Combination of drugs causes tumours to vanish in some terminally ill patients, study finds

Author: Andrew Gregory, Health editor

In a landmark trial, a cocktail of immunotherapy medications harnessed patients’ immune systems to kill their own cancer cells and prompted “a positive trend in survival”, according to researchers at the Institute of Cancer Research (ICR), London, and the Royal Marsden NHS foundation trust.

One patient, who was expected to die four years ago, told the Guardian of the “amazing” moment nurses called him weeks after he joined the study to say his tumour had “completely disappeared”. The 77-year-old grandfather is now cancer-free and spent last week on a cruise with his wife.

Scientists found the combination of nivolumab and ipilimumab medications led to a reduction in the size of tumours in terminally ill head and neck cancer patients. In some, their cancer vanished altogether, with doctors stunned to find no detectable sign of disease.

Combining the two immunotherapy drugs could prove an effective new weapon against several forms of advanced cancer, experts believe. Results from other trials of the drug combination have previously suggested similar benefits for terminally ill kidney, skin and bowel cancer patients.

As well as boosting the long-term survival chances of patients, scientists said, the immunotherapy treatment also triggered far fewer side-effects compared with the often gruelling nature of “extreme” chemotherapy, which is the standard treatment offered to many patients with advanced cancer.

The results from the phase 3 trial, involving almost 1,000 dying head and neck cancer patients, were early and not statistically significant but were still “clinically meaningful”, the ICR said, with some patients living months or years longer and suffering fewer side effects.

“These are promising results,” Prof Kristian Helin, the ICR chief executive, told the Guardian. “Immunotherapies are kinder, smarter treatments that can bring significant benefits to patients.”

About 12,000 people in the UK are diagnosed with head and neck cancer every year and many will be diagnosed at advanced stages. There is an urgent need for better, kinder treatments for these patients that can keep them alive longer than the current standard of care.

When Barry Ambrose, 77, from Bury St Edmunds, was diagnosed with throat cancer in 2017, he was told that it had already spread to his lungs – and that hospital palliative care was his only option.

But in a turn of events that saved his life, Ambrose was offered the chance to join the new study. “When I was told about the trial … I didn’t hesitate to join – what did I have to lose? It turned out to be a lifeline.

“Although I had to make biweekly trips from Suffolk to the hospital for the treatment, I had virtually no side-effects and was able to carry on as normal doing the things I love: sailing, cycling, and spending time with my family.”

Within about eight weeks of starting the treatment, scans revealed the tumour in his throat had been eradicated.

“When the research nurses called to tell me that, after two months, the tumour in my throat had completely disappeared, it was an amazing moment,” said Ambrose. “While there was still disease in my lungs at that point, the effect was staggering.”

He later underwent chemotherapy, followed by surgery. He currently has no evidence of disease.

“The treatment I’ve received at the Royal Marsden has been second to none and I’m so fortunate they’ve continued to find treatment that works for me – they’re the gift that keeps on giving,” said Ambrose. Last week he enjoyed a cruise off the coast of the UK with his wife, Sue.

The results of the trial show the immunotherapy combination enjoyed a particularly high success rate in a group of patients whose tumours had high levels of an immune marker called PD-L1.

Survival rates in those with high levels of PD-L1 who received the immunotherapy cocktail were the highest ever reported in a firstline therapy trial of relapsed or metastatic head and neck cancer.

These patients lived an average of three months longer than those having chemotherapy. The median overall survival for these patients was 17.6 months, the highest average ever reported in this group of patients.

Researchers said they hoped future findings from the CheckMate 651 trial, funded by Bristol Myers Squibb, will show further benefits of the therapy in patients with advanced head and neck cancers.

“Despite the lack of statistical significance, these results are clinically meaningful,” said Prof Kevin Harrington, professor of biological cancer therapies at the ICR and consultant clinical oncologist at the Royal Marsden, who led the CheckMate 651 trial. “We will need to do longer follow-up to see whether we can demonstrate a survival benefit across all patients in the trial.”

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Cancer Cell Map Initiative reveals protein interactions that drive cancer

Author: Leah Sherwood, The Science Advisory Board assistant editor

A research group has mapped previously unknown interactions between proteins that drive cancer, thereby revealing potential new biomarkers and drug targets. The findings were published in a trio of papers in Science on October 1.

The research is the work of the Cancer Cell Map Initiative (CCMI), a multi-institution research program founded in 2015 at the University of California, San Diego (UCSD) and San Francisco (UCSF) campuses.

From the gene level to the protein level
The CCMI approach seeks to gain a more expansive view of the activity underlying cancer by zooming in from the gene level to the protein level, which is far more detailed. “This is an entirely new way to do cancer research,” Nevan Krogan, PhD, director of UCSF’s Quantitative Biosciences Institute and co-senior author of the papers, said in a statement. “We realized we need another way to look at cancer that takes it a step beyond DNA.”

Genes contain instructions for building proteins, which then interact with other proteins. When gene mutations cause disruptions, they are reflected in the interactions among protein complexes that regulate activities in the body or turn individual functions on or off. For example, if a gene mutation results in misshapen protein, it may not interact correctly with other proteins, causing a loss of function that, in some cases, can lead to cancer.

“We’re elevating the conversation about cancer from individual genes to proteins, allowing us to look at how the varying mutations we see in patients can have the same effects on protein function,” Trey Ideker, PhD, professor at the UCSD School of Medicine and co-senior author, said. “We’ve produced the first map looking at cancer through the lens of interactions between proteins.”

Mapping protein-protein interactions
The CCMI scientists used affinity purification-mass spectrometry (AP-MS), a technique for isolating and identifying binding partners to a target protein, to catalog protein-protein interactions (PPIs) across mutant and normal protein forms and across cancerous and noncancerous cell lines. The targets were protein complexes formed by about 60 genes commonly involved in either breast cancer or cancers of the head and neck.

In the first paper (Science, October 1, 2021, Vol. 374:6563), CCMI scientists analyzed PPI data from head and neck squamous cells. By comparing the results from the cancerous and noncancerous cell lines, they identified hundreds of distinct cancer-specific interactions, some of which may be potential therapeutic targets. Of the 771 PPIs identified, 84% had not been previously reported in public databases.

The PPI mapping for head and neck cancer also uncovered a specific set of interactions with the phosphoinositide 3-kinase (PI3K) pathway — which is commonly mutated in tumors — that were predictive of drug response.

In the same Science issue, another paper targeted 40 proteins associated with breast cancer. Again, the AP-MS process identified hundreds of PPIs, approximately 79% of which had not been previously reported. The study also identified two proteins connected to the tumor suppressor gene BRCA1, as well as two proteins that regulate PIK3CA.

A third paper from the issue combined the new PPI data from the first two CCMI papers with existing public data to generate a map of protein pathways that revealed previously hard-to-detect mutations potentially important in tumor metastasis.

Looking for new biomarkers and druggable targets
By revealing the protein biochemistry of tumor pathways, the PPI networks mapped by the CCMI team can facilitate cancer diagnosis and prognosis and the identification of druggable targets. For example, many of the biomarkers that physicians depend on to determine whether a particular cancer drug might benefit a patient are mutated genes. According to Ideker, however, understanding the interactions between protein complexes can reveal a new class of potential biomarkers.

“The problem is that we’ve only found a few genes that we can work with in this way to help guide prescription of an FDA-approved drug,” he said. “Our studies provide a new definition of biomarkers based not on single genes or proteins but on the large, multiprotein complexes.”

A specific example is given in the breast cancer paper, where the authors identified the enzyme ubiquitin conjugating enzyme E2 N (UBE2N) as a potential biomarker of response to poly (ADP-ribose) polymerase inhibitors (PARPi) and other therapies targeted at DNA repair.

“Identification of UBE2N as a potential biomarker for PARPi response could be clinically valuable to help stratify patients with UBE2N alteration for targeted therapy,” they wrote.

Still missing: the specific pathways
In a perspective article (pp. 38-39) accompanying the CCMI papers in Science, Stanford University scientists Ran Cheng and Peter Jackson noted that the missing piece of the puzzle is a consolidated map that organizes specific mutations into pathways that drive tumor growth.

“A clearer picture would emerge if mechanisms critical for tumor growth were better consolidated into specific pathways,” wrote Cheng and Jackson. “Identifying and consolidating these pathways and identifying how combinations of pathways drive cancer will simplify our search for effective cancer therapies.”

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How Stanley Tucci lost his taste — and almost his love of food — to cancer

Author: Hailey Eber

With his recent hit culinary quest show, “Searching for Italy,” and food-focused cult films such as 1996’s “Big Night” and 2009’s “Julie & Julia,” Stanley Tucci has established himself as not just an actor but also a serious epicurean.

But, in his new memoir, “Taste: My Life Through Food” (Gallery Books), the 60-year-old reveals that he almost lost his love for food after he was diagnosed with an oral cancer four years ago.

“There were times when I believed I would never ever be able to cook or enjoy a meal again with the people I love,” writes Tucci, who grew up in a large Italian family in Katonah, NY, and spent a year living in Italy in his early teens.

When a dentist first told Tucci that the pain in his mouth might be due to an oral cancer of some sort, he writes that he “was stunned to the point of almost fainting.”

Kate, his first wife and the mother of three of his children, died in 2009 after a lengthy battle with breast cancer. He was eventually diagnosed with cancer of the salivary gland and was hesitant to get treatment having seen how painful and ultimately futile it was for Kate. But knowing the cure rate for his type of cancer was nearly 90 percent — and that his current wife, Felicity, was pregnant — he went through it.

Doctors initially wanted to remove the tumor at the base of his tongue, but that would have meant losing half his tongue and the ability to speak normally, which wasn’t an option. Chemotherapy and radiation would mean the loss of taste, smell and saliva production, but it would likely only be temporary.

For seven weeks, five days a week, he endured radiation treatments that required him to wear a special mask to immobilize his head. His side effects included severe vertigo, nausea and loss of appetite.

“After a week of treatments, anything I was capable of putting into my mouth tasted like old wet cardboard,” he writes. “A few days later everything tasted like the same old wet cardboard but slathered with someone’s excrement.”

He was also plagued with digestive issues.

“The morphine I was given to dull the pain and help me sleep caused such dreadful constipation that at one point I thought it might only be relieved by the use of a mini pipe bomb,” Tucci reveals in the book.

While he was getting chemotherapy or required IV fluids, he, somewhat ironically turned to food TV to pass the time.

“This was an act of pure masochism, as even just the thought of food disgusted me. In hindsight I suppose it was a way to cling to what I loved or remember what I’d once had because I was so desperate to have it again,” he writes. “I was determined to make myself heal faster.”

Stanley Tucci with Nicola Salvadori, courtesy of CNN

The treatments left him so weak and emaciated that, he “practically begged to have a feeding tube implanted in my stomach.” It remained there for six months, but even while relying on the tube for sustenance, it was important to Tucci that he ate well. He ultimately eschewed protein shakes in favor of cooking and pureeing the sorts of foods — pasta and beans in broth — he might have eaten in healthier times.

“I would struggle through the smell of the ingredients just to be able to stand at the stove and create something I knew I could eat,” he writes. “What it tasted like didn’t matter, as it was going directly into my stomach by way of the tube, but it was important to me that if someone were to eat it by mouth they would find it appetizing.”

At that point, he even relied on the feeding tube for water, because if he tried to actually drink water, “It burned like battery acid.”

Tucci, who lives in England, underwent treatment in New York. His brother- and sister-in-law, John Krasinski and Emily Blunt, let him and his family stay in their Westchester home. Other celeb buddies, including Oliver Platt, Colin Firth, Blake Lively and Ryan Reynolds, were also quite supportive.

Reynolds was by Tucci’s side, when, six months after his last treatment, he had a scan that showed “no evidence of disease.” But the side effects persisted.

“For over two years my mouth was incredibly sensitive,” Tucci writes. “I couldn’t drink anything carbonated and certainly could not eat anything spicy. I was able to drink and taste alcohol but mostly stuck to white wine with copious amounts of ice.”

He’s also struggled with having limited saliva and being prone to choking, especially with foods such as steak and bread, which proved difficult when filming the first season of his TV show.

Yet, such challenges have also made him appreciate the joys of eating and drinking.

Tucci writes: “My illness and the brutal side effects of the treatment caused me to realize that food was not just a huge part of my life, it basically was my life.”

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HB-200 vaccines show promised in HPV16+ cancers

Author: Sara Karlovitch

In an interview with Targeted Oncology, Marshall Posner, MD, discusses the use of the HB-201 and HB-202 vaccines in patients with human papillomavirus 16- positive cancers.

Adding pembrolizumab (Keytruda) to the HB-200 vaccines may help to improve efficacy in patients with human papillomavirus 16- positive (HPV16+) cancers, according to data from a phase 1 study.

HPV16+ cancers are caused by the expression of E7 and E6 oncoproteins, which is a source of immunogenic neoantigens. A tumor-specific T-cell response is induced by replicating arenavirus vectors HB-201 and HB-202.

The study (NCT04180215) assessed HB-201 monotherapy and HB-201 and HB-202 alternating 2-vector therapy intravenously with or without 1 intratumoral dose in HPV16+ cancers. An interim analysis looked at 38 patients with confirmed HPV16+ cancers. In total, 18 patients received HB-201 monotherapy, 9 received the monotherapy intravenously with or without 1 intratumoral dose and 11 patients received HB-201/HB-202 alternating therapy.

In an interview with Targeted Oncology™, Marshall Posner, MD, a professor of medicine, hematology and medical oncology at Mount Sinai, discusses the use of the HB-201 and HB-202 vaccines in patients with HPV16+ cancers.

TARGETED ONCOLOGY: Can you go over the safety, efficacy, and immunogenicity of arenavirus-based vectors HB-201 and HB-202 in patients with HPV16+ cancers?

POSNER: This is a first in human phase 1 trial with expansion cohorts, to occur later, of 2 vaccines. One is a lympho-choriomeningitis virus-based arenavirus vaccine and the other is a pichinde virus-based vaccine, both of which express the E6 and E7 proteins, and both are based on viruses infecting antigen presenting cells. The E6 and E7 proteins were going to be processed and presented to the immune system in the context of an inflammatory response to the virus. Neither of these viruses are human attacking viruses, so they won’t cause any significant pathology in humans. And these were the phase one studies looking at the HB-201 vaccine by itself, and then alternating regimen with Hb-201 and HB-202, which has been shown in animal models to be actually synergistic in anti-tumor activity. This particular presentation is about the safety and potential efficacy of combining these vaccines with pembrolizumab. So, the later on trials will include pembrolizumab in the process, but this was an early attempt to see what pembrolizumab could do, but primarily to look at the safety.

We presented the first 3 patients who have progressed on the vaccines and subsequently had pembrolizumab added to the treatment. This was a modification of the original protocol to allow us to really perform the phase 1 study in an earlier fashion. All the patients who were on this particular cohort had prior checkpoint blockade inhibitor and/or other chemotherapies and checkpoint blockade inhibitors. So, this was a heavily pretreated group who had failed multiple rounds of therapy in the recurrent metastatic setting. I personally know 2 of the patients had a really extensive visceral involvement with the cancer. So, this was really a group of patients for whom you would expect to see side effects, other problems related to the tumor itself and not expect a response. And yet with them, we saw some stabilization of disease, we saw minimal impact of adding pembrolizumab. No treatment emergent adverse events that were concerning or that led to modification or reduction of dose for stopping the pembrolizumab and other treatment.

What we did see was stabilization of disease, some evidence of a response, but not robust. And we also saw no change in a robust up regulation of responsive T cells. In an L spot test, which involves stimulating the T cells from a peripheral blood with protein. The protein targets the antigen. What they saw in the initial study inpatients with the vaccine, was a big upregulation of both T cell responses and CDA responses specifically. In the addition of pembrolizumab, they did not see a further increase. They saw a maintenance or a slight reduction. So, it’s unclear what that’s about. But it does indicate that we already have robust responses, and they certainly weren’t inhibited by adding the pembrolizumab in any significant fashion.

The results of the trial will allow us to move forward in the trial that we’re doing by adding pembrolizumab to more patients. Moving forward, when we hit our recommended phase 2 dose of either the single vaccine or the double vaccine treatment, we added pembrolizumab. In the subsequent phase 1 and phase 2 expansion. I think the aim here is to go forward with a combination, rather than to do the expansion cohort with just the vaccine, but that’s up to the company and not up to me. It proved to be reasonably tolerable. There was a good safety signal and a good signal of some evidence of at least clinical responsiveness in the patients. So that was the end result of the study.

What was the reasoning behind adding pembrolizumab to the HB-200 vaccines in this patient population?

There’s some suggestion that given the patients don’t make a robust response to HPV by itself, that adding pembrolizumab would boost the response obtained with a vaccine by blocking inhibitory signals in the tumors. That is going to take some more work, you’re not going to see that early on in these kinds of trials. Although the data is suggested that it will, it’s really a small number of patients. So, that’s the rationale for doing that. It’s possible that pembrolizumab isn’t the right immune stimulant and that we need to simulate some other part of the immune system and I think as further studies go on, looking at the combination of pembrolizumab with other immune modulating drugs, that we’ll see some changes that will suggest other agents to combine with the vaccines.

What is the mechanism of action of the HB-200 vaccines with pembrolizumab and without pembrolizumab?

The presumption is that the vaccines will enhance CDH stimulation. And you’ll have activated CDA cells entering the tumor and killing the tumors based on their immune activation from the vaccine. Adding pembrolizumab would hopefully eliminate intertumoral, PD0-L1 and PD-1, inhibition of that immune response as well as inhibition of immune response with the T cells. So, those are the gross mechanisms of action. But really micro analysis of that is going to take some look at the material that the company has collected and some of the scientific laboratory investigation that they’re doing to look at that. We’re at the dawn of immunotherapy. I think the question goes right back to why do we only see a small fraction of patients responding to immunotherapy with head and neck cancer? Not as many as you would see, for example, with melanoma, but it’s still a fabulous result. But the question is really basically why are HPV-negative and HPV-positive patients not responding and are their mechanisms the same or different? Do we need to really look different modulators to the immune system in these patients?

Ho A, Posner M, Niu J, et al. First report of the safety/tolerability and preliminary antitumor activity of HB-201 and HB-202, an arenavirus-based cancer immunotherapy, in patients with HPV16+ cancers. Jour. Clin. Oncol. 2021;39(15):2502 doi: 10.1200/JCO.2021.39.15_suppl.2502.

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Checkpoint inhibitors whiff in head and neck cancer trials

Author: Charles Bankhead

Three different checkpoint inhibitors missed the primary endpoints in separate randomized trials of head and neck cancer.

In one trial, adding avelumab (Bavencio) to standard treatment did not significantly improve progression-free survival (PFS) in cisplatin-eligible or ineligible patients with locally advanced head and neck squamous cell carcinoma (HNSCC). In another trial, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not improve overall survival (OS) as first-line treatment for recurrent/metastatic HNSCC.

Both trials were reported during the European Society for Medical Oncology (ESMO) virtual meeting. Although subgroup analyses suggested benefits for certain patients, neither study should influence clinical practice at this point, said ESMO invited discussant Amanda Psyrri, MD, of the University of Athens in Greece.

In the avelumab study, known as GORTEC-REACH, results in cisplatin-eligible patients were consistent with those of the previously reported JAVELIN trial with avelumab, said Psyrri. A signal of benefit was evident in cisplatin-ineligible patients but did not achieve statistical significance.

With regard to the CheckMate 651 trial of nivolumab and ipilimumab, Psyrri said, “Combined PD-1 and CTLA-4 inhibition does not appear to be an effective strategy in recurrent/metastatic HNSCC. Future research efforts may identify predictive biomarkers for response to anti-PD-1 and anti-CTLA-4 combinations in HNSCC.”

Additionally, a smaller trial of pembrolizumab (Keytruda) showed no significant improvement in OS versus chemotherapy for platinum-treated relapsed/metastatic nasopharyngeal carcinoma.

This trial evolved from evidence of potential synergy with PD-1/L1 inhibition, cetuximab (Erbitux), and radiotherapy, said Jean Bourhis, MD, of University Hospital Center Vaudois in Lausanne, Switzerland. The trial included a total of 707 patients with stage III/IV HNSCC, divided into cohorts by eligibility to receive cisplatin. The cisplatin-ineligible cohort comprised 277 patients, and the cisplatin-eligible group included 430 patients.

Cisplatin-ineligible patients all received radiotherapy and cetuximab and were randomized to avelumab or no additional treatment. Cisplatin-eligible patients received cisplatin-based chemoradiation with or without avelumab. The primary endpoint for both cohorts was PFS.

After a median follow-up of 21.3 months in the cisplatin-ineligible cohort, the 2-year PFS rate favored the avelumab arm (44% vs 31%), but the difference did not achieve statistical significance (HR 0.84, 95% CI 0.61-1.15, P=0.14). The difference in the secondary endpoint of metastatic progression did reach statistical significance (14.3% with cetuximab vs 5.4% with avelumab-cetuximab, HR 0.31, P=0.007).

In the cisplatin-eligible group, a planned interim analysis showed a 1-year PFS rate of 73% without avelumab and 64% with the PD-L1 inhibitor, which translated into a hazard ratio of 1.27, crossing the boundary for futility and favoring standard of care, said Bourhis. The key secondary endpoint of OS showed a numerical advantage for the avelumab arm at 2 years (58% vs 54%), but the difference did not achieve statistical significance (P=0.69).

CheckMate 651
This trial followed the progression of treatment standards for relapsed/metastatic HNSCC from chemotherapy, to cetuximab plus chemotherapy, to a migration toward immunotherapy with recent approvals for pembrolizumab with or without chemotherapy, said Athanassios Argiris, MD, of Hygeia Hospital in Marousi, Greece. The combination of nivolumab and ipilimumab has produced durable responses and a survival benefit in several types of advanced solid tumors.

The trial involved 947 patients with untreated platinum-eligible recurrent/metastatic HNSCC. They were randomized to nivolumab-ipilimumab or to the combination of cetuximab, platinum, and 5-fluorouracil. The primary endpoints were OS in all patients and in the patients with a combined positive score (CPS) ≥20 for PD-L1 expression, who accounted for about 38% of the total population.

The primary analysis in all patients showed a median OS of 13.9 months with nivolumab-ipilimumab versus 13.5 months with standard treatment, a nonsignificant difference (P=0.4951). In the CPS ≥20 subgroup, median OS was 17.6 months with nivolumab-ipilimumab and 14.6 months with standard care, representing a 22% reduction in the hazard ratio but did not meet prespecified criteria for statistical significance. The survival benefit in the CPS ≥20 subgroup increased over time, from 63% versus 58% at 1 year to 41% versus 33% at 2 years.

Argiris noted that OS in the control group exceeded expectations based on historical data with standard therapy. Nivolumab-ipilimumab delayed symptom deterioration, was associated with improved overall health status, and had a favorable safety profile versus the control group.

This pembrolizumab study followed favorable results from a phase I trial of patients with heavily treated recurrent/metastatic PD-L1-positive nasopharyngeal carcinoma (NPC). Moreover, NPC has a strong association with Epstein-Barr virus (EBV) infection, which in turn is associated with PD-L1 expression, said Anthony Chan, MD, of the Chinese University of Hong Kong.

The phase III KEYNOTE-122 trial included 233 patients with recurrent/metastatic EBV-positive NPC previously treated with platinum-based chemotherapy. They were randomized to pembrolizumab or investigator’s choice of chemotherapy, which continued until disease progression or intolerable toxicity. The primary endpoint was OS.

About 85% of the patients were Asian, about 40% had CPS ≥10 PD-L1 expression (47% in the pembrolizumab arm), and about 60% of the patients had recurrent metastatic disease.

The primary analysis showed a median OS of 17.2 months with pembrolizumab and 15.3 months with chemotherapy, a nonsignificant difference (HR 0.90, 95% CI 0.67-1.19). The 2-year OS rate favored the pembrolizumab arm (40.2% vs 32.2%). Subgroup analysis showed no consistent pattern of benefit with pembrolizumab, including PD-L1 status. A majority of patients in both arms received one or more subsequent therapies, said Chan.

PFS, objective response rate, disease control rate, and duration of response all did not differ significantly between treatment groups, but trended in favor of the chemotherapy arm.

EBV-positive NPC is a chemosensitive disease; as a result, the chemotherapy control arm was expected to be difficult to top, said ESMO invited discussant Lisa Licitra, MD, of the Istituto Nazionale dei Tumori and University of Milan.

“Immuno-oncology is not lost; anti-PD-1 therapy remains the standard in first line,” she said.

Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007

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2021-09-24T06:54:20-07:00September, 2021|Oral Cancer News|

Saliva testing may allow early detection of human papillomavirus–driven head and neck cancers

Author: Elsevier

Cancer causing high-risk human papillomaviruses (HR-HPV) are responsible for the rising incidence of HR-HPV–driven head and neck cancers (HNC), particularly oropharyngeal cancers (OPC, or throat cancers). Investigators have determined that HR-HPV DNA can be detected in saliva in most patients with HPV-driven OPC at the time of diagnosis. This work highlights a potentially life-saving screening program based on salivary HR-HPV DNA testing for early cancer detection and patient monitoring. Their findings appear in The Journal of Molecular Diagnostics.

“Despite the upsurge in HPV-driven HNC, there are no early detection methods or screening strategies for this cancer type, unlike cervical cancer, which is caused by the same virus. Biomarkers enabling early detection, monitoring and disease prognostication are warranted to combat the rising incidence of HPV-driven OPC,” observed lead investigator Chamindie Punyadeera, Ph.D., head, Saliva & Liquid Biopsy Translational Laboratory, School of Biomedical Science, Faculty of Health, Queensland University of Technology (QUT), and Translational Research Institute, Brisbane, QLD, Australia.

Dr. Punyadeera and her colleagues investigated the efficacy of salivary HPV detection as a biomarker of HPV-HNC and survival patterns in patients with OPC to evaluate the utility of salivary HR-HPV as a prognostic biomarker for OPC.

Saliva testing was performed on 491 patients at the time of first diagnosis of HNC and 10 patients with recurring HNC. Forty-three percent were positive for salivary HR-HPV DNA. HPV16, a high-risk strain of the virus, was detected in 92% of the HPV-positive saliva samples. The vast majority of HPV-HNC had arisen from the oropharynx, especially from the palatine tonsils and the base of the tongue, confirming that the oropharynx is the hotspot for these cancers. Seventy-two percent of OPC patients were positive for HR-HPV DNA in their saliva, and tumor p16 overexpression was observed in 89.3%. These findings support the utility of saliva testing as a biomarker for facilitating early detection and screening of HR-HPV DNA.

Two hundred and fifteen patients with OPC were followed for up to five years. Salivary HR-HPV–positive patients had a clear survival advantage over their salivary HR-HPV–negative counterparts. The median event-free survivals were 205 months for HR-HPV–positive patients, compared to 82 months for HR-HPV–negative patients. Although the number of patients with recurrent cancer in the study was small, findings indicate that salivary HR-HPV tends to be positive in the majority of patients at the locoregional point of occurrence.

“When the noninvasive nature and convenience of the collection are considered, salivary HR-HPV testing is an ideal mode of screening asymptomatic individuals and the long-term monitoring of HPV-driven HNC patients. Our findings indicate that in the near future, salivary HR-HPV testing will become part of routine clinical management for HPV-driven OPC patients,” noted Dr. Punyadeera.

“Liquid biopsy in HNC has the potential to be truly transformative,” explained co-investigator Sarju Vasani, MD, Royal Brisbane and Women’s Hospital; and the Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. “It has the potential to personalize treatment selection and aid in assessing disease prognosis. It can help us select patients for adjuvant treatment and will alert us to recurrence before imaging or clinical examination has detected any specific abnormality. It is only a matter of time before these biomarkers translate from research settings to clinical practice.”

In some countries, including the United States, HNC and particularly OPC, have surpassed cervical cancers as the most common HPV-driven cancer. Patients are usually diagnosed at an advanced stage. In the early stages, these cancers are difficult to locate with imaging studies or physical examination. The oropharynx is difficult to access, and detection is further complicated if these smaller lesions are hidden in the crevices of the tonsils. These cancers can metastasize at an early stage, even when the primary cancer is still undetectable in size.

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2021-09-22T09:38:25-07:00September, 2021|Oral Cancer News|

Bifunctional protein shows promise in HPV-related cancers

Author: Charles Bankhead, Senior Editor, MedPage Today September

A bifunctional fusion protein with immunotherapeutic activity proved active in advanced, difficult-to-treat cancers associated with human papillomavirus (HPV), according to pooled data from two prospective studies.

Overall, 21 of 75 patients had confirmed responses with bintrafusp alfa, which inhibits tumor growth factor-beta (TGF-β) and PD-L1 interaction with its receptor. Responses were durable in many cases and occurred in patients with a variety of HPV-associated cancers. With a median follow-up of 33 months, the two cohorts had a median overall survival (OS) of 21.3 months, reported James Gulley, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, during the virtual European Society for Medical Oncology (ESMO) meeting.

“Overall survival appears to have a plateau of around 40-45% out to beyond 3 years,” said Gulley. “The median survival compares favorably to the reported overall survival with PD-1 inhibitors of 8 to 12 months.”

“The need for effective treatment options in patients with HPV-associated malignancies is high,” he added. “Therefore, these results showing efficacy of bintrafusp alfa across different HPV-related tumor types are of interest. Clinical trials of bintrafusp alfa in HPV-associated malignancies are ongoing.”

The frequency and durability of responses are “really remarkable in a quite difficult-to-treat patient population,” said ESMO invited discussant Sebastian Kobold, MD, of Ludwig Maximilian University in Munich.

“It’s especially stunning because we all know that cervical cancers in previous trials have shown rather disappointing results with PD-1-targeting single agents, indicating that’s [the anti-PD-1 component of the drug] probably not the explanation for the results seen here, because there were no complete responses in the previous trials,” he continued.

“Single-agent TGF-beta blockade was typically associated with overall response rates ranging from zero to 10%, indicating it’s not that single agent alone. Potentially, it’s the synergy of targeting both pathways that leads to these quite impressive results,” he added.

HPV infection causes almost 700,000 cancers worldwide each year, including about 35,000 in the U.S. Since the mid-2000s, the incidence of non-cervical HPV-related cancers has increased substantially, Gulley noted.

PD-L1 expression has an association with HPV infection in patients with HPV-related cancers, and anti-PD-1/L1 agents have demonstrated activity in patients with recurrent/metastatic HPV-related malignancies. However, the durability has been modest, associated with a median OS ≤12 months.

HPV infection also has been associated with upregulation of tumor TGF-β signaling, suggesting that simultaneous inhibition of TGF-β and PD-1/L1 might offer an effective treatment option for HPV-related malignancies.

Gulley reported combined data from a phase I and a phase II trial of bintrafusp alfa in patients with previously treated HPV-related cancers but no prior exposure to PD-1/L1 inhibitors. The phase I trial included 43 patients with cervical cancer (n=25), squamous cell carcinoma of the head and neck (SCCHN; n=14), and anal cancer (n=4). The phase II trial included 32 patients with cervical (n=14), SCCHN (n=5), anal (n=5), and other cancers (n=8).

The 75 patients had a median age of 56, and women accounted for 73% of the study population. Two-thirds of the patients had received at least two prior regimens, and 89% tested positive for HPV at enrollment.

Single-agent bintrafusp alfa led to four complete responses and 17 partial responses. Eleven other patients had stable disease, resulting in a disease control rate of 42.7%. Four patients had delayed partial response, bringing the total response rate to 32%. Responses occurred across multiple tumor types, including cervical, anal, SCCHN, rectal, penile, vaginal, and vulvar cancer.

Median duration of response was 17.3 months. Gulley said 15 of the initial 21 responses lasted for at least 6 months, and 12 lasted a year or longer.

In addition to the median OS of 21.3 months, 59.7% of patients were alive at 12 months and 51.5% at 21 months.

The most common treatment-related adverse events (AEs; all grades) were pruritus (25.3%), dermatitis acneiform (24.0%), anemia (18.7%), fatigue (17.3%), and maculopapular rash (17.3%). The most common grade 3/4 AE was anemia (6.7%).

Immune-related AEs occurred in 49.3% of patients, including hemorrhage (32.0%), anemia (18.7%), skin lesions (14.7%), and infusion-related AEs (5.3%). Most immune AEs were grade 1/2.

Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007.

Primary Source
European Society for Medical Oncology
Source Reference: Strauss J, et al “Long-term follow-up of patients with human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1” ESMO 2021; Abstract 957O.

The research was supported by the National Cancer Institute (NCI), Merck Healthcare KGaA, and EMD Serono.
Gulley reported a cooperative research and development agreement between EMD Serono/Merck Healthcare KGaA and NCI.
Kobold disclosed relationships with Novartis, TCR2, Celyad, Arcus Biosciences, and Bristol Myers Squibb.

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2021-09-21T07:23:47-07:00September, 2021|Oral Cancer News|

Stanley Tucci’s tongue cancer

Author: Michele R. Berman, MD

Actor Stanley Tucci is known for his roles in films such as “The Devil Wears Prada,” “The Hunger Games,” “The Lovely Bones,” “Spotlight,” and “Julie and Julia.” But now he is becoming known for another role — cancer survivor.

In an interview in the September 2021 issue of Virgin Atlantic’s inflight magazine Vera, 60-year-old Tucci revealed that he was diagnosed with cancer at the base of his tongue 3 years ago. “It was too big to operate, so they had to do high-dose radiation and chemo,” he explained.

Tucci was very reluctant to undergo this treatment, since he had seen the effects of this regimen on his first wife, Kate, who died from breast cancer in 2009. “I’d vowed I’d never do anything like that, because my first wife died of cancer, and to watch her go through those treatments for years was horrible,” he said.

He was equally concerned about how his illness would affect his five children. “The kids were great, but it was hard for them,” he noted. “I had a feeding tube for 6 months. I could barely make it to the twins’ high school graduation.”

Now, Tucci said that he is confident that the cancer is unlikely to return: “[Cancer] makes you more afraid and less afraid at the same time. I feel much older than I did before I was sick. But you still want to get ahead and get things done.”

And that’s exactly what he has done for the past 2 years. He launched a new CNN series, “Stanley Tucci: Searching for Italy,” and has written a book, Taste: My Life Through Food, which is set to be released in October.

Cancer of the Tongue
Cancers of the head and neck can form in the oral cavity (including the lips, the front two-thirds of the tongue, the gums, the lining inside the cheeks and lips, the floor of the mouth under the tongue, the hard palate, and the small area of the gum behind the wisdom teeth), the pharynx, the larynx, the paranasal sinuses and nasal cavity, and the salivary glands.

It should be noted that the anterior two-thirds of the tongue is considered part of the oral cavity, while the base of the tongue is part of the oropharynx. The tongue begins to develop around the fourth week of intrauterine life. The anterior portion of the tongue is derived from the first pharyngeal arch, while the base of the tongue originates from the mesoderm of the second, third, and fourth pharyngeal arches. This difference in origin causes the characteristics of these two cancers to be quite distinct, and therefore treatment for each type is quite different.

According to the Surveillance, Epidemiology, and End Results (SEER) Program, the estimated number of new cases of all types of tongue cancer in 2021 was 17,960 (0.9% of all new cancer cases), with an estimated 2,870 deaths. The 5-year relative survival is 68.1% for all stages. For patients with localized disease, the 5-year survival rate is 82.9%.

Clinical Presentation
Cancers at the base of the tongue can grow in either an infiltrative or exophytic pattern. Because the base of the tongue has no pain fibers, these tumors are often asymptomatic until there is significant progression.

Signs and symptoms may include the following:

Weight loss
Referred otalgia secondary to cranial nerve involvement
Trismus secondary to pterygoid muscle involvement
Fixation of the tongue that is caused by infiltration of the deep muscle
A mass in the neck

Lymph node metastases are common. Approximately 70% of patients with advanced base-of-the-tongue cancers have ipsilateral cervical lymph node metastases, while ≤30% have bilateral cervical lymph node metastases.

Risk Factors
The most common risk factors for oropharyngeal squamous cell carcinomas (SCCs) include:

Smoking history of more than 10 pack-years and other tobacco use
Heavy alcohol use
Human papillomavirus (HPV) infection, especially HPV 16
Personal history of head and neck cancer

Because cigarette smoking is declining in the U.S., smoking-related oropharyngeal cancer is decreasing; however, oropharyngeal cancer due to HPV infection is increasing. According to the SEER Program’s tissue repository data from 1988 to 2004, the prevalence of HPV-negative oropharyngeal cancers declined by 50%, while HPV-positive cancers increased by 225%.

HPV-positive oropharyngeal cancers may represent a distinct disease entity associated with an improved prognosis. Several studies have indicated that patients with HPV-positive tumors have significantly improved survival.

Oropharyngeal tumors are more likely to be HPV positive compared with oral cavity tumor sites and non-oropharyngeal sites. HPV-positive oropharyngeal cancers predominantly arise in the palatine or lingual tonsils.

As with any cancer, the treatment of patients with base-of-tongue cancer depends on a number of factors, including pathology, histology, clinical stage, patient’s age, and general medical condition. In patients with tongue cancer, immunohistochemical staining for p16 status is important.

For early-stage base-of-tongue SCC, surgical resection and/or radiation therapy is frequently used. For advanced-stage tumors, surgical resection may be paired with radiation and chemotherapy or with chemoradiation therapy (CRT). The typical regimen for early- and advanced-stage lesions involves 6 weeks of radiation with a platinum-based chemotherapy agent.

Although effective, radiation therapy and CRT can have significant side effects and can affect quality of life. Common side effects include dry mouth, mucositis, speech issues, dysphagia, aspiration, or respiratory distress. Patients may require a feeding tube or tracheostomy during treatment to protect their nutritional status or airway.

Studies are also being conducted to assess EGFR inhibitors, such as the monoclonal antibody cetuximab (Erbitux), for SCC of the base of the tongue. Immune checkpoint inhibitors are also being investigated.

It is essential that treatment approaches also include treatment of bilateral lymph nodes, either with radiation therapy or surgical resection.

Michele R. Berman, MD, is a pediatrician-turned-medical journalist. She trained at Johns Hopkins, Washington University in St. Louis, and St. Louis Children’s Hospital. Her mission is both journalistic and educational: to report on common diseases affecting uncommon people and summarize the evidence-based medicine behind the headlines.

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2021-09-15T06:17:25-07:00September, 2021|Oral Cancer News|

World’s largest trial Of “Game-Changer” early cancer test begins in UK

Author: Maddy Chapman

Yesterday, England’s National Health Service (NHS) launched the world’s largest trial of a blood test that can detect more than 50 types of cancer before symptoms appear.

The trial aims to recruit 140,000 volunteers from different ethnic backgrounds, aged between 50 and 77, and living in eight areas across England. The test itself, the Galleri test, is a simple blood test that checks for the earliest signs of cancer. Ideally, it can be used to identify cancers at their earliest stages – stage one or two.

When it comes to detecting cancer, the earlier the better. A diagnosis at stage one can increase chances of survival by five to 10 times, compared to a diagnosis at stage four. The new test, developed by healthcare company GRAIL, is particularly effective at identifying cancers that are difficult to diagnose early – head and neck, bowel, lung, pancreatic, and throat cancers, for example.

“This quick and simple blood test could mark the beginning of a revolution in cancer detection and treatment here and around the world,” NHS chief executive Amanda Pritchard said in a statement.

“By finding cancer before signs and symptoms even appear, we have the best chance of treating it and we can give people the best possible chance of survival.”

The Galleri test works by identifying fragments of DNA that have been shed by tumors into the bloodstream. Participants in the trial, who must not have received a cancer diagnosis in the last three years, will therefore be asked to give an initial blood sample, before returning after 12 months, and then again after two years, to give repeat samples.

The trial is being run by Cancer Research UK and King’s College London Cancer Prevention Trials Unit in partnership with NHS England and GRAIL. It is a randomized control trial, meaning that half of the individuals involved will have their blood sample tested with the Galleri test and half will not. The samples of this latter group will be stored and may be screened in the future, allowing the scientists to find out whether the test does in fact help to identify cancers early. Neither group will know if they’re in the test group, unless early signs of cancer are detected, in which case the individual would be notified and referred for further tests.

Currently, the trial is operating through eight NHS Cancer Alliances spanning Cheshire and Merseyside, Cumbria, Greater Manchester, the North East, West Midlands, East Midlands, East of England, Kent and Medway, and South East London. Results are expected by 2023, and, if successful, it could be rolled out to a further 1 million people in England in 2024 and 2025.

According to the NHS, one in two people will develop some form of cancer in their lifetime. It is therefore hugely important that we develop screening methods capable of identifying these cancers as early as possible, to open up a broader range of treatment options and improve chances of survival.

Previous research in the US has found that the Galleri test identified more than 67 percent of 12 pre-specified stage one to three cancers, which account for approximately two-thirds of annual US cancer deaths. It also picked up around 41 percent of all cancers.

“The test could be a game-changer for early cancer detection and we are excited to be leading this important research,” said Professor Peter Sasieni, Director of The Cancer Research UK & King’s College London Cancer Prevention Trials Unit and one of the trial’s lead investigators.

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2021-09-15T06:09:46-07:00September, 2021|Oral Cancer News|

FDA gives ISA101b fast track designation for HPV 16+ oropharyngeal cancer

Author: Hayley Virgil

The first patients with human papillomavirus 16–positive oropharyngeal cancer have been dosed with ISA101b, which was given a fast track designation by the FDA, as part of a phase 2 study.

ISA101b has received a fast track designation from the FDA for the treatment of patients with recurrent and metastatic human papillomavirus (HPV) 16–positive oropharyngeal cancer, according to a press release from drug developer ISA Pharmaceuticals.1

The fast track designation is intended to facilitate the development of investigational therapies that may help to address unmet medical needs for serious or life threatening diseases. An ongoing randomized, double-blind phase 2 trial is examining cemiplimab (Libtayo) with or without ISA101b and has an estimated enrollment of 194 patients (NCT03669718).

“Recurrent and metastatic HPV16-positive OPC is a form of head and neck cancer with a high unmet medical need. The Fast Track designation for ISA101b underlines the potential benefit of this immunotherapy for patients suffering from this disease,” Leon Hooftman, chief medical officer at ISA Pharmaceuticals, said in a press release.

ISA101b elicits strong and specific immune responses to HPV16 virus proteins and creates a robust T-cell immune response against cancerous cells or tissues. In the ongoing trial, patients in the experimental arm will receive ISA101b 3 times over 3 weeks plus cemiplimab every 3 weeks for up to 24 months, and the control arm will receive a matched placebo plus cemiplimab at the same dose.

The primary outcome measures are overall response rate and safety, with a key secondary end point of duration of response.

To be eligible for the trial, patients need to be 18 years or older, have a diagnosis of histologically confirmed recurrent or metastatic HPV16-positive oropharyngeal cancer with tumors that express PD-L1, and be candidates for anti–PD-L1 therapy. Patients who have experienced disease progression on or after a platinum-based chemotherapy regimen are also eligible. Additionally, an ECOG performance status of 0 or 1 is required, as well as measurable disease by CT or MRI imaging.

Patients with untreated metastatic or unresectable tumors that do not express PD-L1 and aren’t candidates for an anti–PD-L1 therapy are not eligible for enrollment. Additionally, those with known brain metastases or leptomeningeal metastases or a serious or uncontrolled medical disorder are not allowed. Patients with a history of other malignancies 3 years or fewer prior to entry are also excluded, with the exception of basal cell or squamous cell carcinoma of the skin that was treated with local resection only, carcinoma in situ of the cervix, prostate or breast cancer, or low grade non-muscle invasive superficial bladder cancer in situ.

The compound is currently being studied in HPV16-positive cancers in combination with cemiplimab in several phase 2 clinical trials. Similarly, ISA101b is also being examined as a single agent in HPV16-positive cervical cancer, an indication for which the compound has received an orphan drug designation.2

1. ISA Pharmaceuticals receives fast track designation for lead product ISA101b. News release. ISA Pharmaceuticals. September 14, 2021. Accessed September 14, 2021.
2. ISA Pharmaceuticals receives US orphan-drug designation for ISA101b in HPV16-positive cervical cancer. News release. ISA Pharmaceuticals. July 1, 2020. Accessed September 14, 2021.

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2021-09-15T06:04:52-07:00September, 2021|Oral Cancer News|
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