Calls grow for treatment deintensification of HPV-positive OPC

Source: ww.pharmacytimes.com
Author: Bryan Fitzgerald, PharmD, BCOP
Health-System Edition, July 2021, Volume 10, Issue 4

Oropharyngeal cancer (OPC) is a type of head and neck cancer that affects structures in the back of the throat, including the base of the tongue, the posterior pharynx, the soft palate, and the tonsils.1 In the United States, rates of OPC are increasing each year, with an estimated 54,010 new cases in 2021.2 Well-established risk factors include alcohol abuse; exposure to tobacco, including chewing tobacco, cigarettes, and pipes; and infection with human papillomavirus (HPV).

With an estimated 43 million infections in 2018, HPV is the most common sexually transmitted infection in the United States.3 HPV infection is causally linked with cancers of the anogenital region, including anal, cervical, penile, vaginal, and vulvar cancers. When HPV is spread orally, infections can also lead to the development of OPC. In the United States, more than 70% of OPC cases are caused by HPV.4

HPV is a group of more than 100 viruses, including certain high-risk strains associated with the development of cancer. The HPV-16 strain is responsible for causing the majority of HPV-positive (HPV+) OPC cases, with HPV-18, HPV-33, and HPV-35 also contributing, albeit significantly less than HPV-16.1 In these high-risk HPV strains, the viral genome encodes several oncogenic proteins that inhibit tumor suppressor proteins, leading to chromosomal instability and malignancy in infected cells.

HPV+ OPC is considered a genetically distinct form of OPC. Compared with HPV-negative (HPC–) OPC cases, HPV+ OPC is associated with a favorable prognosis with improved rates of response prognosis with improved rates of response to treatment and overall survival. Because of the difference in tumor biology, the National Comprehensive Cancer Network (NCCN) has adopted different staging criteria for HPV+ and HPV– disease and recommends that HPV status be used to stratify patients with OPC.1

The treatment landscape for localized OPC typically involves a multidisciplinary approach consisting of chemotherapy, radiation, and/or surgery. For fit patients with locally advanced OPC who are able to tolerate intensive therapy, concurrent radiation with systemic high-dose cisplatin chemotherapy is the preferred treatment regimen.1 Unfortunately, treatment of OPC is associated with a high risk of treatment-related morbidity, which may leave patients cured of their malignancy but with lifelong complications, such as dysgeusia, dysphagia, and xerostomia, but also systemic complications from cisplatin chemotherapy, including hearing loss and neurotoxicity.

Because patients with HPV+ OPC are generally younger with more favorable prognoses, clinicians have hypothesized that less intensive treatment could result in fewer long-term complications from treatment but with continued favorable cancer-related outcomes.5 This concept, called deintensification, has become popular in recent years. Several strategies for treatment deintensification have been proposed, including reducing the dose of radiation; substituting cisplatin for an alternative agent with less toxicity, such as cetuximab; and surgical resection. Several phase 3 comparison trials have been conducted, and other trials are ongoing.

Aptly named De-ESCALaTE (NCT01874171), this phase 3 trial randomized patients with 334 HPV+ OPC to receive radiation plus cetuximab or cisplatin.6

Unfortunately, the trial results did not favor substitution of cisplatin with cetuximab. At 2 years, the incidence of severe toxicities did not significantly differ between cetuximab and cisplatin (P = .98), nor did rates of overall toxicities (P = .49). Significant differences in 2-year overall survival rates and recurrence rates were seen. However, these results favored cisplatin (HR, 5.0; P = .001 for overall survival; HR, 3.4; P = .0007 for recurrence).6

RTOG-1016 (NCT01302834) was a second phase 3 trial published comparing cetuximab with cisplatin in HPV+ OPC patients.7 This trial analyzed 805 patients who were randomized to receive radiation plus cetuximab or cisplatin. Similar to the De-ESCALaTE trial, the RTOG-1016 trial results favored cisplatin over cetuximab, with 5-year overall survival rates of 84.6% versus 77.9%.8

Because of the De-ESCALaTE and RTOG-1016 results, experts advise against the substitution of cisplatin for chemoradiation regimens for patients with localized HPV+ OPC, and cisplatin plus radiation continues to be the preferred systemic treatment option per the NCCN guidelines.1,5 Because cisplatin continues to be standard of care for the treatment of localized OPC, the role of deintensification for patients with HPV+ OPC may lie in adjustments to surgical strategies or radiation therapy. Treatment deintensification should be pursued only through clinical trials, and experts encourage clinicians to conduct and analyze phase 2 trials before moving on to phase 3 studies.1,5

CONCLUSION
The treatment landscape of cancer is ever-changing. Specifically in localized HPV+ OPC, the difference in tumor biology presents a unique clinical area where reducing the intensity of treatment may be warranted, particularly with long- and short-term toxicities associated with cisplatin. Interestingly, phase 3 data have shown evidence of harm in removing cisplatin from chemoradiation regimens for HPV+ OPC; therefore, cisplatin-based chemoradiation remains the standard of care for these patients. Future trials may support treatment deintensification in ways other than removing cisplatin.

REFERENCES
1. NCCN. Clinical Practice Guidelines in Oncology. Head and neck cancers, version 3.2021. Accessed June 16, 2021. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf

2. Cancer stat facts: oral cavity and pharynx cancer. National Cancer Institute. Accessed June 16, 2021. https://seer.cancer.gov/statfacts/html/oralcav.html

3. Genital HPV infection – fact sheet. CDC. Updated January 19, 2021. Accessed June 17, 2021. https://www.cdc.gov/std/hpv/stdfact-hpv.htm
4. HPV and oropharyngeal cancer. CDC. Updated September 3, 2020. Accessed June 17, 2021. https://www.cdc.gov/cancer/hpv/basic_info/hpv_oropharyngeal.htm

5. Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a head and neck cancer intergroup framework for future de-escalation studies. J Clin Oncol. 2020;38(22):2552-2557. doi:10.1200/JCO.20.00056

6. Mehanna H, Robinson M, Hartley A, et al; De-ESCALaTE HPV Trial Group. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393(10166):51-60. doi:10.1016/S0140-6736(18)32752-1

7. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X

8. Gardasil 9. Prescribing information. Pfizer; 2017. Accessed June 23, 2021. https://www.fda.gov/fi les/vaccines,%20blood%20&%20biologics/published/Package-Insert—Gardasil.pdf

On treating advanced head and neck cancer without cisplatin – an oncology grand rounds discussion

Source: www.medpagetoday.com
Author: Mark L. Fuerst

An oncology grand rounds discussion with Sachin Jhawar, MD.

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous set of diseases with different features and treatment recommendations. Physicians face challenges in initial treatment decision-making and response assessments, including the changing role of surgery, the incorporation of human papilloma and Epstein Barr virus status, as well as the potential for treatment de-escalation using patient-related and tumor-related factors.

A recent “Oncology Grand Rounds” article in the Journal of Clinical Oncology provides an overview of treating advanced HNSCC when cisplatin is not an option, including concurrent chemotherapy, cetuximab, targeted therapy, and immunotherapy.

In the following interview, the paper’s lead author, Sachin Jhawar, MD, of Ohio State University Comprehensive Cancer Center in Columbus, reviews the main issues.

What is the focus of the article?
Jhawar:
We focused on patients with locally advanced disease who would be receiving definitive non-surgical treatment when possible treatment with concurrent cisplatin, delivered either every 3 weeks or weekly, is always the preferred treatment.

We specifically wanted to delve into the subset of patients who we would not recommend to receive cisplatin because of age or comorbidities. This could be concurrent chemotherapy (carboplatin/paclitaxel), concurrent cetuximab, and altered or standard fractionation radiation schedules without systemic therapy, as well as when to consider immunotherapy and palliative radiation for those with recurrent or metastatic disease.

There is also a great deal of institutional preference involved. At our institution, we prefer concurrent carboplatin/paclitaxel in patients who cannot receive cisplatin. Generally, we reserve definitive radiation alone options for patients who are completely ineligible for any systemic therapy.

If definitive therapy would be considered too difficult, or for those who have metastatic disease, still other palliative regimens are available.

When should clinicians consider nivolumab or pembrolizumab?
Jhawar:
At this time, immuno-oncology agents such as nivolumab or pembrolizumab are approved and used regularly only in the recurrent or metastatic setting. Even in the recurrent setting, they are generally considered only if surgery or re-irradiation therapy is not an option.

These novel agents should only be considered earlier in a patient’s treatment course in place of more traditional systemic options via a clinical trial.

What are the potential benefits of the combined use of immunotherapy, chemotherapy, and vaccines?
Jhawar:
The potential benefits of combination strategies using checkpoint inhibitors and other immuno-oncology treatments, including vaccines, in combination with more traditional therapies including surgery, radiation, and chemotherapy are still being worked out. It is likely that we will first see applications of these newer therapies in the recurrent and metastatic setting, but they may be incorporated earlier into patient care as more data about safety and efficacy emerges.

We have seen regular use of immuno-oncology treatments in other disease sites, and these therapies are being introduced earlier in the treatment course for patients. I would expect a similar pattern to emerge for HNSCC, although we will need to wait for phase III randomized controlled trial data for these immunotherapies to be ready for prime time.

It should be noted, however, that given the heterogeneity of HNSCC, there are certain scenarios in which we are working towards de-escalation of therapy, and addition of more therapies may not be needed.

In the patients with HPV-positive oropharyngeal squamous cell carcinoma and less than 10 pack-year smoking histories, the cure rates are more than 90% with current standard-of-care treatment. We are now working towards de-escalating therapy. It is not clear what role, if any, immuno-oncology will play in these already favorable situations.

What about the potential synergy of molecular targeted agents with radiation?
Jhawar:
There are multiple potential targets that could lead to synergy with radiation. Cetuximab actually acts on one of these targets, the epidermal growth factor receptor. Other potential targets that are being studied for combinations with radiation include cell signaling pathways (mTOR, AKT), cancer metabolism, tumor hypoxia, and DNA repair pathways (PARP, ATR).

There are other studies that have been completed or are ongoing that use agents to improve radioprotection of normal tissues. To date, none of these targeted agents are being regularly used on their own or in combination in the care of patients outside of clinical trials.

What improvements with new targeted therapies and immunotherapies do you foresee?
Jhawar:
As our understanding of the molecular mechanisms of carcinogenesis, aberrant cancer signaling pathways, and the tumor microenvironment improves, I expect that the number of targets and, therefore, the number of molecular targeted agents will grow. This will lead to a large increase in the number of clinical trials and expansion of our armamentarium against HNSCC.

Similarly, as our understanding of the interplay between cancer and the immune system and mechanism of immune escape improves, I suspect we will be able to improve response rates from immuno-oncology drugs. Currently, only 10% to 20% of patients respond to immuno-oncology treatments, leaving a great deal of room for improvement.

Taken together, this will allow for more individualized, patient-specific care and afford the ability to test novel combinations to improve cure rates. Simultaneously, this will decrease toxicity by choosing the right treatment for the right patient, rather than having a one-size-fits-all approach to therapy.

What’s the take-home message for practicing oncologists?
Jhawar:
There is a great deal of change forthcoming in the treatment of HNSCC, but at this time standard-of-care therapy still consists of some combination of traditional cancer therapies, including radiation, surgery, and chemotherapy.

Read the study here and expert commentary about the clinical implications here.

FDA grants fast track designation to NBTXR3 in locally advanced head and neck cancers

Source: www.targetedonc.com
Author: Nichole Tucker

An FDA Fast Track Designation was granted to the first-in-class radioenhancer NBTXR3 with or without cetuximab (Erbitux) for the treatment of patients with locally advanced head and neck squamous cell cancer who are not eligible for platinum-based chemotherapy, according to a press release from Nanobiotix.1

NBTXR3 showed preliminary signals of antitumor activity in this patient population in a phase I study of 12 patients with advanced-stage head and neck squamous cell carcinoma (HNSCC). Specifically, 10 of the 11 evaluable patients had a complete response (CR) or a partial response to treatment, which included 2 CRs at dose levels ≤10% and 5 CRs at dose levels >10%.2

Treatment with NBTXR3 was also found to be safe and tolerable in patients with HNSCC. There were no serious adverse events or dose-limiting toxicities (DLTs) observed, which allowed patients to continue with their treatment as planned. The adverse events found to be related to injection with NBTXR3 included grade 1/2 injection pain and tumor hemorrhage.

Patients in the study received either a single intratumor injection or single-arterial injection of NBTXR3 on day 1 followed by intensity-modulated radiation therapy 2 hours later, which lasted for up to 7 weeks. Radiotherapy was continued in all patients unless their tumor did not shrink by 50% of the baseline size. Those patients who did achieve the tumor shrinkage goals then received salvage tumor surgery.

The primary end point of the study was the determination of the recommended dose of the drug and early dose-limiting toxicities. Secondarily, the investigators evaluated safety and tolerability, objective response rate, local progression-free survival, progression-free survival, kinetics profile, and the feasibility of local administration of NBTXR3.

Patients aged 70 years or older who were intolerant to cisplatin or cetuximab or that could not receive the combination of chemoradiation were eligible for treatment in the study. Patients were required to have histologically or cytologically confirmed squamous cell carcinoma of the oral cavity or oropharynx; have a T3 or T4 primary tumor or stage III or IVA disease; be clinically eligible for intra-arterial or intratumor implantation by injection; have a Karnofsky performance status ≥70; and have adequate bone marrow, kidney, and liver function.

The study excluded patients who had prior radiotherapy; tumor-related dyspnea; prior or concurrent non-head and neck malignancies, excluding adequately treated basal or squamous cell cancer of the skin, and in situ cervical cancer; concurrent treatment with any other anticancer therapy; tumor-related dyspnea; tumor ulceration which implies vascular risk; non-measurable disease; and those with infections and illnesses that may have interfered with treatment.

The data from this trial are part of a proof-of-concept for launching a phase III study in which NBTXR3 will undergo further assessment for the treatment of head and neck cancers.3

References
1. Nanobiotix announces fast track designation granted by US FDA for investigation of first-in-class nbtxr3 in head and neck cancer [news release]. Cambridge, Massachusetts: Nanobiotix; February 10, 2020. https://bit.ly/2vpwDQU. Accessed February 10, 2020.
2. Le Tourneau C, Calugaru V, Jouffroy T, et al. A phase 1 trial of NBTXR3 nanoparticles activated by intensity-modulated radiation therapy (IMRT) in the treatment of advanced-stage head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2017;35(suppl 5;abstr 6080). doi: 10.1200/JCO.2017.35.15_suppl.6080.
3. Nanobiotix announces plan for global phase III head and neck cancer registration trial along with overall development update [news release]. Cambridge, Massachusetts: Nanobiotix; January 7, 2020. https://bwnews.pr/2Hczpfc. Accessed February 10, 2020.

2020-02-11T08:31:16-07:00February, 2020|Oral Cancer News|

Palbociclib plus cetuximab shows antitumor activity among head and neck cancer subset

Source: www.healio.com
Author: Adkins D, et al.

A combination of palbociclib and cetuximab demonstrated substantial antitumor activity among patients with platinum- or cetuximab-resistant HPV-unrelated head and neck squamous cell carcinoma, according to results of a multigroup phase 2 trial published in The Lancet Oncology.

“Currently, effective therapeutic options for patients with cetuximab-resistant HNSCC are few. Traditional chemotherapy has marginal activity, with 6% of patients or fewer achieving a tumor response,” Douglas R. Adkins, MD, professor in the oncology division of the department of medicine at Washington University School of Medicine in St. Louis, and colleagues wrote. “The most effective therapy for these patients might be pembrolizumab [Keytruda, Merck] or nivolumab [Opdivo, Bristol-Myers Squibb], which have resulted in responses in 11% to 16% of patients and median OS of 6.9 months to 8 months. Novel treatment strategies are needed for patients with recurrent or metastatic HNSCC.”

The combination of the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (Ibrance, Pfizer) and epidermal growth factor receptor inhibitor cetuximab (Erbitux, Eli Lilly) appeared safe and tolerable in the phase 1 portion of the multicenter trial, conducted across eight U.S. university sites.

For phase 2, Adkins and colleagues divided 62 patients with HPV-unrelated HNSCC (median age, 66 years; interquartile range [IQR], 58-70; 71% men) into two groups: those who were platinum-resistant (group 1; n = 30) and those who were resistant to cetuximab (group 2; n = 32). Primary tumor sites included the oral cavity (42%) and larynx (29%), and 81% of patients had received one or two prior lines of treatment for metastatic or recurrent disease.

All participants received oral palbociclib (125 mg daily on days 1-21) and IV cetuximab (400 mg/m2 on day 1 of cycle one, followed by 250 mg/m2 once weekly) in 28-day cycles. Objective response, defined as complete and partial responses per RECIST 1.1 criteria, served as the primary endpoint.

Researchers followed patients in group 1 for a median 5.4 months (IQR, 4.4-12.1) and those in group 2 for a median 5.5 months (IQR, 4.3-8.3).

Among 28 evaluable group 1 patients, 11 (39%; 95% CI, 22-59) attained an objective response, including three complete responses. Repeat scans confirmed all but one of the responses. Half of the group 1 patients (n = 14) had stable disease and three (11%) demonstrated progressive disease. Median duration of response was 4 months (IQR, 1.8-5.6), median PFS was 5.4 months (95% CI, 3.4-7) and median OS was 9.5 months (95% CI, 5.3-16.5).

Palbociclib plus cetuximab shows antitumor activity among head and neck cancer subsetAmong 27 evaluable group 2 patients, five (19%; 95% CI, 6-38) achieved an objective response, including one complete response. Four of the responses were later confirmed. Thirteen of the group 2 patients (48%) had stable disease and nine (33%) demonstrated progressive disease. Median duration of response was 6 months (IQR, 2-15.5), median PFS was 3.7 months (95% CI, 2.9-4.3) and median OS was 6.3 months (95% CI, 4.9-10).

In each group, only one patient with a tumor response previously had received immunotherapy.

The most prevalent grade 3 to grade 4 adverse event associated with palbociclib was neutropenia, which occurred in 34% (n = 21) of all patients. The researchers did not document any treatment-related deaths.

The researchers cited various limitations to their study, including its single-group design, and noted that the results will need to be confirmed in a controlled trial with a larger sample size. They acknowledged that immunotherapy might have affected OS outcomes, and that the study design did not permit the evaluation of whether palbocilib’s antitumor activity occurred directly or by reversal of primary cetuximab resistance.

These data suggest a need for further study of palbociclib in patients with recurring or metastatic HNSCC, according to a related editorial by Garth W. Strohbehn, MD, hematology/oncology fellow at University of Chicago, and Everett E. Vokes, MD, professor of medicine and radiation oncology physician-in-chief at University of Chicago Medicine.

“However, we should be circumspect about the prospect of CDK 4/6 inhibitors as standardized, cost-effective therapies in recurrent and metastatic HNSCC,” the authors wrote. “Bringing this class of drugs to head and neck oncology clinics, as either monotherapies or immunotherapy partners, will require appropriately controlled studies linked to biomarker evaluation with both survival and cost-effectiveness endpoints.” – by Jennifer Byrne

Source:
Adkins D, et al. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30405-X.
Strohbehn GW and Vokes EE. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30484-X.

Disclosures: Adkins reports research funding from Pfizer as part of the work presented in the study; personal fees for advisory/consultant roles from Celgene, Cue Biopharma, Eli Lilly, Loxo Oncology, Merck and Pfizer; and research funding from AstraZeneca, Atara, Blueprint Medicine, Bristol-Myers Squibb, Celgene, CellCeutix, Celldex, Eli Lilly, Enzychem, Exelixis, Gliknik, Kura, Matrix Biomed, Medimmune Innate, Novartis, Pfizer and Polaris outside the submitted work. Please see the study for all other authors’ relevant financial disclosures. Vokes reports consultant/advisory roles with AbbVie, Amgen, AstraZeneca, Bristol-Myers, Celgene, EMD Serono, Genentech, Merck, Novartis and Regeneron. Strohbehn reports no relevant financial disclosures.

No De-escalation of Therapy for HPV+ Throat Cancer

Source: www.medscape.com
Author: Alexander M. Castellino, PhD

Another trial has shown that de-escalating therapy does not work in patients with good prognosis human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma or throat cancers.

Results from the De-ESCALaTE HPV study show that using the targeted drug cetuximab with radiotherapy does not improve side effects and, more importantly, has worse survival compared with the standard of care — chemotherapy with cisplatin and radiotherapy.

The finding echoes the results from the US National Cancer Institute’s Radiation Therapy Oncology Group (RTOG) 1016 trial, the top-line results of which were released earlier this year, and details of which were presented this week at the American Society of Radiation Oncology (ASTRO) 2018 meeting.

“Do not change your clinical practice of using cisplatin with radiotherapy in these patients,” cautioned Hisham Mehanna, MBChB, PhD, chair of head and neck surgery at the University of Birmingham, United Kingdom, and lead investigator of the De-ESCALaTe study. He presented the results during a presidential session here at the European Society for Medical Oncology (ESMO) 2018 Congress (abstract LBA9).

“Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin. This was a surprise — we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV+ should be given cisplatin, and not cetuximab, where possible,” Mehanna said in a statement.

Hope for Fewer Side Effects
Cetuximab with radiation is already approved by the US Food and Drug Administration for use in head and neck cancer, including oropharyngeal cancer, and is an accepted standard of care, especially for patients who cannot tolerate cisplatin.

The hope behind de-escalation of therapy was that this regimen would offer similar efficacy but have fewer side effects than the standard regimen of cisplatin plus radiation.

“The side effects of treatment for patients with head and neck cancers are devastating. They experience loss of speech, loss of taste, and have trouble swallowing,” explained ESMO expert Jean-Pascal Machiels, MD, PhD, head of the department of medical oncology at the Cliniques Universitaires Saint-Luc, Brussels, Belgium.

“With HPV increasing rapidly in the Western world, HPV+ head and neck cancers are typically seen in younger patients who respond well to treatment and live for three to four decades. These patients would like to live without the toxicities associated with treatment,” he added.

“Based on a large study in 2006, many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as chemotherapy with radiotherapy and caused fewer side effects,” Mehanna commented. That study showed that for patients with squamous cell carcinoma of the head and neck, treatment with cetuximab and high-dose radiotherapy improved locoregional control and reduced mortality. At the same time, side effects were no worse (N Engl J Med. 2006;354:567-578).

 

OCF NOTE: The foundation’s donors were funders of the RTOG 1016 clinical trial over several years.

Patients with HPV-positive oropharynx cancer should receive chemoradiation

Source: medicalxpress.com
Author: provided by European Society for Medical Oncology

Patients with human papilloma virus (HPV)-positive throat cancer should receive chemoradiotherapy rather than cetuximab with radiotherapy, according to late-breaking research reported at the ESMO 2018 Congress in Munich.

“Many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as chemotherapy with radiotherapy and caused less side effects but there has been no head-to-head comparison of the two treatments,” said study author Prof Hisham Mehanna, Chair, Head and Neck Surgery, Institute of Cancer and Genomic Sciences, University of Birmingham, UK.

Throat cancer is rapidly becoming more common in Western countries. For example in the UK, incidence was unchanged in 1970 to 1995, then doubled in 1996 to 2006, and doubled again in 2006 to 2010.The rise has been attributed to HPV, a sexually transmitted infection. Most throat cancer was previously caused by smoking and alcohol and affected 65-70 year-old working class men. Today HPV is the main cause and patients are around 55, middle class, working, and have young children.

HPV-positive throat cancer responds well to a combination of cisplatin chemotherapy and radiotherapy, and patients can survive for 30-40 years, but the treatment causes lifelong side effects including dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate chemotherapy, for example because of poor kidney function or older age, receive cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, and radiotherapy.

This study compared side effects and survival with the two treatments in 334 patients with HPV-positive throat cancer enrolled from 32 centres in the UK, Ireland, and the Netherlands. Patients were randomly allocated to radiotherapy and either cisplatin or cetuximab. Eight in ten patients were male and the average age was 57 years.

During the two-year study there were ten recurrences and six deaths with cisplatin compared to 29 recurrences and 20 deaths with cetuximab. Patients on cisplatin had a significantly higher two-year overall survival rate (97.5%) than those on cetuximab (89.4%; p=0.001, hazard ratio [HR] 4.99, 95% confidence interval [CI] 1.70-14.67). Cancer was over three times more likely to recur in two years with cetuximab compared to cisplatin, with recurrence rates of 16.1% versus 6.0%, respectively (p=0.0007, HR 3.39, 95% CI 1.61-7.19).

There were no differences between groups in the overall number of side effects, or of acute or late severe (grade 3-5) toxic events including dry mouth and difficulty swallowing. There were significantly more serious adverse events such as renal and haematological problems with cisplatin than with cetuximab.

Mehanna said: “Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin. This was a surprise—we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV positive should be given cisplatin, and not cetuximab, where possible.”

Commenting on the study for ESMO, Dr. Branislav Bystricky, Head, Medical and Radiation Oncology Department, University Hospital Trencin, Slovakia, said: “It was believed that cetuximab causes less side effects and was therefore a good option for HPV-positive throat cancer patients who are young and expected to survive for several decades, as well as those less able to tolerate chemotherapy. This study shows that the best treatment choice for patients with HPV-positive throat cancer is cisplatin and radiotherapy. This combination gives ‘double’ the benefit since it is more effective in terms of survival and does not worsen all grade toxicity compared to cetuximab with radiotherapy.”

Bystricky noted that the results were in agreement with interim findings of the US National Cancer Institute’s RTOG 1016 trial, which is scheduled to report this month. He said: “We now have two studies showing that these patients should not be given cetuximab. Future research should examine whether genotyping for the KRAS-variant can select a group of patients that will benefit from cetuximab treatment with radiotherapy.”

HPV16 vaccine yields added benefit in recurrent throat cancer

Source: www.medpagetoday.com
Author: Ian Ingram, Deputy Managing Editor, MedPage Today

Adding a tumor-specific vaccine to PD-1 checkpoint inhibition was safe and effective in HPV16-positive patients with recurrent or metastatic oropharyngeal cancer, a small phase II trial found.

Among 24 patients treated with nivolumab (Opdivo) and the ISA101 long peptide vaccine, 22 of whom had oropharyngeal cancer, 33% responded and median overall survival was 17.5 months, Cornelis Melief, PhD, of ISA Pharmaceuticals in the Netherlands, reported here at the 4th annual Cancer Immunotherapy Conference.

All eight of the responders had oropharyngeal cancer (36%), with two complete and six partial responses. The median duration of response among these patients was 10.3 months, and responses were seen in both platin- and cetuximab-refractory patients, and those refractory to both.

Melief noted that one of the partial responders had total clearance of the primary tumor, but a solitary lung metastasis remained, but was stable at 2.5 years.

Rate of overall survival at 6 and 12 months was 75% and 70%, respectively. The combination was well tolerated and safe, said Melief, with no increase in the rate of serious adverse events. A randomized trial is planned to confirm the findings.

“The results of our trial are among the first clinical data to support the general concept of combining cancer vaccination with immune checkpoint blockade to enhance efficacy of vaccine-activated T cells in the immunosuppressive tumor environment,” Melief’s group wrote in JAMA Oncology, where the findings were also published.

The findings compare favorably to outcomes in a larger group of p16-positive patients in CheckMate 141, which tested nivolumab in recurrent or metastatic, chemotherapy-refractory squamous cell head and neck cancer, and led to FDA approval in that setting.

Overall response among the 63 p16-positive patients in that trial was 15.9%, and median overall survival was 9.1 months.

Median progression-free survival (PFS) in the current study was just 2.7 months, similar to that in CheckMate 141: 2.0 months in nivolumab-treated patients, which was no different from the PFS with standard therapy at 2.3 months (HR 0.89, 95% CI 0.70-1.13, P=0.32).

“These findings are nearly double the response rate and median overall survival reported in the CheckMate 141, KEYNOTE-012, and KEYNOTE-055 trials,” said Theodoros Teknos, MD, of Seidman Cancer Center in Cleveland, calling the study an important incremental discovery in the burgeoning field of immunotherapy for head and neck cancer.

In KEYNOTE-012, the rate of overall response rate was 12% in a similar patient group (survival was not reported). In KEYNOTE-055, the rates were 20% and 8 months, respectively.

“Based on the findings reported in this study, additional investigation in the form of a larger randomized clinical trial evaluating the contribution of HPV16 vaccination to PD-L1 inhibition is warranted,” he told MedPage Today. “Nested in this trial, it would be advisable to perform robust analysis of immunologic subsets and cytokine profiling to identify biomarkers of response to this treatment approach.”

Teknos, who was not involved in the study, noted that the subgroup analysis again calls into question the use of PD-L1 as a biomarker. While 43% of the PD-L1 ≥1% group were responders, 18% of the PD-L1 < 1% group were as well.

Melief also presented data on the ISA101 vaccine in 62 late-stage HPV-positive cervical cancer patients treated with the ISA101 vaccine in combination with chemotherapy and highlighted the survival difference among those with a vaccine-induced T-cell response. Median overall survival was 22.7 months in those that had an HPV-specific response above the median versus 12.9 months for those with a response below the median (HR 0.286, 95% CI 0.149-0.551, P=0.0066).

He noted that this was not due just to immunocompetence differences between patients, as the effect was found to be independent of patients’ immune status.

The current study enrolled 24 patients from 2015 to 2016 — 20 men and four women. Outside of the oropharyngeal cancer patients, there was one patient with anal and cervical cancers each. Patients received three 100 μg doses of the subcutaneous ISA101 vaccine (days 1, 22, and 50). Starting on day 8, intravenous nivolumab was given every 2 weeks for a year or until disease progression or unacceptable toxicity.

Toxicities were of the expected variety: fever and injection site reactions with ISA101, and diarrhea, fatigue, and hepatoxicity with nivolumab. Two patients had grade 3 and 4 adverse events that led to discontinuation of nivolumab (an asymptomatic transaminase level elevation and a lipase elevation, respectively).

Expert says Nivolumab Poised to Change Standard of Care in SCCHN

Source: www.onclive.com
Author: Laura Panjwani

Robert-Ferris

Nivolumab (Opdivo) is a game-changing agent for the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN), according to Robert L. Ferris, MD, PhD.

“Recent findings have shown us that this agent is really the new standard-of-care option for all platinum-refractory patients with head and neck cancer,” says Ferris, vice chair for Clinical Operations, associate director for Translational Research, and co-leader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute. “This is regardless of whether patients are PD-L1–positive or negative or whether they are HPV-positive or negative.”

The PD-L1 inhibitor received a priority review designation by the FDA in July 2016 based on the CheckMate-141 study, which demonstrated a median overall survival (OS) with nivolumab of 7.5 months compared with 5.1 months with investigator’s choice of therapy (HR, 0.70; 95% CI, 0.51-0.96; P = .0101) in patients with recurrent or metastatic SCCHN.

The objective response rate (ORR) was 13.3% with nivolumab and 5.8% for investigator’s choice. The FDA is scheduled to make a decision on the application for the PD-1 inhibitor by November 11, 2016, as part of the Prescription Drug User Fee Act.

Ferris was the lead author on an analysis that further evaluated preliminary data from CheckMate-141, which was presented at the 2016 ASCO Annual Meeting. In an interview with OncLive, he discusses the findings of this study, potential biomarkers for nivolumab, and questions that remain regarding the use of the immunotherapy in SCCHN.

OncLive: What were the updated findings from CheckMate-141 presented at ASCO?

Ferris: The data that were presented at the 2016 ASCO Annual Meeting were further evaluations and follow-up on some preliminary data—originally presented at the 2016 AACR Annual Meeting—that listed the OS results.

At ASCO, we recapped the primary endpoint of OS as an important endpoint for immunotherapies because response rate and progression-free survival may not be as accurate. Ultimately, the FDA and people at large want OS. In this study, OS was 36% at 1 year in the nivolumab-treated arm and 16.6% in the comparator arm, which was investigator’s choice of single-agent chemotherapy, consisting of methotrexate, docetaxel, or cetuximab. In this phase III randomized trial, nivolumab was given in a 2:1 randomization: 240 patients received nivolumab and 120 received investigator’s choice.

Also at ASCO, we presented further evaluations consisting of what the regimens are in the comparator arm. There was about 20% each of docetaxel and methotrexate and 12% of cetuximab. Approximately 60% of the patients had prior cetuximab exposure and we stratified by cetuximab as a prior therapy. We also demonstrated the ORR, which was 13.3% in the nivolumab-treated arm versus 5.8% in the investigator’s choice arm.

Therefore, there was an improvement in overall response, but the difference seemed more modest than the OS benefit—which was a doubling—with 20% more patients alive at 1 year. This reinforces the concept that perhaps response rate may not be the best endpoint. Progression-free survival (PFS) was double at 6 months, with about 20% in the nivolumab arm versus about 9.9% in the investigator’s choice arm. The median PFS was not different, but the 6-month PFS was twice as high. The time to response was about 2 months in each arm at the first assessment.

Your analysis also looked at biomarkers. Can you discuss these findings and their significance?

The p16 or HPV-positive group had a better hazard ratio for OS than the overall study population. The hazard ratio was .73 for the overall population, using a preplanned interim analysis. With the HPV-positive group, we had a hazard ratio of .55 and the HPV-negative group had a hazard ratio of .99. It is still favoring the nivolumab-treated patients but, with the curves separated earlier in the HPV-positive group, one could see the improvement with nivolumab at about 1 to 2 months. It took 7 or 8 months with the HPV-negative group to show a separation of the curves in favor of nivolumab.

We looked at PD-L1 levels, and PD-L1—using a 1% or above level—had an improvement in the PD-L1–positive patients in favor of nivolumab in terms of OS and ORR. When we looked at 5% and 10% thresholds of PD-L1, the OS did not seem to improve. Therefore, in all levels above 1%, the OS was similarly beneficial over the PD-L1 less-than-1% group. However, essentially all levels of PD-L1–positivity and PD-L1–negativity still favored nivolumab, but the benefit was more when its levels were greater than 1%.

We could combine HPV status with PD-L1 status and look at subsets; however, essentially every subset benefited, whether it was PD-L1–negative or positive. This indicates that, in this group of patients, who progress within 6 months of platinum-based therapy, that no current systemic therapeutic options benefit patients as well as nivolumab.

With regard to these findings, what are you most excited about?

Head and neck cancer is a difficult disease. Until recently, we didn’t know the impact of this enrichment for HPV-positive virus-induced subsets and we didn’t know if this was an immune responsive cancer. Clearly, it is. We have all of the hallmarks that we have seen for a bright future—based on the melanoma data—and a series of other cancers indicating response rates in the 15% to 20% range, suggesting that we now have a platform of the PD-1 pathway to combine with other checkpoints and to integrate earlier in disease with radiation and chemotherapy.

We have a demonstration of head and neck cancer as an immune-responsive cancer. We are beginning to get an idea of the biomarkers and starting to be able to segment patients who will benefit. Now, we have a large comparative trial with an OS endpoint and tissue to look at biomarkers to try and understand what the best future combinations will be.

What are some questions that you still hope to answer regarding nivolumab in head and neck cancer?

We have to get down deeper into the nonresponders. We should acknowledge that the majority of patients neither had a response nor benefited. Understanding who is more likely to benefit is useful, but we also need to understand the levels of alternative checkpoint receptors or other biomarkers of resistance.

We have sequential lymphocyte specimens from the peripheral blood, tissues, and serum so those are intensively under evaluation. There are interferon gamma signatures that have risen from the melanoma checkpoint field that will certainty be applied, as well.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

2016-08-24T13:28:58-07:00August, 2016|Oral Cancer News|

Nivolumab Improved Survival For Patients With Head and Neck Squamous Cell Carcinoma

Source: www.aacr.org
Author: AACR Newsroom Staff
 

NEW ORLEANS — Treatment with the immunotherapeutic nivolumab (Opdivo) improved survival for patients with recurrent or metastatic head and neck squamous cell carcinoma that progressed after platinum-based chemotherapy compared with single-agent chemotherapy of the investigator’s choice, according to results from the CheckMate-141 phase III clinical trial presented here at the AACR Annual Meeting 2016, April 16-20.Maura Gillison

“Recurrent or metastatic head and neck squamous cell carcinoma that is not responsive to platinum-based chemotherapy progresses very rapidly, and patients have a very poor prognosis,” said Maura L. Gillison, MD, PhD, a professor in the Department of Internal Medicine at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. “Treatment usually involves single-agent chemotherapy. However, no therapy has been shown to improve survival for this patient population. New treatment options are desperately needed.

“This study is the first randomized clinical trial to clearly demonstrate improved overall survival for patients with platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma,” continued Gillison. “We hope that the results will establish nivolumab as a new standard of care option for this patient population and thereby fulfill a huge unmet need.”

CheckMate-141 was a randomized, phase III clinical trial designed to determine whether the PD-1 inhibitor nivolumab could extend overall survival for patients with platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma compared with treatment of the investigator’s choice, which was any of the commonly used therapeutics docetaxel, methotrexate, or cetuximab.

Of the 361 patients enrolled in the clinical trial, 240 were randomly assigned to nivolumab and 121 to single-agent chemotherapy of investigator’s choice.

At the interim analysis, which was conducted after 218 events, patients assigned to nivolumab were found to have a 30 percent reduction in risk of death compared with those assigned therapy of investigator’s choice. Median overall survival was 7.5 months for those assigned nivolumab versus 5.1 months for those assigned therapy of investigator’s choice. At 12 months, 36 percent of the patients treated with nivolumab were alive compared with 17 percent of those assigned therapy of investigator’s choice.

Because certain types of head and neck squamous cell carcinoma, particularly those arising in the oropharynx (back of the throat, including the base of the tongue and tonsils), have been linked with human papillomavirus (HPV) infection, the investigators also evaluated the data based on the HPV status of the patients’ tumors.

The effect of nivolumab on overall survival was seen for both patients with HPV-positive disease and those with HPV-negative disease. Among patients with HPV-positive disease, median overall survival was 9.1 months for those assigned nivolumab versus 4.4 months for those assigned therapy of investigator’s choice, and among patients with HPV-negative disease, median overall survival was 7.5 months for those assigned nivolumab versus 5.8 months for those assigned therapy of investigator’s choice.

A survival benefit in patients treated with nivolumab was observed for the overall study population. Exploratory analysis suggested that the benefit was greater for patients treated with nivolumab whose tumors had PD-L1 expression (of 1 percent or greater) or were HPV-positive.

“Overall, our data are extremely exciting. This clinical trial has established head and neck squamous cell carcinoma as responsive to immunotherapy. We are hopeful that this represents the tip of the iceberg with regard to future benefit of immunotherapy for patients with head and neck squamous cell carcinoma,” added Gillison.

This study was funded by Bristol-Myers Squibb. Gillison’s role in the study was funded in part by the Oral Cancer Foundation. Gillison has consulted for Bristol-Myers Squibb, Eli Lilly and Company, and Merck in the past year.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

 

Immunotherapy Continues to Advance in Head and Neck Cancer

Source: www.onclive.com
Author: Megan Garlapow, PhD
 

Concomitant administration of motolimod with cetuximab (Erbitux) increases the innate and adaptive immune response in the blood and the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC), overcoming negative prognostic biomarkers of cetuximab therapy alone, according to the biomarker data from a recent phase Ib clinical trial that was presented at the 2016 Head and Neck Cancer Symposium. The trial was recently amended to add nivolumab to the combination of cetuximab and motolimod.

Robert-FerrisDr. Robert Ferris, MD PhD

 

“We know that PD-1 and PD-L1 are overexpressed in head and neck cancer, and so it was somewhat irresistible to combine our baseline treatment of cetuximab and motolimod with the PD-L1 inhibition pathway. EGFR itself drives PD-L1, so combining cetuximab with anti-PD-1 inhibitor makes sense. So, we’ve amended this trial. We’re now accruing to treatment with cetuximab, motolimod, and the anti–PD-L1 nivolumab in this trial,” said lead author Robert Ferris, MD, PhD, professor, Departments of Otolaryngology, Radiation Oncology, and Immunology, Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

According to the authors of the phase Ib data presented at the symposium, the rationale for combining cetuximab with motolimod (VTX2337) as neoadjuvant therapy was that cetuximab induces cellular immunity that correlates with neoadjuvant clinical response. The phase I dose-escalation and safety of the combination had been established (NCT 01334177).

This study of neoadjuvant cetuximab and motolimod had accrued 14 patients with HNSCC that was stage II-IV, resectable, and located in the oropharynx, oral cavity, hypopharynx, or larynx. These patients were biopsied, treated with cetuximab and motolimod for 4 weeks, and then underwent surgery. The endpoints of the trial were the modulation of immune biomarkers.

Interferon-inducible cytokine IP-10 increased after the patients were administered neoadjuvant cetuximab and motolimod (P = .0001). After the neoadjuvant treatment, the peripheral blood lymphocytes had an increased frequency of EGFR-specific CD8 T cells. After the neoadjuvant treatment, regulatory T cells had decreased suppressive receptors and transforming growth factor-β, which induces Foxp3. Also, after the neoadjuvant treatment, circulating MDSCs had decreased PD-L1 (P <.07) and macrophages had increased CD16 expression (P <.07).

After the neoadjuvant treatment with cetuximab and motolimod, genotyping of T-cell receptors showed increased clonality in peripheral blood lymphocytes (P = .003 by Wilcox signed rank test) and tumor-infiltrating lymphocytes (P = .081 by Wilcox signed rank test). Most patients are more oligoclonal than healthy individuals, and some are very clonal with highly prominent expanded clones. Genotyping of T-cell receptors found that clonality was increased by the combination of cetuximab and motolimod compared with treatment with cetuximab alone.

Recent studies have indicated that the PD-1/PD-L1 pathway is upregulated in the HNSCC microenvironment, and that EGFR blockade prevents interferon-γ-mediated upregulation of PD-L1. Thus, this study has been amended to add nivolumab to the adjuvant treatment with cetuximab and motolimod. The endpoints are still the modulation of immune biomarkers.

The aim is to target the tumor microenvironment, such that tumor immune escape is reversed and T cells eliminate HNSCC. Antitumor T cells are reprogrammed to reverse inhibitory signals. Combining the toll-like receptor agonist, motolimod, with cetuximab and with PD-1 pathway inhibitors, such as nivolumab, may enhance the priming and activity of T cells.

“Targeting the tumor microenvironment requires understanding as well as reversal of immune escape mechanisms in the cellular compartment. Reprogramming antitumor T cells to reverse inhibitory signals can be done by directly disrupting those inhibitory signals, the so-called checkpoint receptor field, and can be done potentially by combining proinflammatory signals, such as toll-like receptor agonists, to chemo-attract cells into the microenvironment and to create good inflammation to overcome suppressive factors,” said Ferris.

Recent findings have shown tremendous promise for nivolumab in head and neck cancer. Bristol-Myers Squibb (BMS) announced in January 2016 that nivolumab improved overall survival versus investigator’s choice of therapy for patients with platinum-refractory squamous cell carcinoma of the head and neck in the phase III CheckMate-141 trial. Findings from the study are being discussed with the FDA and other health authorities, according to BMS.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
2016-02-29T10:49:56-07:00February, 2016|Oral Cancer News|
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