trastuzumab deruxtecan with T-DM1, presented another efficacious therapy for patients in the second-line setting, George explained.

Furthermore, to better understand the potential role of combination trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without tucatinib, the phase 3 HER2CLIMB-05 trial (NCT05132582), is investigating the triplet as a potential frontline strategy in HER2-positive breast cancer.

“A lot of change is happening, especially in the HER2-positive space,” George said, “It's very important to be aware of the new drugs, new drug approvals, and the changing indications for these drugs. We just must keep our eyes and ears open. These drugs are changing the outcomes in [the HER2-positive] disease population, and our patients are doing much better compared with even 5 or 10 years ago.

, George, medical oncologist, Stacy Goldstein Breast Cancer Center at Rutgers Cancer Institute of New Jersey, discussed the variety of innovative HER2-positive breast cancer treatment options that have recently been approved or are undergoing investigation in clinical trials to broaden the standards of care for patients in this subgroup.

: Could you discuss the current standard of care for patients with HER2-positive breast cancer?

 There have been a lot of new drug approvals, especially in the last 3 years. HER2-positive breast cancer is one of the aggressive subtypes of breast cancer, and patients have poor survival [outcomes].

However, with the approval of trastuzumab, this has significantly changed treatment outcomes in patients with HER2-positive breast cancer. Previously, this subgroup of patients did worse than patients with metastatic triple-negative breast cancer in terms of survival. However, with the new drugs that are available, this has changed.

Since the approval of trastuzumab, there have been a slew of other new HER2-targeted therapies that have been approved, [including] antibody-drug conjugates and TKIs. In the first-line setting, based on the data from the CLEOPATRA study, the current standard is taxane-based chemotherapy with dual anti-HER2 therapy, [which is] routinely trastuzumab and pertuzumab after patients get at least 6 to 8 cycles of taxane. [CLEOPATRA] showed an improvement in progression-free survival [PFS] and overall survival [OS] of 57.1 months [with pertuzumab plus trastuzumab and docetaxel, vs 40.8 months with placebo plus trastuzumab and docetaxel].

In the second-line setting, the current standard of care is ado-trastuzumab [emtansine]. However, that will soon change based on the new data from DESTINY-Breast03 [and trastuzumab deruxtecan], which was recently presented at the 2021 ESMO Congress.

DESTINY-Breast03 studied the utilization of trastuzumab deruxtecan in HER2-positive breast cancer. What are the clinical implications of using this therapy?

Trastuzumab deruxtecan was first approved by the FDA in 2019, based on the single-arm phase 2 study DESTINY-Breast01 [NCT03248492]. That study showed that patients who were heavily treated [with] at least 2 prior lines of chemotherapy had significant benefit with this agent. 

DESTINY-Breast03 was the first global phase 3 head-to-head study, which compared trastuzumab deruxtecan with T-DM1. Patients got trastuzumab deruxtecan at 5.4 mg/kg, given every 3 weeks, or T-DM1 at 3.6 mg/kg every 3 weeks. The primary outcome was PFS assessed by blinded and independent review.

[Initial data showed] that at a median follow-up of 16 months, the median PFS by independent review] with trastuzumab deruxtecan was not reached. However, it was 6.8 months with T-DM1. By investigator review, the median PFS was about 25.1 months with trastuzumab deruxtecan

There was a benefit seen across all subtypes, including patients with brain metastases. Patients with brain metastases could enroll in the study as long as there was a 2-week washout period from the completion of radiation. In those with brain metastases, the median PFS with trastuzumab deruxtecanwas 15 months compared with 3 months with T-DM1. The intracranial objective response was 33.4% with T-DM1 and 63.9% with trastuzumab deruxtecan. the complete response (CR) rate in the brain was 27.8% with trastuzumab deruxtecan compared with 2.8% in T-DM1.

T-DM1 has been the standard of care since the EMILIA study, after which it was approved in the second-line setting. Patients tolerated [T-DM1] well. But now, with the significant clinical benefit that we are seeing in [DESTINY-Breast03], trastuzumab deruxtecan is most likely going to replace T-DM1 in this setting. Especially in patients who have brain metastases, this would be a big benefit because trastuzumab deruxtecan is superior to T-DM1 in patients with brain metastases.

Then, an important question comes up: what is the role for T-DM1 in this space? Do we use T-DM1 in [the] third-line setting? We have other agents in the third-line setting. Tucatinib [Tukysa] is also approved in the second-line setting for patients with brain metastases. How to sequence these drugs [is going to be an interesting question for providers].

Which unmet needs in patients with HER2-positive breast cancer would you like to see addressed in the future? Are there any ongoing clinical trials aiming to address these needs?

A very important study is the phase 3 DESTINY-Breast04 trial [NCT03734029], which showed there was benefit in the HER2-low subgroup. Right now, there is no treatment for the HER2-low subgroup. It’s not even characterized as a separate subgroup. However, with the data that we are seeing with trastuzumab deruxtecan, specifically in DESTINY-Breast04, we are going to focus on this subgroup, and it will be interesting to see how trastuzumab deruxtecanor any of the other anti–HER2-targeted therapies will show efficacy in this space.

The DESTINY-Breast04 study did meet its primary end point, which was PFS, [along with] secondary end points, such as OS in the hormone receptor–positive subgroup of patients.

Some interesting combinations [to explore] would be CDK4/6 inhibitors with trastuzumab deruxtecan. We will have to do a phase 1 study to see how the tolerability of this combination is going to be with hormonal therapy. There are a lot more interesting trials that will be coming out, looking at different combinations in this new subtype of breast cancer, the HER2-low tumors.

What are you most excited about in the future of breast cancer research?

What's exciting is the number of new drugs that are getting approved. [In] 2019, we had trastuzumab deruxtecan and tucatinib. Margetuximab was approved [in 2020]. A lot of new drugs are being approved, and they're approved in the later settings in patients who are heavily pretreated, but they're moving up to frontline settings, so it will be interesting to see how that changes [the treatment paradigm].

Right now in the first-line setting, we are [incorporating] taxane. Is there a subgroup of patients [where] we could eliminate the use of [frontline] taxanes? There is taxane-based neuropathy associated with them. [There are] long-term [adverse effects], and it affects the quality of life for our patients.

It will be interesting to see if there is a subgroup where we could eliminate the taxanes. Can we add drugs like trastuzumab deruxtecan in the first-line setting, and also drugs like tucatinib? Since both tucatinib and trastuzumab deruxtecan have CNS penetration, does that delay the onset of CNS metastases, or does that completely eliminate it? Can we use that as a prophylaxis? We know that HER2-positive breast cancers have a high incidence of CNS metastases.

We currently have HER2CLIMB-05 ongoing, and is open at Rutgers, looking at the combination of trastuzumab and pertuzumab with or without tucatinib. Patients are treated with tucatinib in the first-line setting. It will be interesting to see what that shows.

Another important study that we'll be opening soon is cellular therapy. CAR T-cell therapy is being used in hematologic malignancies. We're trying to use adoptive T-cell therapy in patients with metastatic HER2-positive breast cancer. That's another emerging arena of treatment.

A lot of change is happening, especially in the HER2-positive space. It’s important to be aware of the new drug approvals and the changing indications for these drugs. We just have to keep our eyes and ears open. These drugs are changing the outcomes in [the HER2-positive] disease population, and our patients are doing much better compared to even 5 or 10 years ago.

Mridula George, MD, discusses the variety of innovative HER2-positive breast cancer treatment options that have recently been approved or are undergoing investigation in clinical trials to broaden the standards of care for patients in this subgroup.

Ashling Wahner

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