Jared Weiss, MD, discusses outcomes with first-line Versamune HPV plus pembrolizumab in HPV16–positive recurrent or metastatic HNSCC.

Dr Weiss on Outcomes With Versamune HPV Plus Pembrolizumab in HPV16+ HNSCC

Jared Weiss, MD, professor, medicine, Division of Oncology, Department of Medicine, University of North Carolina (UNC) School of Medicine;associate director, finance, UNC Lineberger Clinical Protocol Office,UNC Lineberger Comprehensive Cancer Center in Chapel Hill, discusses outcomes with the novel therapeutic cancer vaccine Versamune HPV (PDS0101) plus standard first-line pembrolizumab (Keytruda) in patients with human papillomavirus (HPV)16–positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

Results from the phase 2 VERSATILE-002 trial (NCT04260126), presented at the 2024 ESMO Congress, demonstrated strong clinical activity and a tolerable safety profile in patients with HPV16-positive HNSCC, Weiss begins. Patients with recurrent or metastatic HPV16-positive HNSCC were enrolled onto the study and treated with a standard dose of pembrolizumab plussubcutaneous injection of Versamune HPV.

At the data cutoff of May 17, 2024, and with a median follow-up of 16 months, patients with a combined positive score of 1 or higher (n = 53) achieved a median overall survival of 30 months (95% CI, 19.7-not evaluable) and a median progression-free survival of 6.3 months, he states.

The objective response rate (ORR) was 35.8%, including 9.4% complete responses, and the disease control rate (DCR) was 77.4%. Notably, 21% of patients experienced tumor shrinkage between 90% and 100%. Twenty-seven patients remain in follow-up for survival, and 10 were still on treatment at the time of this analysis.

The safety profile was consistent with expectations for pembrolizumab, based on results from the phase 3 KEYNOTE-048 trial (NCT02358031) and typical clinical practice, Weiss continues. Most treatment-related adverse events were mild, with injection site reactions (grade 1 or 2) being the only notable addition. Notably, 9 patients reported grade 3 or higher adverse effects, he adds.

These results support the ongoing investigation of the Versamune HPV vaccine combined with pembrolizumab in the phase 3 VERSATILE-003 trial, which will compare the regimen against pembrolizumab monotherapy in patients with HPV16-positive HNSCC.

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Jared Weiss, MD, discusses outcomes with first-line Versamune HPV plus pembrolizumab in HPV16–positive recurrent or metastatic HNSCC.


Adding the novel therapeutic cancer vaccine Versamune HPV (PDS0101) to standard pembrolizumab (Keytruda) could produce robust, durable responses and improve survival outcomes in the first line for patients with human papillomavirus (HPV)16–positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to Jared Weiss, MD.

Updated data from the phase 2 VERSATILE-002 trial (NCT04260126) presented at the 

 showed that the regimen was well-tolerated and produced high clinical activity. At a data cutoff of May 17, 2024, and a median follow-up of 16 months, patients with a combined positive score of 1 or higher (n = 53) achieved a median overall survival (OS) of 30 months (95% CI, 19.7-not evaluable) and a median progression-free survival of 6.3 months. The objective response rate was 35.8%, 9.4% of which were complete responses, and the disease control rate was 77.4%. Moreover, 21% of patients experienced tumor shrinkage between 90% and 100%. Twenty-seven patients continue to be followed for survival, 10 of whom remained on study treatment at the time of this analysis. Regarding safety, only 9 patients reported grade 3 or higher treatment-related adverse effects. 

Findings support the continued evaluation of Versamune HPV plus pembrolizumab in the phase 3 VERSATILE-003 study (NCT04260126), which will compare the regimen with pembrolizumab monotherapy in HPV16-positive HNSCC.

“One exciting thing about the data presented here was that the survival improvement was not just in the median; the tail of the [OS] curve was substantially raised. If that is confirmed in the phase 3 study, it would change the SOC for recurrent metastatic disease and introduce a conversation about cure rate in this previously incurable [disease],” said Weiss, a professor of medicine in the Division of Oncology, Department of Medicine at the University of North Carolina (UNC) School of Medicine, as well as associate director for finance in the UNC Lineberger Clinical Protocol Office at the UNC Lineberger Comprehensive Cancer Center in Chapel Hill.

®, Weiss discussed the need for better therapeutics in HPV-driven HNSCC due to the increasing risk of progression on curative therapies, detailed key results with the novel therapeutic HPV vaccine plus pembrolizumab in VERSATILE-002 trial, and emphasized the importance of validating the regimen’s efficacy and safety in a phase 3 trial.

: What unmet needs still exist for patients with HPV-driven HNSCC?

: [Unmet needs] are a bit lost in some of the conversation these days about HPV-driven HNSCC. The big story here is that these cancers are easier to cure, if you look at the landscape of locally advanced disease. If I meet an HPV-negative patient in clinic, I have a less than 50% chance of curing them. In contrast, if I meet a patient with HPV-driven cancer, I have over a 90% chance of curing them. At first glance, there wouldn’t seem to be an unmet need in the recurrent metastatic setting. The problem is that, because of slow uptake of preventive vaccination in pediatric populations, the epidemic of HPV-driven HNSCC will not peak until sometime in the 2030s. Although we may cure a larger proportion of patients, the denominator of patients at risk for [progressing on curative therapies] is rapidly rising. Consequently, these patients have an unmet need for better therapeutics.

What was the rationale for incorporating this therapeutic vaccine into first-line treatment with pembrolizumab in the VERSATILE-002 trial?

Viral-induced cancers provide a unique therapeutic vulnerability: cancer associated neoantigens. The Versamune HPV product is a therapeutic vaccine against this, comprising peptides against HPV16 E6 and E7 together with the strong adjuvant R-DOTAP.

VERSATILE-002 was a single-arm, nonrandomized phase 2study comprising standard-of-care [SOC] pembrolizumab with the added therapeutic vaccine product for cancers that were both PD-L1–positive and HPV16-positive.

What key findings from VERSATILE-002 were presented at the 2024 ESMO Congress?

The primary end point of the study was response rate. That was met and has been previously reported. The big findings presented at ESMO 2024 were [on] survival. [Survival] is one of the 2 key reasons, from a human perspective, that we treat [patients with] recurrent metastatic cancer. We want our patients to feel better and we want to preserve and ideally improve quality of life [QOL]. [QOL is] critically important, but very hard to measure. In contrast, our second important human end point is very objective: survival. Here, OS was an impressive 30 months.

Were any new or notable toxicities observed with the regimen?

The safety profile looks like what we expect from pembrolizumab alone, both as reflected in [the phase 3] KEYNOTE-048 trial [NCT02358031] as well as in day-to-day clinical practice. The only thing that was added here were injection site reactions. These occurred in most patients and were all grade 1 or 2.

What further investigations are planned for this regimen?

The purpose of this phase 2 study was to provide a go or no go signal for phase 3 [investigation]. This study met its primary end point and showed impressive survival with a nice tail to the curve. The consequence of that is not approval, but rather [continuation to] the phase 3 [VERSATILE-003] study, and that study is being planned.

What are the potential implications of this research?

When I was trained in HNSCC, I was taught that the cure rate for recurrent metastatic disease was essentially zero. That was happily violated with KEYNOTE-048, where we saw that we could provide durable control [with pembrolizumab]. Now, 10 years after phase 1, we can use the word ‘cure’ for a small but non-zero portion of the population. Ever since, the field of oncology research in general has been desperately seeking to raise that tail to provide a cure, or something that looks as close as possible to cure, to a greater proportion of patients.

Weiss J, Kaczmar J, Harrington KJ, et al. VERSATILE-002: survival with first-line treatment with PDS0101 therapeutic vaccine and pembrolizumab in HPV16-positive recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). 

. 2024;35(suppl 2):S628. doi:10.1016/j.annonc.2024.08.940

Articles

Jared Weiss, MD, discusses survival benefits seen with the therapeutic cancer vaccine Versamune HPV plus first-line pembrolizumab in HPV16-positive HNSCC.

First-Line Versamune HPV Vaccine Bolsters Responses With SOC Pembrolizumab in HPV16+ Recurrent HNSCC

Katharine A. Price, MD, discusses the potential role for injectable HPV-targeted immunotherapy vaccines in HPV16-positive head and neck squamous cell carcinoma.  

Dr Price on the Potential Role for HPV-Targeted Immunotherapy Vaccines in HPV+ HNSCC

Katharine A. Price, MD, associate professor, oncology, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the potential role for injectable HPV-targeted immunotherapy vaccines for patients with HPV16-positive head and neck squamous cell carcinoma (HNSCC).

Several HPV-targeted vaccines are currently being investigated within the HNSCC treatment space, with the most promising data emerging in the first-line recurrent/metastatic setting in combination with checkpoint inhibitors. Although there are some studies looking at these vaccines in treatment-refractory patients, the response rate in that population tends to be lower, Price states. Ongoing trials are also exploring the use of therapeutic vaccines without immunotherapy, she notes. Based on the trajectory of current trials, it is likely that the first indication for these vaccines will be in patients with recurrent/metastatic disease and a combined positive score (CPS) of 1 or greater, Price speculates.

, patients with a CPS of 20 or higher may derive more benefit from these vaccines, similar to what is observed with immunotherapy, Price reports. Some trials are now restricting enrollment to patients with a CPS of 20 or higher, although the planned phase 3 VERSATILE-003 trial will enroll patients with a CPS of 1 or greater, she notes. However, for patients with PD-L1–negative disease, a treatment gap may still exist with the emergence of these therapeutic vaccines, Price says.

Another interesting area of investigation with therapeutic vaccines is in patients with biochemical or molecular recurrences, Price continues. With the increasing use of circulating tumor DNA (ctDNA) assays in routine practice, more patients are being identified who have rising ctDNA levels after curative-intent treatment but no evidence of disease, she elaborates. In these cases, it is conceivable that therapeutic vaccines could be used to prevent or delay significant recurrence, with ctDNA levels serving as a marker for treatment response, Price states.

As research progresses, therapeutic vaccines are likely to become integrated into various treatment paradigms, including the curative-intent setting. For now, the focus remains on studying these vaccines in the first-line recurrent/metastatic disease space, Price concludes.

Katharine A. Price, MD, discusses the potential role for injectable HPV-targeted immunotherapy vaccines in HPV16-positive head and neck squamous cell carcinoma.

Ongoing research is developing increasingly targeted cancer vaccines to boost cure rates for patients with human papillomavirus (HPV)–positive head and neck squamous cell carcinoma (HNSCC), as well as develop more effective therapies for those with HPV-negative disease, according to Katharine A. Price, MD.

®, Price discussed the current status of the HNSCC treatment paradigm, data informing the use of injectable HPV-targeted immunotherapy in patients with HPV16-positive disease, and the importance of broadening access to and education about preventive HPV vaccination.

Price highlighted the clinical implications of the phase 2 VERSATILE002 trial (NCT04260126), which evaluated the cancer vaccine Versamune HPV (formerly PDS0101) plus pembrolizumab (Keytruda) in patients with frontline HPV16-positive HNSCC.

 This combination generated a median overall survival of 30 months among 53 patients with frontline recurrent/metastatic HNSCC. The investigator-assessed best overall response rate was 34% among patients with a PD-L1 combined positive score (CPS) of at least 1 (n = 53) and 48% among those with a CPS of at least 20 (n = 21).

She also noted the design of the phase 3 VERSATILE003 trial, which will investigate Versamune HPV plus pembrolizumab in patients with previously untreated, recurrent/metastatic HPV16-positive HNSCC.

“I don’t think [these cancer vaccines] will be curative for patients who are not [in the curative setting] most of the time, but I think they will be an incremental step forward in improving outcomes and quality of life [QOL], if there are patients in whom we can delay the use of chemotherapy and other more toxic treatments,” Price said.

Price is an associate professor of oncology and a consultant in the Division of Medical Oncology in the Department of Oncology at Mayo Clinic in Rochester, Minnesota.

: What are the current and projected incidences of head and neck cancer and its related causes?

: Head and neck cancer [comprises] a heterogeneous group of cancers, so we can look at incidence—both current and projected—in different ways. If we start broadly and look worldwide at all HNSCC, we’ve seen an increase over the past decade; some data will say even as high as an approximately 60% increase compared with the decade before. In the United States [US] and in many other countries, a lot of that is driven by the increasing incidence of HPV-associated oropharynx cancer. [However, there is] still a high global burden of [head and neck] cancer overall.

In most areas of the world, tobacco use has declined over time, so we’ve seen a decreasing association of smoking-driven cancers, such as [laryngeal] cancer. There have been some declines, mostly related to the decreased use of tobacco. However, there are some concerning and unexplained slight rises in incidence. The one that’s caught our attention in the world of head and neck cancer is a slight increase in the incidence of oral tongue cancer in nonsmoking patients, mostly women. We don’t understand exactly why that [incidence is rising], and it’s still a small number, relatively speaking.

[Head and neck cancer is] an interesting landscape right now. The global burden of HNSCC and the burden in the US are still significant. There’s a lot of attention on health disparities, and I might be a bit more in tune with this because I practice in an area that serves a population that is highly rural. The incidence of HPV-driven cancers in rural areas is continuing to rise steeply, whereas the incidence in more urban areas is going up but has leveled off a bit. A lot of that is related to disparities in preventive HPV vaccination.

Are these preventive HPV vaccination disparities generally due to a lack of access or public opinion about vaccination in general?

If we separate it and consider preventive HPV vaccination as a tool to prevent HPV-associated head and neck cancers and you look at maps of the US, the [map of the] incidence and mortality from HPV-associated cancers can be superimposed on the map of preventive vaccination rates. The lowest preventive vaccination rates are in the Midwest and Southeast compared with the coasts. Those are areas where there are higher incidences of HPV-associated cancer. Those two [factors] are intertwined.

There are a lot of reasons for preventive HPV vaccination hesitancy or lack of uptake, and that’s a complicated issue. Health care access and delivery to more rural areas play a role in that. [A lesser role is played by a lack of] understanding the real reason for preventive HPV vaccination. When we look at access to care for a patient with cancer, rural areas are more challenging [areas to deliver treatment], and we see differences in outcomes [vs in more urban areas]. A lot of data have been published in the oral cavity cancer field about outcomes being different based on access to care and treatments in tertiary referral centers vs non-tertiary centers. These issues are all interconnected, and there’s not one fix for them; however, we should always be working to even out disparities in our health care system, both from a prevention and an access-to-care standpoint.

What is the current prognosis of patients with recurrent and metastatic head and neck cancer, and what is their associated QOL?

Approximately 20% of patients with HPV-associated cancers will have a recurrence after their original treatment. We can stratify that. Patients with large T4 tumors will be at higher risk [for recurrence, as will] patients with a higher nodal burden. Given that a lot of patients are being diagnosed with HPV-positive [head and neck] cancer and it’s the eighth most common cancer in men, we’re still dealing with a lot of patients who have recurrent and metastatic disease, which for most is an incurable cancer and will shorten their life expectancy. 

For HPV-related cancers, QOL is a difficult issue because there are so many factors that go into it. Even [in the context of] a radiation and chemotherapy–based treatment, a patient’s functional outcomes will be different based on the location of their cancer and their radiation field. However, most patients with HPV-associated cancer have a good QOL after all that. Most patients will go back to their life, work, eating, etc.

There are a lot of research efforts—we’ve done some of this work at Mayo Clinic, and lots of other centers have [done this work as well]—investigating: who can we de-escalate therapy for? Some patients can receive de-escalated therapy, but some patients cannot. Having done some of the trials that have evaluated significantly de-escalating radiation therapy after surgery, for HPV-positive patients, QOL tracks with the amount of radiation therapy [they receive]. Higher radiation tends to be [associated with] longer-term adverse effects [AEs] that impact QOL.

We’ve made progress. A challenge [remains] patients who can’t [have treatment] de-escalated and are still stuck with significant treatment toxicities. Even in the time I’ve been practicing, [I have seen] slight shifts in treatment, such as shifts in radiation. Intensity-modulated radiation therapy was a big leap forward. Proton therapy was another incremental leap forward. We’ve seen improvement in toxicities with the migration of treatment trends and expertise over time, but [these are still a] challenge.

For HPV-negative cancers, survival benefits have not changed much over the years. That’s the group of patients that I wake up at night and worry about. For example, [the only treatment options for] patients with oral cavity cancer [are associated with high rates of morbidity]. Most of those patients undergo surgery and then require radiation or radiation and chemotherapy afterward. That group suffers a lot, and we need new treatments, creativity, and new treatment paradigms to try to improve outcomes.

What investigational therapies are of interest to you for patients with HPV-positive and HPV-negative disease?

I and others have done work evaluating the use of therapeutic vaccines for HPV-associated head and neck cancers. A lot of great data are emerging for that, and several randomized studies are [reading out] that will help inform [the use of these cancer vaccines]. The area of viral-driven cancers, such as HPV-associated cancers, is exciting.

Some of my colleagues, Ari Rosenberg, MD, [of UChicago Medicine in Illinois] and Cesar Perez, MD, [of Florida Cancer Specialists & Research Institute in Lake Nona] talked at the 

about some new classes of therapies: antibody-drug conjugates and bispecific antibodies. The preliminary response rates [with these agents are high, and we are] seeing more durability of response. This seems to be the first big improvement in treatment, specifically for HPV-negative patients. We almost never see better response rates in HPV-negative vs HPV-positive patients, and [those improvements have been] encouraging.

There is a lot of excitement about those classes of drugs, particularly for the HPV-negative group, and they can also be applied to the HPV-positive group. Both of those groups will benefit. We’re going to see some exciting data coming out over the next couple years, and hopefully we will even have some of those [regimens] be incorporated into curative-intent treatment paradigms, particularly for HPV-negative patients.

Where might injectable HPV-targeted immunotherapy vaccines fit into the HNSCC treatment paradigm?

Several of these agents are being studied. If we consider the studies that have been done and the ones that are reading out, most of the promising data [with these agents] are in the first-line recurrent/metastatic setting in combination with checkpoint inhibition. There are some data about the use of these therapeutic vaccines in treatment-refractory patients, but as expected, the response rate [in that population] is much lower. There will be some data emerging about response to the therapeutic vaccine alone without immunotherapy. However, if we follow the trajectory of the ongoing trials, based on data with these agents, the first indication will probably be in the first-line recurrent/metastatic setting in combination with current immunotherapy for patients with a CPS of 1 or greater.

Some of the data from the 2024 ASCO Annual Meeting showed that [patients with a] CPS greater than or equal to 20 seemingly have more benefit [with therapeutic vaccines], just as they do with immunotherapy. Some of the [ongoing] trials [investigating therapeutic vaccines in patients with HNSCC] are restricting [enrollment] to that population. The VERSATILE003 trial will not restrict [enrollment to patients with a CPS of] 20 or higher, but it will [restrict enrollment to patients with] a CPS of 1 or higher. For patients with a PD-L1–negative CPS, there is still going to be a treatment void [with the emergence of these therapeutic vaccines].

One of the [populations in which] it would be interesting to see [the efficacy of these therapeutic vaccines is patients with] a biochemical or molecular recurrence. We’re finding a lot of these patients now because we’re using circulating tumor DNA [ctDNA] assays more frequently in routine practice. [These are] patients who have received curative-intent treatment and have no evidence of disease, but then start to have rising ctDNA levels. One could imagine a scenario where we treat those patients with a therapeutic vaccine, follow that level, and see if we can prevent or delay a more significant recurrence in the future.

My colleague, David M. Routman, MD, a radiation oncologist [at Mayo Clinic], is currently running a study [investigating the] therapeutic vaccine [PDS0101] alone or with pembrolizumab prior to curative-intent treatment with either surgical resection or chemoradiation [in patients with HPV-associated oropharynx cancer]. We’ll likely see these therapeutic vaccines be incorporated into other treatment paradigms and into the curative-intent setting. However, right now, the ongoing studies are focusing on [studying these therapeutic vaccines in] first-line, recurrent/metastatic disease.

Based on the data that have read out from VERSATILE002, what CPS subgroup may experience the greatest benefit with the Versamune HPV vaccine?

We always [need to strike] a balance between selecting the patients who are likely to have the most benefit vs [developing an agent] to offer to more patients. [Regarding] a new treatment in a setting where we don’t have a lot of great therapeutic options, I tend to favor being a little more broad and [testing] it in different patients until we have better predictors [of efficacy]. It’s almost a philosophical question of study design. [As oncologists who treat] a lot of patients and are heavily clinically involved, we want to be able to offer a new and different therapy to the patient sitting in front of us, as long as there’s reason to believe it would be beneficial.

In VERSATILE002, and the same will be for VERSATILE003, the CPS cutoff was 1 or higher. We saw responses in patients with a CPS lower than 20. The data will ultimately unfold, and we may end up with indications that are more restrictive; it will just depend on what the randomized data look like compared with immunotherapy alone.

What safety data were seen with the addition of the therapeutic vaccine to pembrolizumab in VERSATILE002?

We didn’t see any signal for worse AEs [with the therapeutic vaccine] or any safety signals compared with immunotherapy alone. Most of the AEs were grades 1 and 2, and even more importantly, most were just related to the vaccine injection site: redness, swelling, and a bit of discomfort for a couple days. We saw some systemic fatigue, mild nausea, and the occasional fever, but [these AEs were] minimal and did not seem to enhance the immunotherapy toxicity profile.

At least in the phase 2 [setting, the therapeutic vaccine] looked safe. If that holds up in the phase 3 setting, [the therapeutic vaccine will be] an important treatment to consider for patients who might not have robust [responses and will subsequently] develop recurrent/metastatic disease, or those who, if they develop recurrence early, are still recovering from their curative-intent treatment. There are clinical scenarios where it’d be helpful to know that there’s a treatment that’s not going to be too toxic.

How has the increased knowledge regarding HPV-associated cancers increased the necessity to advocate for preventive HPV vaccination?

Ask everybody who has influence in the cancer world or elsewhere, such as primary care, to be advocates for preventive HPV vaccination. We’re fortunate that we have a tool that can make a difference in the incidence over time of this disease, but it’s underutilized. Vaccination rates are not where they need to be. As the community that sees the result of not being vaccinated, we have a unique perspective on this and can use that voice to help patients [and health care providers] understand [the importance of HPV vaccination].

I’ve done a lot of talks and outreaches, both with health care providers in the primary care setting and with different groups of individuals—not necessarily patients with cancer, but just regular people and adolescents. There is a lot of misunderstanding about preventive HPV vaccination; most people I’ve talked to outside of the head and neck cancer world don’t even know that it’s a cancer-preventing vaccine. They think it’s just preventing sexually transmitted disease. A lot of messaging has been missed, and as a community, we can use our collective voice and influence to try to help [rectify that].

PDS Biotech VERSATILE-002 phase 2 clinical trial meets primary study endpoints in first line recurrent/metastatic HPV16-positive head and neck cancer. News release. PDS Biotechnology. May 9, 2024. Accessed August 19, 2024. https://pdsbiotech.com/index.php/investors/news-center/press-releases/press-releases1/131-2024-news/918-iotech002hase2linicalrialeetsrim20240509

PDS Biotech aligns with FDA on phase 3 trial in HPV16-positive first-line recurrent or metastatic head and neck cancer. News release. PDS Biotechnology. August 1, 2024. Accessed August 19, 2024. https://pdsbiotech.com/index.php/investors/news-center/press-releases/press-releases1/131-2024-news/933-iotechlignswithonhase3rialin16osit20240801

Katharine A. Price, MD, discusses the use of HPV-targeted immunotherapy vaccines in patients with HPV16-positive head and neck squamous cell carcinoma.

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