The Development of STING Agonists and Emerging Results as a Cancer Immunotherapy.

PURPOSE OF REVIEW: New therapies are needed to potentiate the effects of current immunotherapies and overcome resistance. The stimulator of interferon genes genes (STING) pathway is an innate immune activating cascade that may enhance current cancer immunotherapies. RECENT FINDINGS: Preclinical data has shown that the addition of a STING agonist enhances the effect of current treatments such as immune checkpoint inhibitor antibodies and radiation therapy. Early phase trials have demonstrated modest efficacy of STING agonists and revealed new mechanistic and technical challenges. STING agonists are a new class of agents that activate the immune response to improve tumor control. A wide range of preclinical experiments, translational data, and ongoing clinical trials support the therapeutic use of STING agonists in patients. Trials to determine optimal drug combinations and novel delivery mechanisms are continuing in development.

Systemic and Targeted Therapies in Adenoid Cystic Carcinoma.

OPINION STATEMENT: Adenoid cystic carcinoma (ACC) is an often-indolent type of salivary gland cancer (SGC). A subset of patients develops progression or aggressive disease warranting systemic therapy in the recurrent/metastatic (R/M) setting. We recommend genomic testing for all patients with R/M disease to aid with prognostication and eligibility for potential experimental therapies. Here, we review the currently available treatment options (cytotoxic chemotherapies and vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKIs)). Based on limited data, we nominate regimens which may have more favorable efficacy profiles. Among the cytotoxic chemotherapies, several regimens are acceptable when incorporating a platinum agent. Among the VEGFR-targeting TKIs, lenvatinib and axitinib are the preferred options. Larger, randomized studies prioritizing combinations with mechanistic synergism are needed. Predictive biomarkers are critical, as there is currently little evidence to guide sequencing of available options for individual patients. Immunotherapy is an available option, but has been associated with only modest benefit in ACC. We go on to review other therapies that have been studied and nominate those with promise based on early clinical data.

Oral keratosis of unknown significance shares genomic overlap with oral dysplasia.

OBJECTIVES: To identify molecular characteristics of keratosis of unknown significance and to nominate pathways of molecular progression to oral cancer. Our work could provide a rationale for monitoring and treating these lesions definitively. METHODS: Patients with oral leukoplakia were eligible for our prospective observational study. We correlated alterations in cancer-associated genes with clinical and histopathologic variables (keratosis of unknown significance vs. moderate-to-severe dysplasia) and compared these alterations to a previously molecularly characterized oral cancer population. RESULTS: Of 20 enrolled patients, 13 (65%) had evidence of keratosis of unknown significance, while seven (35%) had dysplasia. Nine patients (45%) developed oral cancer (4/13 with keratosis of unknown significance, 5/7 with dysplasia). At a median follow-up of 67 (range 22-144) months, median overall survival was significantly shorter for patients with dysplasia (hazard ratio 0.11, p = .02). KMT2C and TP53 alterations were most frequent (75% and 35%, respectively). There were molecular similarities between keratosis of unknown significance and dysplasia patients, with no significant differences in mutational frequency among genes with ≥15% rate of alteration. CONCLUSIONS: Among patients with leukoplakia, both patients with keratosis of unknown significance and patients with dysplasia developed oral cancer. Molecular alterations between these two groups were similar at this sample size.

Alternative Trastuzumab Dosing Schedules Are Associated With Reductions in Health Care Greenhouse Gas Emissions.

PURPOSE: Cancer care-related greenhouse gas (GHG) emissions harm human health. Many cancer drugs are administered at greater-than-necessary doses, frequencies, and durations. Alternative dosing strategies may enable reductions in cancer care GHG emissions without compromising patient outcomes. MATERIALS AND METHODS: We used streamlined life-cycle analysis in a case-control simulation to estimate the relative reductions in GHG emissions that would be expected to result from using each of three alternative dosing strategies of trastuzumab (6-month adjuvant treatment duration, once every 4-week dosing, and both) in human epidermal growth factor receptor 2 (HER2)+ breast cancer. Using primary data and conversion factors from the environmental science literature, we estimated per-patient relative reduction in GHG emissions and, using SEER data, health impacts (in terms of disability-adjusted life-years [DALYs] and excess mortality per kg CO2) on bystanders for each alternative dosing strategy. RESULTS: Compared with the trastuzumab dosing strategy commonly used at baseline (12-month duration of adjuvant therapy and once every 3-week dosing in all settings), adoption of both 6-month adjuvant trastuzumab and once every 4-week trastuzumab dosing would reduce GHG emissions by 4.5%, 18.7%, and 14.6% in the neoadjuvant, adjuvant, and metastatic settings, respectively. We estimate that US-based adoption of alternative trastuzumab dosing would reduce annual DALYs and excess lives lost due to environmental impact of US-based trastuzumab therapy for HER2+ breast cancer by 1.5 and 0.9, respectively. CONCLUSION: Alternative dosing strategies may materially reduce the population health impacts of cancer care by reducing environmental impact. Regulatory decision making and health technology assessments should consider a treatment's environmental and population health impacts. Clinical trials of alternative dosing strategies are justified on the basis of environmental and population health impacts.

Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings.

Patients with breast cancer frequently experience financial hardship, often due to the high costs of anti-cancer drugs. We sought to develop alternative trastuzumab dosing strategies, compare their pharmacokinetic effectiveness to standard dosing, and assess the expected financial implications of transitioning to them. We extracted clinical data from the records of 135 retrospectively identified patients with HER2-positive early breast cancer at a single, urban comprehensive cancer center who were treated with trastuzumab between 2017 and 2019. We performed pharmacokinetic simulations on a range of trastuzumab dose levels and frequencies, assessing efficacy by trough trastuzumab concentration (Ctrough) and population and individual likelihoods of Ctrough exceeding trastuzumab minimum effective concentration (MEC). We performed deterministic financial modeling to estimate the treatment-associated financial savings from alternative dosing strategies. Trastuzumab maintenance doses of 4 mg/kg every 3 weeks (Q3W) and 6 mg/kg every 4 weeks (Q4W) had nearly identical probabilities of Ctrough being above MEC as standard of care 6 mg/kg every 3 weeks. In the primary financial analysis, both trastuzumab 4 mg/kg Q3W and 6 mg/kg Q4W were associated with significant drug- and administration-related out-of-pocket cost savings over the duration of therapy, ranging from $765 (neoadjuvant, Q4W) to $2791 (adjuvant, Q4W). In particular, Q4W trastuzumab increased savings related to lost wages and travel cost avoidance. Low-dose and reduced frequency trastuzumab in appropriately selected patients may significantly reduce total drug utilization and meaningfully reduce patient financial toxicity. Prospective clinical trials evaluating low-dose or reduced-frequency administration of therapeutic monoclonal antibodies are warranted and needed.

Provider-Level Barriers to Human Papillomavirus Vaccination in Survivors of Childhood and Young Adult Cancers.

Purpose: We sought to understand clinician-level barriers to providing HPV vaccination to survivors of childhood and young adult cancers (CYACs). Methods: We conducted 30-minute qualitative interviews with primary care and specialty clinicians who care for survivors of CYACs at our academic medical center. Blinded reviewers analyzed transcripts and used an inductive approach to identify barriers to vaccination in this population. Results: We conducted 24 interviews (n = 11 primary care clinicians, n = 13 oncology clinicians). Thematic analysis revealed that primary care clinicians are universally viewed as holding ultimate responsibility for human papillomavirus (HPV) vaccination among survivors of CYACs. Both primary care and oncology clinicians believed vague, inconsistent HPV guidelines engendered uncertainty toward HPV vaccination's role and timing following completion of CYAC therapies. As such, compared with other vaccines, the HPV vaccination is not as consistently offered to survivors. Respondents identified direct guidance from oncologists to primary care clinicians and to patients as a potential strategy for improving HPV vaccination rates in this population. Finally, oncology clinicians frequently deprioritize the issue of preventing second, noniatrogenic cancers and consequently miss opportunities to discuss vaccination's merits with their patients. Conclusions: Despite not holding ultimate responsibility for vaccination, oncology clinicians have an opportunity to play an important role in ensuring access and overcoming hesitancy among survivors of CYACs. Developing clearer and more collaborative guidelines, helping to integrate vaccination into institutional electronic health record protocols, offering direct guidance to primary care colleagues, and participating in conversations with survivors of CYACs may help improve vaccination rates.

Value and Unmet Needs in Non-Invasive Human Papillomavirus (HPV) Testing for Oropharyngeal Cancer.

The burden of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) has risen, now representing the most common HPV-related malignancy. For years, researchers have explored the utility of measuring HPV-related markers from mouth, throat, and blood samples, often with the aim of gathering more information about an existing HPV-related tumor in a given patient. We review the widely varying methods for collecting and testing saliva and blood samples and offer guidance for standardizing these practices. We then review an array of clinical contexts in which non-invasive testing holds the most promise for potentially addressing unmet needs. In particular, such testing could help clinicians and researchers monitor the effects of vaccination and treatment. Meanwhile, due to the currently incomplete understanding of how carrying HPV relates to infection and subsequent oncogenesis, non-invasive testing methods may not be suitable for the screening setting at this time.

Artificial Intelligence Can Cut Costs While Maintaining Accuracy in Colorectal Cancer Genotyping.

Rising cancer care costs impose financial burdens on health systems. Applying artificial intelligence to diagnostic algorithms may reduce testing costs and avoid wasteful therapy-related expenditures. To evaluate the financial and clinical impact of incorporating artificial intelligence-based determination of mismatch repair/microsatellite instability status into the first-line metastatic colorectal carcinoma setting, we developed a deterministic model to compare eight testing strategies: A) next-generation sequencing alone, B) high-sensitivity polymerase chain reaction or immunohistochemistry panel alone, C) high-specificity panel alone, D) high-specificity artificial intelligence alone, E) high-sensitivity artificial intelligence followed by next generation sequencing, F) high-specificity artificial intelligence followed by next-generation sequencing, G) high-sensitivity artificial intelligence and high-sensitivity panel, and H) high-sensitivity artificial intelligence and high-specificity panel. We used a hypothetical, nationally representative, population-based sample of individuals receiving first-line treatment for de novo metastatic colorectal cancer (N = 32,549) in the United States. Model inputs were derived from secondary research (peer-reviewed literature and Medicare data). We estimated the population-level diagnostic costs and clinical implications for each testing strategy. The testing strategy that resulted in the greatest project cost savings (including testing and first-line drug cost) compared to next-generation sequencing alone in newly-diagnosed metastatic colorectal cancer was using high-sensitivity artificial intelligence followed by confirmatory high-specificity polymerase chain reaction or immunohistochemistry panel for patients testing negative by artificial intelligence ($400 million, 12.9%). The high-specificity artificial intelligence-only strategy resulted in the most favorable clinical impact, with 97% diagnostic accuracy in guiding genotype-directed treatment and average time to treatment initiation of less than one day. Artificial intelligence has the potential to reduce both time to treatment initiation and costs in the metastatic colorectal cancer setting without meaningfully sacrificing diagnostic accuracy. We expect the artificial intelligence value proposition to improve in coming years, with increasing diagnostic accuracy and decreasing costs of processing power. To extract maximal value from the technology, health systems should evaluate integrating diagnostic histopathologic artificial intelligence into institutional protocols, perhaps in place of other genotyping methodologies.

Multi-step screening of neoantigens' HLA- and TCR-interfaces improves prediction of survival.

Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.

COVIDOSE: A Phase II Clinical Trial of Low-Dose Tocilizumab in the Treatment of Noncritical COVID-19 Pneumonia.

Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the mortality of coronavirus disease 2019 (COVID-19). The IL-6 receptor-blocking monoclonal antibody tocilizumab has been repurposed for COVID-19, but prospective trials and dose-finding studies in COVID-19 have not yet fully reported. We conducted a single-arm phase II trial of low-dose tocilizumab in nonintubated hospitalized adult patients with COVID-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L. We hypothesized that doses significantly lower than the emerging standards of 400 mg or 8 mg/kg would resolve clinical and laboratory indicators of hyperinflammation. A dose range from 40 to 200 mg was evaluated, with allowance for one repeat dose at 24 to 48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Thirty-two patients received low-dose tocilizumab, with the majority experiencing fever resolution (75%) and CRP decline consistent with IL-6 pathway abrogation (86%) in the 24-48 hours following drug administration. There was no evidence of a relationship between dose and fever resolution or CRP decline over the dose range of 40-200 mg. Within the 28-day follow-up, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 3 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (16%) patients. Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with COVID-19. Results of this trial provide rationale for a randomized, controlled trial of low-dose tocilizumab in COVID-19.

FGFR3 Alterations in the Era of Immunotherapy for Urothelial Bladder Cancer.

FGFR3 is a prognostic and predictive marker and is a validated therapeutic target in urothelial bladder cancer. Its utility as a marker and target in the context of immunotherapy is incompletely understood. We review the role of FGFR3 in bladder cancer and discuss preclinical and clinical clues of its effectiveness as a patient selection factor and therapeutic target in the era of immunotherapy.

Predictors of immunotherapy benefit in Merkel cell carcinoma.

Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as first-line treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0-28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p = 0.04 for stage; odds ratio 0.75, p = 0.05 for disease-free interval). Single-nucleotide variants in ARID2 and NTRK1 were associated with response (p = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.

Circulating tumor cell analysis in locally advanced and metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Circulating tumors cells (CTCs) are considered an early step towards metastasis and have been linked to poor prognosis in several types of cancer. CTCs in squamous cell carcinoma of the head and neck (SCCHN) have an unclear role. METHODS: In this prospective study, patients with locally advanced or metastatic SCCHN had CTC counts assessed before starting systemic treatment using the CellSearch System. Select cases also had sequential CTC evaluation. Presence of CTCs was correlated with patient characteristics and outcomes. RESULTS: Forty-eight patients enrolled, and 36 had evaluable clinical data and baseline CTC counts. Twenty-five patients had locally advanced disease (LAD) and 11 had metastatic disease. ≥1 CTCs were detected in six patients with LAD (24%) and four with metastatic disease (36%). On univariate analysis, smoking was associated with CTCs. CONCLUSION: CTCs are not associated with prognosis in patients with LAD and metastatic disease; however, they are present in this patient population, and ≥1 CTCs is associated with a history of smoking. LEVEL OF EVIDENCE: 1b; individual prospective cohort study.

Chemotherapy after immune checkpoint blockade in patients with recurrent, metastatic squamous cell carcinoma of the head and neck.

OBJECTIVES: Given that immune checkpoint inhibitors (ICIs) are now preferred agents in first-line treatment of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), we retrospectively studied outcomes on post-ICI therapies. MATERIALS AND METHODS: We collected data from the medical records of 60 patients with R/M SCCHN who received ICIs followed by at least one further line of cytotoxic or biologic therapy at our institution from 2014 to 2019. We also compared outcomes with those of historical trials in the ICI-naïve, second-line or greater setting. RESULTS: Patients who received platinum-based regimens as their post-ICI therapies experienced improved overall response (ORR) (50% versus 10%, p < 0.01) and improved overall survival (OS) (15.1 months versus 7.3 months, HR 0.46, p = 0.04) compared to the rest of the cohort. Patients receiving platinum re-challenge were more likely to respond than all other patients in the cohort (OR 8.37, p = 0.01). The ORR for patients on 5-fluorouracil (5-FU)-containing regimens (63%) was also higher than other patients in the cohort (p = 0.03). Immunotherapy-based regimens compared favorably to historical data of first exposure to ICIs (disease control rate 54% versus 36%). Singlet regimens were associated with shorter OS than other regimens (HR = 2.38, p = 0.01). CONCLUSIONS: Platinum- and 5-FU-based doublet or triplet regimens may be superior options in the post-ICI setting. Immunotherapy re-challenge following ICI therapy may also be a reasonable option.

Association of Programmed Death 1 Protein Ligand (PD-L1) Expression With Prognosis in Merkel Cell Carcinoma.

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer. Prior to the advent of immunotherapy, treatment options were limited. In our study, we evaluate the impact of tumor cell PD-L1 expression and tumor immune microenvironment on survival in MCC patients who were not treated with immune checkpoint inhibitors. Methods: Clinical data and tissue samples were collected from 78 patients with confirmed MCC treated at Dana-Farber Cancer Institute. Specimens were analyzed for the distribution of PD-L1 by immunohistochemistry staining (IHC) and standardized analysis. Results were correlated with survival data. Results: In this study, membrane and cytoplasmic MCC tumor cell staining for PD-L1 was detected in 22.4% (15 of 67) of cases and PD-L1 staining of intratumoral microvessels and PD-L1 positive immune cells at the infiltrative margins of the tumor in 92.5% (62 of 67) of cases. In patients untreated with immune checkpoint inhibitors, median overall survival was not different for patients based on PD-L1 expression (PD-L1+ 64 months vs. PD-L1- not reached; HR = 1.26, 95% CI: 0.46-3.45; p = 0.60). Conclusion: PD-L1 expression is frequently detected in MCC tumor cells and tumor microenvironment. PD-L1 expression did not affect prognosis in this cohort that had not received PD-1/L1 blockade.

COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19.

Background Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. Methods We conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) >= 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. Findings A total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75.0% vs. 34.2%, p = 0.001) and CRP decline (86.2% vs. 14.3%, p < 0.001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related in this small study (p=0.80 and p=0.10, respectively). Within the 28-day follow-up, 5 (15.6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15.6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. Interpretation Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.

Chromosome 3q arm gain linked to immunotherapy response in advanced cutaneous squamous cell carcinoma.

AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients. METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts. RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy. CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.

Everolimus in Anaplastic Thyroid Cancer: A Case Series.

Background: Anaplastic thyroid cancer (ATC) is a very aggressive disease and accounts for over 50% of thyroid-cancer related deaths. mTOR inhibition has shown anti-tumor activity in ATC. We report our experience treating patients with ATC with everolimus off-protocol. Methods: Patients with confirmed ATC and treated with everolimus at DFCI were identified and reviewed retrospectively. NexGen sequencing was performed, and radiologic responses were correlated with mutational profile. Results: Five patients were treated from 2013 to 2016. Three patients had a response, which included one patient who achieved a partial response for 27.9 months, and two patients who had stable disease for 3.7 and 5.9 months, respectively. Genomic analysis was available in two patients and revealed that the partial responder had mutations involving the PI3K/mTOR pathway. Conclusion: Everolimus has anti-tumor activity in ATC, and responses may correlate with mutations involving the PI3K/mTOR pathway. Further studies are warranted.

Improved outcomes in PI3K-pathway-altered metastatic HPV oropharyngeal cancer.

While it has been recognized that human papillomavirus-associated (HPV-associated) oropharyngeal cancer (OPC) portends an improved prognosis, distinct patterns of disease recurrence have emerged. Molecular characterization of this subset of HPV patients remains unexplored. We evaluated 52 metastatic HPV+ OPC patients from our institution and paired massively parallel sequencing data with clinical parameters and survival outcomes in 81% of patients. Genomic data were then compared with 2 molecularly defined, curable HPV+ cohorts. Metastatic HPV+ OPC patients with pulmonary-only metastases demonstrated worse outcomes. Nonexclusive somatic alterations in KMT2D and PIK3CA were most frequent, with PRKDC alterations occurring at higher frequency when compared with all sequenced HPV+ OPC patients. PI3K pathway alterations were associated with improved outcomes among metastatic HPV+ OPC patients. We demonstrate subtle differences in the mutational landscape between curable and metastatic HPV+ OPC populations, with a trend towards more frequent DNA repair protein alterations in the latter. We demonstrate improved outcomes when PI3K pathway alterations are present in these patients. We provide molecular insights for this important HPV+ subgroup that have significant therapeutic implications.