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David J. Stewart, MD, head, Division of Medical Oncology, University of Ottawa/The Ottawa Hospital, discusses a study that investigated the impact of delaying approval on overall survival.

Dr. Stewart on the Impact of Delaying Approval on Overall Survival

Pembrolizumab (Keytruda) in combination with standard of care (SOC) resulted in a statistically significant improvement in event-free survival (EFS) when used for the treatment of newly diagnosed, resectable, locally advanced head and neck squamous cell carcinoma (LA-HNSCC), according to findings from the KEYNOTE-689 (NCT03765918) trial. 

Historically, patients with LA-HNSCC have been treated with either upfront surgery followed by adjuvant therapy or definitive (chemo)radiotherapy. However, outcomes have been suboptimal, and patients suffer from adverse effect toxicities.

KEYNOTE-689 was a randomized trial comparing the SOC with the integration of pembrolizumab, given as neoadjuvant and adjuvant. The trial demonstrated a statistically significant improvement in EFS with the addition of pembrolizumab, with the median EFS being 51.8 months in the pembrolizumab arm vs 30.4 months in the SOC arm.

Additionally, the study showed significant pathological responses in the primary tumor and lymph nodes after neoadjuvant pembrolizumab. While overall survival was not statistically significant at the first interim analysis, follow-up is ongoing. Moreover, the adverse event profile of pembrolizumab and SOC was, in general, similar to SOC alone, and generally well managed.

These results suggest that integrating pembrolizumab into the treatment paradigm for resectable LA-HNSCC represents a significant advancement over the current SOC.

“The current standard of care was established over 20 years ago which, despite multimodality treatment, resulted in suboptimal outcomes. The KEYNOTE-689 results represent a dramatic improvement over the current standard of care. I think it is an exciting time for patients, and all providers who take care of patients with head and neck cancer,” Ravindra Uppaluri, MD, PhD, told 

In the interview, Uppaluri, chief of head and neck surgery at the Dana-Farber Brigham Cancer Center, and chief of the otolaryngology group at the Brigham and Women's Hospital, further discussed these data from the KEYNOTE-689 presented at this year’s AACR meeting.

background regarding locally advanced head and neck cancer?

Newly diagnosed patients with stage III or IV locally advanced head and neck cancer are either treated with upfront surgery, followed by adjuvant therapy, or, nonsurgically, with definitive radiation, without or with chemotherapy. The adjuvant treatment after surgery is dictated by the surgical pathology findings from the resection specimens taken at the time of tumor surgery.

Patients who are considered low risk, those who have primary tumor clear margins and/or have tumor-involved lymph nodes without extranodal extension, are treated with adjuvant radiation after surgery. But if a patient has high-risk features, such as positive margins or extranodal extension, then those patients receive adjuvant chemoradiation after finishing surgery. It's a long process, and this paradigm has been in place for nearly 2 decades now, with the last studies done in the early 2000s. Given this static nature, we have hit a roadblock of improving patient outcomes, and remember these treatments are quite toxic.

It has been an exciting time in oncology, in general, because of immune checkpoint blockade therapies, and this has resulted in a new standard in recurrent/metastatic head and neck cancer. However, combining immune checkpoint blockade with chemoradiation in locally advanced head and neck cancer in the upfront setting has been negative in several phase 3 clinical trials.

With this context and preclinical findings, Douglas Adkins, MD, who is a medical oncologist at [Washington University in St. Louis] and I started early phase studies looking at integrating immune checkpoint inhibitors into surgical management of head and neck cancer patients. Our findings, and also [those] from other studies, were favorable and provided the impetus for the development of KEYNOTE-689.

What did the trial design of KEYNOTE-689 entail?

The trial was a randomized trial with over 700 patients with newly diagnosed locally advanced stage III/IV head and neck cancer, who were planned for surgery and then randomized to either standard of care or integrating pembrolizumab, neoadjuvant—that is, before surgery—and after surgery, along with standard of care, and comparing those 2 arms. It is a really novel trial design in head and neck cancer compared with all the other trials that have been done because of this perioperative component.

I want to highlight that it really requires multidisciplinary teams to make this happen. It is not just single-specialty folks saying we are going to treat cancer patients in a given way. It requires a multidisciplinary group of people to come together to implement this kind of workflow. The primary end point was event-free survival, which is defined as any disease progression or recurrence or death after randomization in the trial.

There were some secondary end points also. The neoadjuvant approach will alter the tumor microenvironment because it will activate the immune system. Studying the immune changes in the tumor, which is called pathologic response, was a secondary end point. An additional secondary end point was overall survival. It is clear from other studies that event-free survival is linked to overall survival, and this is being studied as a secondary end point.

What key findings were presented at AACR?

The key findings that were presented included the endpoints as described above and additional associations that were observed. The statistical design used a sequential strategy, where patient populations were analyzed based on the tumor combined positive score [CPS].

CPS is a commonly used biomarker for describing PD-L1 expression of tumors and the tumor environment, and a CPS of 10 or greater was the first analysis. For the CPS 10 or greater population, EFS was significantly improved in the pembrolizumab with standard of care versus the standard of care arm.

Sequential analysis showed that EFS improved for participants with a CPS of 1 or greater and for all participants in the pembrolizumab with standard of care group compared with the standard of care. For all participants, the median event-free survival across all patients was 51.8 months in the pembrolizumab arm vs 30.4 months after a median of 38.3 months of follow-up. This is highly significant in terms of event-free survival in these patients and was really the most exciting part of the study.

How do these results compare to previous standard-of-care treatments for this patient population?

The previous standard of care was established over 20 years ago, and despite this multimodality treatment, the outcomes were not optimal. KEYNOTE-689 findings dramatically improve over the standard of care. I think it is an exciting time for patients, providers, and all who take care of patients with head and neck cancer.

What findings from the secondary end points of the study were presented?

As I mentioned, there were 2 key secondary end points. One was the major pathological response. We expected that by giving an immune checkpoint blockade before surgery, we would observe pathological responses.

In a blinded, independent pathologic review, neoadjuvant pembrolizumab significantly induced pathologic responses in the primary tumor and lymph nodes compared with the standard of care.

Another secondary end point was overall survival, which on this first interim analysis was not significant. We do see a separation of curves favoring the pembrolizumab plus standard of care arm but at this point, longer follow-up is needed to look at these patients.

Were there any significant adverse events observed in the study, and how were they managed?

In terms of adverse events, both arms of the study had similar general rates. The most common adverse effects were related to the chemoradiation. As expected, in the pembrolizumab plus standard of care arm, there were more immune-mediated events, but there were really no new adverse effects that were observed, and these were generally well managed.

How do you see the findings from the study influencing the development of future trials or treatment strategies in this space?

I think that this trial is exciting for our patients and providers together and sets forth what we think will be a new standard of care for these patients. In terms of future studies, I think that seeing the real-world application is going to be the next exciting phase: that is how this approach is going to be integrated into the current standard of care. This will be something important to observe and also support patients and providers on, because it is a change to our current workflow.

The second aspect of what KEYNOTE-689 has done is to open the window into thinking about these approaches in the surgical setting. We now know this is a safe approach, and the majority of patients in both arms actually went on to surgery. There were really no concerns in that regard. Given that, I think there will be newer investigations looking at additional therapeutics that could be integrated into this type of clinical trial design.

In your opinion, what are the most important unanswered questions or areas of future research?

One key limitation to the study—note, this was designed nearly 7 years ago now—was that we had components of delivering pembrolizumab, both before surgery and after surgery. So which component actually led to the better clinical outcomes is unclear. Maybe giving the drug both before surgery and after surgery is important or one component is more important. I think that is a key question that needs to be answered in the future. It will require a lot more patients and a lot more studies, but I do think that's an important key question.

A second area which I think will be explored is integration of additional checkpoint therapies or other therapeutics combined with pembrolizumab, and we would expect the field to move towards these types of studies.

What else is important for an oncologist to know about this study and these findings?

I think there are 2 points I would like to make. First, in general, there's some hesitation by some providers including surgeons, regarding this idea that immunotherapy is delivered before surgery, and that this may lead to tumor progression or unresectable tumors. But KEYNOTE-689 findings are really reassuring in that sense. Nearly 90% of patients in both arms went on to surgery, and in the pembrolizumab arm, there was only 1 tumor found to be unresectable in nearly 300 patients. I think that kind of data, in terms of the safety of this approach, is very reassuring.

The other thing I would emphasize is this idea that—and I think it has been talked about many times—but locally advanced head and neck cancer care really requires multidisciplinary integration. The idea that only one specialty sees a patient and manages that patient is not ideal for locally advanced head and neck cancer. Moving forward, the KEYNOTE-689 new standard of care will clearly be beneficial for patients and really requires care team integration and discussion upfront in getting these therapeutics to patients and getting them to surgery.

Other than this study, are there any other research or trials in the space that have caught your eye?

One of the other studies in this field that is coming up is an adjuvant immunotherapy study from the GORTEC group in Europe, where they have tested adjuvant immunotherapy in a trial called NIVOPOSTOP [NCT03576417]. These studies address this unmet need in these surgically treated patients, and we are all excited about the next era for patients with head and neck cancer with these approaches integrating immunotherapy.

Ravindra Uppaluri, MD, PhD, discussed the KEYNOTE-689 trial, which investigated pembrolizumab in locally advanced head and neck squamous cell carcinoma.

News

Clinical

Conference News

New Standard of Care? KEYNOTE-689 Results in LA-HNSCC

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) led to a highly statistically significant and clinically meaningful benefit in progression-free survival (PFS) vs taxane, trastuzumab (Herceptin) and pertuzumab (THP) for the treatment of patients with first-line HER2-positive (HER2+) metastatic breast cancer, according to high-level findings from an analysis of the phase 3 DESTINY-Breast09 study (NCT04784715).

“This is the first trial in more than a decade to demonstrate superior efficacy across a broad HER2-positive metastatic breast cancer patient population compared to the current 1st-line standard of care. This is a significant milestone for patients and sets the foundation for [T-DXd] in combination with pertuzumab as an important treatment option in the first-line HER2-positive setting,” said Susan Galbraith, executive vice president of oncology hematology research and development, AstraZenca, in a press release.

The PFS benefit was observed across all patient subgroups. Data for the secondary end point of overall survival (OS) was not mature at the time of this planned interim analysis; however, an early positive trend has been observed in the T-DXd combination arm.

Data from the analysis will be presented at an upcoming medical meeting. A second arm assessing T-DXd monotherapy vs THP remains blinded and will continue to final PFS analysis.

Regarding safety, the safety profile of the T-DXd/pertuzumab combination was consistent with the known profiles of each therapy alone.

“The results from DESTINY-Breast09 reinforce the importance of effectively targeting HER2 to achieve durable disease control early in the treatment of HER2-positive metastatic breast cancer. Building on the positive results seen with [T-DXd] in the second-line setting, these new findings suggest that starting treatment with [T-DXd] in combination with pertuzumab at the time of metastatic diagnosis delays disease progression, postponing the time until additional treatment may be needed,” said Ken Takeshita, global head of research and development, Daiichi Sankyo, in the press release.

 for the second-line treatment of HER2+ breast cancer based on data from the DESTINY-Breast03 study (NCT03529110).

DESTINY-Breast09 is a phase 3 study. Patients were randomized to 1 of 3 treatment arms: T-DXd plus placebo, T-DXd plus pertuzumab, or THP.

The study’s primary end point is PFS, and secondary end points include OS, objective response rate, duration of response, time to second PFS, and patient-reported treatment tolerability.

A total of 1157 patients were enrolled across 284 global sites. Patients aged 18 and older were required to have HER2+ metastatic breast cancer, an ECOG performance status of 0 or 1, and adequate organ and marrow function.

The study has an estimated primary completion date of July 24, 2025.

1. ENHERTU® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival vs. THP as 1st-line therapy for patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. April 21, 2025. Accessed April 21, 2025. 

2. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated December 16, 2024. Accessed April 21, 2025. 

https://clinicaltrials.gov/study/NCT04784715

The DESTINY-Breast09 trial showed that first-line fam-trastuzumab deruxtecan plus pertuzumab improved progression-free survival in HER2+ metastatic breast cancer.

DESTINY-Breast09: T-DXd Plus Pertuzumab Leads in HER2+ Breast Cancer

brought GLP-1 receptor agonists, including semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), to front of mind when discussing general weight loss, and emerging research has focused on the weight loss aspect of GLP-1 agonists for patients with breast cancer. While data has been mainly retrospective, it has ranged from specific patient groups, such as those with hormone receptor–positive disease receiving endocrine therapy

or those only receiving semaglutide and tirzepatide with stage I to III breast cancer,

to patients from the broader breast cancer population receiving a range of GLP-1 agonists.

For the more general population, Sherry Shen, MD, and the other investigators of the study looked at patients with stage 0 to IV breast cancer with any receptor status. “

[GLP-1 agonists] are being used as standard care

, but we don’t know the effect on breast cancer outcomes, which is the most important thing,” Shen said in her interview with 

Peers & Perspectives in Oncology: Could you talk about whether weight gain is an adverse event (AE) in patients with breast cancer and how common it is?

Weight gain is a very common AE for many of our patients with breast cancer. Chemotherapy can induce weight gain. That’s contrary to what a lot of people and patients think. But we give a lot of fluids, we give steroids during chemotherapy, and patients completely alter their eating habits, whether that’s due to feeling nausea or queasiness or the period of chemotherapy with all the other new medications that are introduced. A lot of people may focus on carbohydrates rather than other types of foods during chemotherapy due to tolerability, which is OK but can contribute to weight gain. We know that during chemotherapy, other metabolic parameters worsen too. For example, insulin levels and hemoglobin A1C, which is a measure of glucose control, worsens [and] lipid profile components like total cholesterol, triglycerides, and low-density lipoprotein increase. Those can all get worse during chemotherapy as well.

Beyond chemotherapy, endocrine therapy pills, notoriously, can cause weight gain. It’s been variably reported in the literature. By that, I mean there’s a wide range of weight gain rate associated with these pills, but it seems that across the board, many of them cause or contribute to weight gain, some of which is related to menopause and the metabolic changes that come with that. Tamoxifen and the aromatase inhibitors can all contribute to weight gain. Our patients with hormone receptor–positive breast cancer make up 70% to 80% of patients with breast cancer, so most women are going on these pills at some point, even if they’re not getting chemotherapy necessarily. A lot of different breast cancer drugs can cause or contribute to weight gain.

Please discuss the goal of this retrospective study you conducted. 

There is a lot of interest in GLP-1 agonists currently for many different reasons. But how can we use them in the cancer space, and are they relevant for breast cancer? What we set out to do was to look at patients with breast cancer at Memorial Sloan Kettering Cancer Center in New York.

 [We looked at] patients who had a diagnosis of breast cancer already and who received a GLP-1 agonist for whatever reason, [for] weight management or diabetes, at any point. Our main question was, are patients with breast cancer able to lose weight with these drugs? It was a small cohort of 75 patients with a history of breast cancer diagnosis at any point who had been prescribed a GLP-1 agonist within our system. I will say that historically, we made a lot of referrals outside of our system for weight management. So the vast majority of these prescriptions, almost 80%, were for diabetes and not for obesity or weight management.

What do you feel were the key takeaways? Did you find anything unexpected as you were conducting this trial?

What we found was that the average weight loss was about 5% with a GLP-1 agonist and that the longer patients were on the GLP-1 agonist, the more weight they tended to lose. At around 6 months from starting the GLP-1 agonist, it was over 2 kg. At 12 months from the GLP-1 agonist, it was over 4 kg. By the end of their GLP-1 treatment, it was over 6 kg of weight. We also looked at whether there were any factors, like the kind of breast cancer they had, whether it was hormone receptor positive, whether they were taking those endocrine therapy pills, and whether they had diabetes or didn’t have diabetes. We looked at all these to see whether that affected the amount of weight loss and whether certain characteristics were associated with a greater chance of having greater weight loss, and we did not find any significant associations. But that doesn’t mean that it’s not there. It’s just that this was a small cohort study, so we may not have seen a significant effect, and that may be different if we had a larger group of patients.

I don’t think there was anything surprising, but it was nice to see that patients with breast cancer who may or may not be taking these endocrine therapy pills can still lose weight with GLP-1 agonists. I would hesitate to compare the degree of weight loss that we saw in our study findings with the literature that’s out there in the phase 3 studies, because most of our patients, almost 80%, were getting the GLP-1 agonist for diabetes, not for weight management. So I don’t think it’s fair to that what we saw in our study was not as much as what we see in [findings from] the phase 3 trials. Five percent weight loss is still quite significant, and that’s very comparable to what people can achieve in lifestyle management trials. So it’s nice to see that there is weight loss, and this helps us get a sense of the effect size when we think about how we can use these drugs in clinical trials for breast cancer.

When you looked at the different factors, were you able to see what kind of GLP-1 agonist they were receiving?

We did [look at which GLP-1 agonist the patients received]. It was a small cohort, so we cannot and did not compare the different GLP-1 agonists. Forty-nine percent got liraglutide, 60% got semaglutide, 17% got exenatide, 8% got dulaglutide, and 11% got tirzepatide... The percentages don’t add up to 100 because many of the patients, almost half, had used one and then switched to another, for example.

Were there any differences in treatment for patients who also had diabetes?

Sherry Shen, MD, discusses the GLP-1 agonists analyzed for weight change in findings from a retrospective trial of patients with breast cancer. 

David J. Stewart, MD

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