RARE DISEASE
Squamous cell carcinoma of the anal canal
Squamous cell carcinoma of the anal canal
Squamous cell carcinoma of the anal canal
Drug discovery
4
drugs
With orphan designations
Overview
Squamous cell carcinoma of the anal canal (SCCAC) is a rare, HPV-associated malignancy linked to immunosuppression, smoking, and high-risk sexual behavior. It accounts for ~90% of anal cancers, with rising global incidence (+2–3% annually) and mortality. Treatment focuses on sphincter preservation through chemoradiation (CRT), with 5-fluorouracil/mitomycin C as the standard regimen. While CRT achieves 5-year survival rates of 65–80%, locoregional failure occurs in 20–30% of cases [1][2][6][16].
Burden
U.S. incidence: ~10,540 cases annually (2024); 5-year survival 56.9% in PLWH vs. 66.8% overall [7][14][16].
Stage migration: Distant-stage incidence tripled (AAPC +7.5–8.6%) since 2001; mortality increased 3.1% annually [4][14].
HPV vaccination may reduce future cases but remains underutilized (38.6% U.S. coverage) [12][14].
Therapies
Stage I-III: CRT (Nigro protocol) with 5-FU/mitomycin C and 50–59 Gy radiotherapy; local excision for T1N0 tumors [1][8][13].
Recurrent/metastatic disease: Carboplatin/paclitaxel or cisplatin-based regimens; salvage abdominoperineal resection (77% locoregional control) [6][8].
Emerging: PD-1 inhibitors (e.g., retifanlimab) for refractory cases; de-escalation trials (e.g., DECREASE) to reduce CRT toxicity [6][12][20].
Categories: rare gastroenterological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
956 drug discovery papers about Squamous cell carcinoma of the anal canal, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
956 drug discovery papers about Squamous cell carcinoma of the anal canal, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-17 | Induction chemotherapy followed by chemoradiotherapy in patients with locally advanced anal cancers: The PRODIGE 85-FFCD 1804-KANALRAD trial.
The PRODIGE 85-FFCD 1804-KANALRAD trial has been designed as a multicenter, randomized, open-label, phase III trial to compare the efficacy of induction chemotherapy (4 cycles of modified DCF: Docetaxel, Cisplatin, and 5-Fluorouracil) prior to standard chemoradiotherapy (CRT) versus standard CRT alone for histologically proven locally advanced squamous cell carcinomas of the anal canal (SCCA), either T3-4 or with lymph node involvement and no metastases. The primary endpoint is event-free survival at 2 years. Secondary endpoints include disease-free survival, complete response rate, patient quality of life, and monitoring of treatment-associated toxicities. A safety analysis is planned after enrollment of the 20 first patients in the experimental arm to ensure the feasibility of CRT after induction chemotherapy. In addition, genetic and epigenetic studies from tissue and circulating DNA will be conducted to assess their prognostic or predictive value. Overall, 310 patients will be recruited in France and will be followed for 3 years after randomization.
2025-05-28 | Genomic characterization of anal canal squamous cell carcinoma (ASCC) and outcomes on matched targeted therapy.
3526 Background: Anal canal squamous cell carcinoma (ASCC) is uncommon but increasing in incidence. 5-year survival of patients (pts) with metastatic ASCC is only 36%; new therapies are an unmet medical need. Genomic alterations (GA) in phosphoinositol-3-kinase (PI3K) signaling pathway have been reported in small datasets of ASCC. Data on clinical outcomes with therapies targeting these GA in pts with ASCC are lacking. Methods: Tumor genomic data of pts with ASCC at Memorial Sloan Kettering Cancer Center (MSK) were obtained using a targeted next generation sequencing assay (MSK IMPACT) from cBioPortal database. GA were annotated for biological significance using the OncoKB database, and only GA with known oncogenic potential were included. GA were categorized as mutations (mut), amplifications (amp), deletions (del) and fusions (fus). Clinical annotations were abstracted from electronic health records and outcomes of pts who participated in clinical trials were assessed. Data were summarized using descriptive statistics and survivals were estimated using Kaplan-Meier method. Results: Of 92,711 pts in cBioPortal, 218 (0.2%) pts had ASCC (male n = 65, 30%). Of these 218 pts, 179 (82%) had at least 1 oncogenic GA. Oncogenic GA were most frequently identified in PIK3CA 40% (87 pts; mut 67, amp 36, with overlap), KMT2D 19% (mut 42), BCL6 17% (amp 37), PTEN 12% (mut 18, del 9), EP300 11% (mut 24), KMT2C 11% (mut 20, del 3), and FBXW7 10% (mut 20, del 1). Oncogenic GA were most frequent in the PI3K-AKT-mTOR signaling pathway (121 pts, 55%). Amps were also seen in FGF3 , FGF4, FGF19 and CCND1 in 4% pts each. Thirteen pts with metastatic treatment refractory ASCC participated in early phase clinical trials; 3 pts enrolled in > 1 studies (total 18 trial participations). GA-matched targeted therapy was administered to 8 pts: oncogene inhibitors in 6 pts (targeting PIK3CA E545K in 3, PIK3CA Q546K in 1, HER2 I767M in 1, FGFR2 amp in 1), and drugs selected for tumor suppressor gene GA in 3 pts (PTCH1 loss in 1, TP53-wild in 1, FBXW7 in 1). Six pts received immunotherapy and 3 pts were treated with antivirals drugs targeting Human Papillomavirus. Out of 4 pts treated with PI3K signaling inhibitors, 1 had partial response and 2 had stable disease, with median progression free survival of 3.6 (95% CI 0-8.6) months and median overall survival of 9.1 (95% CI 5.7-12.5) months. Two out of four pts treated with PI3K pathway inhibitors were on treatment for > 6 months. No response was seen in pts treated with drugs targeting GA other than PIK3CA or with immunotherapy; and one of three pts treated with anti-viral agents had best response of stable disease. Conclusions: This is the largest characterization of GA with known oncogenic potential in ASCC. The PI3K signaling pathway is altered in over half of ASCC, and PI3K-AKT-MTOR inhibitors have the potential for further investigation in pts with activating GA in PIK3CA gene.
2025-04-10 | Priming the Immune System in Anal Cancer: Does Immunotherapy Need a Helping Hand From Chemotherapy?
Evidence suggests that chemotherapy can prime the immune system, enhancing immunotherapy effects for better outcomes. These effects may be further enhanced in highly immunogenic cancers, such as HPV-driven squamous cell carcinoma of the anal canal.
2025-01-30 | Metastatic Status and Dissection Effect of Regional/Extraregional Lymph Nodes in Japanese Patients with Squamous Cell Carcinoma of the Anal Canal: A Multicenter Retrospective Cohort Study.
Squamous cell carcinoma of the anal canal (SCCA) is a rare condition. Standard treatment includes chemoradiotherapy, with surgical treatment reserved for limited cases. In the future, the decrease in surgical frequency makes it more difficult to pathologically assess the depth of tumor invasion and lymph node status; therefore, those studies based on relatively recent surgical cases may offer valuable insights into diagnosing and treating SCCA. This multicenter, retrospective cohort study evaluated 435 patients with SCCA in Japan, of which 84 underwent surgical lymph node dissection. The correlation of regional/extraregional lymph node metastasis with T-primary tumor category/depth of tumor invasion, and the index of estimated benefit from lymph node dissection (IEBLD) was evaluated histopathologically. Primary tumor progression was associated with metastasis and recurrence of the inguinal node and further inferior mesenteric trunk/root node metastasis, an extraregional lymph node. The IEBLD for the inferior mesenteric trunk/root node was 6.9, which was higher than 4.0 IEBLD of the lateral lymph nodes classified as the regional lymph nodes. The assessment of the primary tumor involvement can predict metastases of the inguinal node and inferior mesenteric trunk/root node and recurrence of the inguinal node. Although the UICC TNM Classification considered the inferior mesenteric trunk/root nodes as extraregional lymph nodes, actively targeting them with the treatment can improve the prognosis.
2025-01-27 | Trends in surgery and overall survival in non-metastatic anal cancer: A population-based analysis.
3 Background: The incidence of anal cancer has recently exceeded > 10,000 patients/year in the United States. For non-metastatic squamous cell carcinoma of the anal canal (SCCA), concurrent chemoradiotherapy (CRT) followed by abdominoperineal resection (APR) as salvage surgery for non-responders is a key treatment approach. Over the past two decades, findings from phase III trials (RTOG 98-11 and ACT II) have increased our knowledge about appropriate treatment approaches. ACT II indicated that delayed assessment of tumor response and consideration of APR up until 26 weeks is appropriate, as many patients demonstrate delayed response to treatment. Our analysis examines whether current evidence has influenced real-world clinical practice by analyzing trends in rates of primary APR and overall survival (OS) outcomes. Methods: We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) registry, including patients diagnosed with non-metastatic SCCA between 2004 and 2020. Patients with T0 or T1N0 stage disease were excluded. Descriptive statistics were generated, and chi-square tests were used to compare characteristics between patients who underwent surgery and those who did not. Temporal trends in surgery and radiation therapy were analyzed using the Cochrane-Armitage trend test. Multivariable logistic regression was employed to identify factors associated with surgery uptake, while OS trends were analyzed using Kaplan-Meier and Cox proportional hazard models. Results: A total of 16,718 patients were included, with 33.1% requiring salvage APR following CRT. The proportion of patients requiring surgery significantly declined from 46.6% in 2004 to 31.1% in 2020 (p < 0.001). Factors associated with surgery included younger age, male gender, and non-Hispanic Black race (p < 0.001). Kaplan-Meier analysis revealed significant improvements in OS over the study period (log-rank p = 0.0002), with more recent years (2016-2020) associated with significantly better OS compared to earlier periods (2004-2007, HR = 0.77, p < 0.001). Conclusions: The significant decrease in rates of salvage APR for non-metastatic SCCA likely reflects the global impact of recent phase III trials. Meanwhile, OS rates have been steadily improving. These findings suggest improved overall knowledge regarding treatment strategies and highlight the real-world impact of clinical investigation in non-metastatic squamous cell carcinoma of the anal canal.
vaccines
2024-03-22 | Abstract 1769: Pan-cancer genomic characterization of human papillomavirus associated tumors reveals patterns of somatic alteration that associate with virus status and anatomic site
Abstract Human papilloma virus (HPV) infection causes over 600,000 human cancers yearly and accounts for nearly all cervical cancers, increasing rates of head and neck squamous cell carcinomas (HNSCC), and many anogenital cancers - all with varying clinical outcomes due to a lack of personalized care. While recent integrative genomic studies have described molecular features of individual cancer types, few studies have compared genomic changes between HPV(+) and HPV(-) cancers across anatomic sites. Here, we conducted the first pan-cancer genomic analysis of HPV-associated tumors across multiple anatomic tumor types using whole exome and transcriptome data from The Cancer Genome Atlas (TCGA) cohorts of cervical (n=254) and HNSCCs (n=514), and targeted exome sequencing of 800 cancer genes plus full length HPV16/18 genomes in a clinical cohort of squamous tumors from the head and neck (n=458), cervix (n=78), vulva (n=23), anal canal (n=5), and vagina (n=2). Somatic variant calling and filtering, followed by an integrative pathway analysis of commonly altered targets, defined the catalog of somatic mutations and copy number alterations (CNAs) that drive HPV(+) and HPV(-) tumorigenesis. Sequencing reads from viral RNA or DNA determined HPV status, and HPV type, genome structure, integration events, and viral load were characterized in a subset of samples via de novo assembly of viral aligned reads followed by copy number analysis, breakpoint identification, and the calling of structural variants. Overall HPV positivity was 50% (668 out of 1334 total), with HPV16 accounting for 96%, 89%, and 60% of all HPV(+) anogenital, head and neck, and cervical tumors respectively. Significant differences in somatic mutation frequency between HPV(+) and HPV(-) tumors were observed in the full cohort, as well as in analyses stratified by anatomic site. Interestingly, we noticed recurrently mutated “hotspots” attributable to increased APOBEC-mutagenesis in HPV(+) samples across anatomic sites (PIK3CA:E545K, FGFR3:S249C, EP300:D1399N), while hotspot mutations likely caused by tobacco smoking predominate HPV(-) HNSCC (PIK3CA:H1047R/L, CDKN2A:R80*, TP53:R282W). Focal and arm level CNAs were distinctive, including gains of 11q22 in HPV(+) cervical and HPV(-) HNSCC, and losses of 11q22 in HPV(+) HNSCC. Biological pathways commonly altered include epithelial differentiation, cell death, innate immunity, growth factor/kinase signaling, and cell cycle control. In summary, pan-cancer genomic analysis revealed distinct patterns of somatic alteration of conserved biological pathways that associate with HPV status and anatomic site. These findings improve our understanding of tumor biology unique to HPV-associated cancers and may lead to novel treatment and classification strategies to improve patient outcomes in the clinical setting. Citation Format: Jeremiah Ray Holt, Paul Little, Heejoon Jo, Xiaobei Zhao, Hyo Young Choi, Vonn Walter, Benjamin Wahle, Jose P. Zevallos, Angela Mazul, Katherine A. Hoadley, Michele Hayward, David N. Hayes. Pan-cancer genomic characterization of human papillomavirus associated tumors reveals patterns of somatic alteration that associate with virus status and anatomic site [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1769.
2023-10-23 | Characteristics of anal canal squamous cell carcinoma as an HPV-associated cancer in Japan.
The definition of the anal canal was revised in the TNM classification (8th edition). The Japanese Society for Cancer of the Colon and Rectum (JSCCR) conducted a retrospective multi-institutional study to clarify the characteristics of anal canal cancer (ACC) in Japan. The diagnoses of 1781 patients treated for ACC were squamous cell carcimoma (SCC; n = 428; 24.0%), adenosquamous cell carcinoma (n = 7; 0.4%), and adenocarcinoma (n = 1260; 70.7%). Anal carcinoma is associated with human papillomavirus (HPV) infection and is risk factor for anal SCC. Among 40 cases analyzed at Takano Hospital and 47 cases analyzed at National Cancer Center Hospital, 34 cases (85.0%) and 40 cases (85.1%), respectively were infected with HPV; HPV-16 was the most common genotype (79.4% and 82.5%). In the JSCCR retrospective multi-institutional study, the prognosis analysis by stage was performed for anal SCC cases (202 cases treated by CRT and 91 cases treated by surgery). The 5-year overall survival (OS) rates by stage did not differ between the two treatment groups to a statistically significant extent. Regarding the results of cancer treatment of patients who underwent HPV infection tests, although the 5-year OS rates by stage did not differ to a statistically significant extent due to the small number of cases, HPV-positive patients had better survival. While an HPV vaccine for anal canal SCC has already been approved internationally, HPV vaccination has already been implemented in Japan as a national immunization program for young women but not for men at present. An HPV vaccination for men is urgently needed.
2023-04-27 | Phase II Trial of MEDI0457 and Durvalumab for Patients With Recurrent/Metastatic Human Papillomavirus-Associated Cancers
Abstract Background Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. Methods Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p < 0.15; Ha: p ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. Results Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. Conclusions The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate.
2023-02-01 | Therapeutic Vaccination for HPV-Mediated Cancers
The goal of this narrative review is to educate clinicians regarding the foundational concepts, efficacy, and future directions of therapeutic vaccines for human papillomavirus (HPV)-mediated cancers.Therapeutic HPV vaccines deliver tumor antigens to stimulate an immune response to eliminate tumor cells. Vaccine antigen delivery platforms are diverse and include DNA, RNA, peptides, proteins, viral vectors, microbial vectors, and antigen-presenting cells. Randomized, controlled trials have demonstrated that therapeutic HPV vaccines are efficacious in patients with cervical intraepithelial neoplasia. In patients with HPV-mediated malignancies, evidence of efficacy is limited. However, numerous ongoing studies evaluating updated therapeutic HPV vaccines in combination with immune checkpoint inhibition and other therapies exhibit significant promise.Therapeutic vaccines for HPV-mediated malignancies retain a strong biological rationale, despite their limited efficacy to date. Investigators anticipate they will be most effectively used in combination with other regimens, such as immune checkpoint inhibition.
2022-07-19 | A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 TH1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study
Background There is a strong rational of using anti–programmed cell death protein-1 and its ligand (anti–PD-1/L1) antibodies in human papillomavirus (HPV)–induced cancers. However, anti–PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti–PD-1/L1 is therefore of interest. Combining anti–PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non–small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV + cancers. Methods Patients with HPV + cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously. Discussion Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific T H 1 CD4 T cells sustain the quality and homing of an antigen-specific CD8 + T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based T H 1 inducing vaccine (UCPVax) and an anti–PD-L1 (atezolizumab) immunotherapy in HPV + cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. Clinical Trial Registration https://www.clinicaltrials.gov/ , identifier NCT03946358.
antibodies
2026-08-05 | FDA Approval Summary: Retifanlimab for the treatment of adult patients with metastatic or inoperable locally recurrent squamous cell carcinoma of the anal canal.
On May 15, 2025, the Food and Drug Administration approved retifanlimab in combination with carboplatin and paclitaxel for treating unresectable or metastatic squamous cell carcinoma of the anal canal (SCAC), and as a single agent for second-line SCAC treatment. These approvals were based on POD1UM-303 and POD1UM-202 trials. In POD1UM-303, 308 patients with no prior systemic treatment for advanced disease were randomized 1:1 to receive retifanlimab or placebo, both combined with carboplatin and paclitaxel. The primary efficacy outcome was progression-free survival (PFS) assessed by blinded independent central review, with overall survival (OS) as a key secondary endpoint. The trial demonstrated a statistically significant PFS improvement with a hazard ratio (HR) of 0.63 (95% CI: 0.47, 0.84, p-value 0.0006). Median PFS was 9.3 months (95% CI: 7.5, 11.3) and 7.4 months (95% CI: 7.1, 7.7) in the retifanlimab and placebo arms, respectively. Interim OS results were not statistically significant (HR 0.70 [95% CI: 0.49, 1.01]), although the point estimate for OS was 29.2 months (95% CI: 24.2, NE) in the retifanlimab arm and 23 months (95% CI: 15.1, 27.9) for placebo. Second-line approval was based on POD1UM-202, a single-arm trial of 94 patients receiving single-agent retifanlimab. The independent centrally assessed overall response rate was 14% (95% CI: 8, 23). No new adverse safety signals were identified. The approval of retifanlimab as a single agent or in combination with chemotherapy provides a new therapeutic option for patients with unresectable or metastatic SCAC.
2026-07-22 | Durable Cancer Control and Extended Long-Term Survival Following Salvage Surgery for Squamous Cell Carcinoma of the Anal Canal: A Cohort Study.
Salvage surgery is the standard-of-care for patients with squamous cell carcinoma of the anal canal (SCCa) who experience isolated locoregional failure after upfront chemoradiotherapy. While perioperative morbidity and short-term survival outcomes have been described, long-term outcomes of surgical salvage are unknown. This study examines recurrence patterns and survival in a cohort of patients with extended follow-up. A retrospective chart review was performed on a cohort of consecutive patients who underwent salvage surgery at two specialized cancer centers between 1987 and 2006. Overall, disease-specific and re-recurrence-free survival (OS, DSS, RRFS) were estimated using the Kaplan-Meier method. Prognostic variables were evaluated using univariate and multivariable Cox models. Forty patients were included (29 female, 11 male; median age 56). Median follow-up was 16.5 years (IQR 15.0-20.5) for patients alive at last follow-up. Re-recurrence developed in 52% of patients, 95% of which occurred within 3 years of salvage surgery; re-recurrence was associated with a 91% risk of subsequent SCCa-specific mortality. DSS was 45% (95% CI 30-61) at 5 years, after which point conditional 5-year DSS was 100%. Approximately half of patients who undergo salvage surgery for persistent/recurrent SCCa experience durable cancer control with extended long-term survival. Emerging treatment options such as immunotherapy should be evaluated relative to this benchmark.
2026-07-22 | An evaluation of retifanlimab-dlwr with carboplatin and paclitaxel and as a single agent for squamous cell carcinoma of the anal canal.
Anal squamous cell carcinoma (SCC) is a rare cancer. Metastatic anal SCC is still a significant clinical challenge due to limited treatment options and poor outcomes. This review paper will focus on retifanlimab, a humanized monoclonal antibody targeting the programmed cell death protein 1 (PD-1) pathway, and its role in the treatment of metastatic anal SCC, both as monotherapy or in combination with chemotherapy. This review will evaluate its efficacy, safety, and place within the current therapeutic landscape. The POD1UM-303 trial is the first randomized phase III study for patients with metastatic and locally, advanced unresectable anal SCC. The results from POD1UM-303 are practice-changing, establishing retifanlimab in combination with carboplatin and paclitaxel as a new standard of care for first-line treatment in this setting. Current research includes investigating earlier integration of PD-(L)1 inhibitors with definitive chemoradiotherapy in the locally advanced setting. Further biomarker-driven studies are essential to guide treatment and improve patient selection.
2026-05-29 | Updates on Management of Anal Cancer: A New Era Has Begun.
Squamous cell carcinoma of the anal canal (SCAC) is a rare, human papillomavirus-driven malignancy with a rising global incidence and an increasingly dynamic therapeutic landscape. This review summarizes recent advances and current evidence in the management of SCAC, with a focus on immunotherapy, systemic treatment strategies, and optimization of curative-intent approaches. For locally advanced SCAC, concurrent chemoradiotherapy with fluorouracil and mitomycin C remains the standard of care, on the basis of multiple randomized trials demonstrating improved disease control and organ preservation compared with radiotherapy alone. These studies also show that treatment intensification with alternative chemotherapy, induction therapy, or radiation dose escalation does not improve outcomes. Given the curative intent, maintaining quality of life is a key consideration, and current studies are evaluating radiation dose optimization to reduce treatment-related toxicity, as well as the integration of immunotherapy to improve treatment efficacy. In metastatic SCAC, the combination of carboplatin and paclitaxel is the established first-line chemotherapy backbone. The addition of the PD-1 inhibitor retifanlimab to chemotherapy has demonstrated improved clinical outcomes and is now a preferred first-line approach. In the treatment-refractory setting, anti-PD-1 monotherapy provides modest response rates and remains a standard option for immunotherapy-naïve patients. Together, these findings summarize the current evidence base guiding the management of SCAC.
2026-05-28 | Efficacy and safety of retifanlimab across solid tumors: A systematic review and meta-analysis.
e14585 Background: Retifanlimab is a PD-1 inhibitor with demonstrated activity in several solid tumors, including FDA approved indication in squamous cell carcinoma of the anal canal (SCAC). However, its efficacy and safety across tumor types have not been systematically synthesized. Methods: We conducted a systematic review and meta analysis of prospective trials evaluating retifanlimab in solid tumors. PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and oncology conferences were searched through January 2026. Pooled ORR and CR were estimated using random effects models. Subgroup analyses were performed by tumor type, treatment line, and regimen. Results: Nineteen studies encompassing 1,113 patients across phase I-III trials were included. Tumor types included SCAC, Merkel cell carcinoma (MCC), NSCLC, HNSCC, sarcoma, and MSI-H endometrial cancer. Pooled ORR was 57.2% (95% CI, 48.6–65.9%; I² = 87%); CR rate was 26.3% (95% CI, 19.7–32.8%). First-line treatment showed significantly higher ORR than later lines (79.8% vs 39.5%). By tumor type, higher ORRs were observed in HNSCC (74.8%), NSCLC (74.7%), MCC (69.4%), and SCAC (65.4%). Safety was consistent with PD-1 inhibitor class: any-grade irAEs in 27.8%, grade ≥3 in 6.3%. Conclusions: Retifanlimab demonstrates clinically meaningful antitumor activity across multiple solid tumors, with greatest benefit in first line treatment. Consistency of efficacy and safety signals supports ongoing development. Pooled ORR by tumor type. Tumor Studies Patients ORR (95% CI) SCAC 3 402 65.4% (40.7–90.2%) MCC 2 111 69.4% (37.2–101.6%) NSCLC 2 58 74.7% (39.1–110.3%) HNSCC 2 50 74.8% (53.3–96.4%) Sarcoma 3 88 37.5% (21.8–53.2%)
oligonucleotides
2021-10-01 | Molecular characterization of squamous cell carcinoma of the anal canal
Squamous cell carcinoma of the anal canal (SCCA) is an uncommon malignancy with limited therapeutic options. Nivolumab and pembrolizumab show promising results in patients with SCCA. Human papillomavirus (HPV)-negative tumors are frequently TP53-mutated (TP53-MT) and often resistant to therapy.We present a large molecularly-profiled cohort of SCCA, exploring the underlying biology of SCCA, differences between TP53-wild type (TP53-WT) and TP53-MT tumors, and differences between local and metastatic tumors. SCCA specimens (n=311) underwent multiplatform testing with immunohistochemistry (IHC), in situ hybridization (ISH) and next-generation sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square testing was used for comparative analyses.The most frequently mutated genes included PIK3CA (28.1%), KMT2D (19.5%), FBXW7 (12%), TP53 (12%) and PTEN (10.8%). The expression of PD-1 was seen in 68.8% and PD-L1 in 40.5% of tumors. High TMB was present in 6.7% of specimens. HER2 IHC was positive in 0.9%, amplification by chromogenic in situ hybridization (CISH) was seen 1.3%, and mutations in ERBB2 were present in 1.8% of tumors. The latter mutation has not been previously described in SCCA. When compared with TP53-WT tumors, TP53-MT tumors had higher rates of CDKN2A, EWSR1, JAK1, FGFR1 and BRAF mutations. PD-1 and PD-L1 expression were similar, and high TMB did not correlate with PD-1 (P=0.50) or PD-L1 (P=0.52) expression.Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.
2012-11-29 | Genomic analysis and selected molecular pathways in rare cancers
It is widely accepted that many cancers arise as a result of an acquired genomic instability and the subsequent evolution of tumor cells with variable patterns of selected and background aberrations. The presence and behaviors of distinct neoplastic cell populations within a patient's tumor may underlie multiple clinical phenotypes in cancers. A goal of many current cancer genome studies is the identification of recurring selected driver events that can be advanced for the development of personalized therapies. Unfortunately, in the majority of rare tumors, this type of analysis can be particularly challenging. Large series of specimens for analysis are simply not available, allowing recurring patterns to remain hidden. In this paper, we highlight the use of DNA content-based flow sorting to identify and isolate DNA-diploid and DNA-aneuploid populations from tumor biopsies as a strategy to comprehensively study the genomic composition and behaviors of individual cancers in a series of rare solid tumors: intrahepatic cholangiocarcinoma, anal carcinoma, adrenal leiomyosarcoma, and pancreatic neuroendocrine tumors. We propose that the identification of highly selected genomic events in distinct tumor populations within each tumor can identify candidate driver events that can facilitate the development of novel, personalized treatment strategies for patients with cancer.
small molecules
2026-01-17 | Induction chemotherapy followed by chemoradiotherapy in patients with locally advanced anal cancers: The PRODIGE 85-FFCD 1804-KANALRAD trial.
The PRODIGE 85-FFCD 1804-KANALRAD trial has been designed as a multicenter, randomized, open-label, phase III trial to compare the efficacy of induction chemotherapy (4 cycles of modified DCF: Docetaxel, Cisplatin, and 5-Fluorouracil) prior to standard chemoradiotherapy (CRT) versus standard CRT alone for histologically proven locally advanced squamous cell carcinomas of the anal canal (SCCA), either T3-4 or with lymph node involvement and no metastases. The primary endpoint is event-free survival at 2 years. Secondary endpoints include disease-free survival, complete response rate, patient quality of life, and monitoring of treatment-associated toxicities. A safety analysis is planned after enrollment of the 20 first patients in the experimental arm to ensure the feasibility of CRT after induction chemotherapy. In addition, genetic and epigenetic studies from tissue and circulating DNA will be conducted to assess their prognostic or predictive value. Overall, 310 patients will be recruited in France and will be followed for 3 years after randomization.
2025-05-28 | Genomic characterization of anal canal squamous cell carcinoma (ASCC) and outcomes on matched targeted therapy.
3526 Background: Anal canal squamous cell carcinoma (ASCC) is uncommon but increasing in incidence. 5-year survival of patients (pts) with metastatic ASCC is only 36%; new therapies are an unmet medical need. Genomic alterations (GA) in phosphoinositol-3-kinase (PI3K) signaling pathway have been reported in small datasets of ASCC. Data on clinical outcomes with therapies targeting these GA in pts with ASCC are lacking. Methods: Tumor genomic data of pts with ASCC at Memorial Sloan Kettering Cancer Center (MSK) were obtained using a targeted next generation sequencing assay (MSK IMPACT) from cBioPortal database. GA were annotated for biological significance using the OncoKB database, and only GA with known oncogenic potential were included. GA were categorized as mutations (mut), amplifications (amp), deletions (del) and fusions (fus). Clinical annotations were abstracted from electronic health records and outcomes of pts who participated in clinical trials were assessed. Data were summarized using descriptive statistics and survivals were estimated using Kaplan-Meier method. Results: Of 92,711 pts in cBioPortal, 218 (0.2%) pts had ASCC (male n = 65, 30%). Of these 218 pts, 179 (82%) had at least 1 oncogenic GA. Oncogenic GA were most frequently identified in PIK3CA 40% (87 pts; mut 67, amp 36, with overlap), KMT2D 19% (mut 42), BCL6 17% (amp 37), PTEN 12% (mut 18, del 9), EP300 11% (mut 24), KMT2C 11% (mut 20, del 3), and FBXW7 10% (mut 20, del 1). Oncogenic GA were most frequent in the PI3K-AKT-mTOR signaling pathway (121 pts, 55%). Amps were also seen in FGF3 , FGF4, FGF19 and CCND1 in 4% pts each. Thirteen pts with metastatic treatment refractory ASCC participated in early phase clinical trials; 3 pts enrolled in > 1 studies (total 18 trial participations). GA-matched targeted therapy was administered to 8 pts: oncogene inhibitors in 6 pts (targeting PIK3CA E545K in 3, PIK3CA Q546K in 1, HER2 I767M in 1, FGFR2 amp in 1), and drugs selected for tumor suppressor gene GA in 3 pts (PTCH1 loss in 1, TP53-wild in 1, FBXW7 in 1). Six pts received immunotherapy and 3 pts were treated with antivirals drugs targeting Human Papillomavirus. Out of 4 pts treated with PI3K signaling inhibitors, 1 had partial response and 2 had stable disease, with median progression free survival of 3.6 (95% CI 0-8.6) months and median overall survival of 9.1 (95% CI 5.7-12.5) months. Two out of four pts treated with PI3K pathway inhibitors were on treatment for > 6 months. No response was seen in pts treated with drugs targeting GA other than PIK3CA or with immunotherapy; and one of three pts treated with anti-viral agents had best response of stable disease. Conclusions: This is the largest characterization of GA with known oncogenic potential in ASCC. The PI3K signaling pathway is altered in over half of ASCC, and PI3K-AKT-MTOR inhibitors have the potential for further investigation in pts with activating GA in PIK3CA gene.
2025-04-10 | Priming the Immune System in Anal Cancer: Does Immunotherapy Need a Helping Hand From Chemotherapy?
Evidence suggests that chemotherapy can prime the immune system, enhancing immunotherapy effects for better outcomes. These effects may be further enhanced in highly immunogenic cancers, such as HPV-driven squamous cell carcinoma of the anal canal.
2025-01-30 | Metastatic Status and Dissection Effect of Regional/Extraregional Lymph Nodes in Japanese Patients with Squamous Cell Carcinoma of the Anal Canal: A Multicenter Retrospective Cohort Study.
Squamous cell carcinoma of the anal canal (SCCA) is a rare condition. Standard treatment includes chemoradiotherapy, with surgical treatment reserved for limited cases. In the future, the decrease in surgical frequency makes it more difficult to pathologically assess the depth of tumor invasion and lymph node status; therefore, those studies based on relatively recent surgical cases may offer valuable insights into diagnosing and treating SCCA. This multicenter, retrospective cohort study evaluated 435 patients with SCCA in Japan, of which 84 underwent surgical lymph node dissection. The correlation of regional/extraregional lymph node metastasis with T-primary tumor category/depth of tumor invasion, and the index of estimated benefit from lymph node dissection (IEBLD) was evaluated histopathologically. Primary tumor progression was associated with metastasis and recurrence of the inguinal node and further inferior mesenteric trunk/root node metastasis, an extraregional lymph node. The IEBLD for the inferior mesenteric trunk/root node was 6.9, which was higher than 4.0 IEBLD of the lateral lymph nodes classified as the regional lymph nodes. The assessment of the primary tumor involvement can predict metastases of the inguinal node and inferior mesenteric trunk/root node and recurrence of the inguinal node. Although the UICC TNM Classification considered the inferior mesenteric trunk/root nodes as extraregional lymph nodes, actively targeting them with the treatment can improve the prognosis.
2025-01-27 | Trends in surgery and overall survival in non-metastatic anal cancer: A population-based analysis.
3 Background: The incidence of anal cancer has recently exceeded > 10,000 patients/year in the United States. For non-metastatic squamous cell carcinoma of the anal canal (SCCA), concurrent chemoradiotherapy (CRT) followed by abdominoperineal resection (APR) as salvage surgery for non-responders is a key treatment approach. Over the past two decades, findings from phase III trials (RTOG 98-11 and ACT II) have increased our knowledge about appropriate treatment approaches. ACT II indicated that delayed assessment of tumor response and consideration of APR up until 26 weeks is appropriate, as many patients demonstrate delayed response to treatment. Our analysis examines whether current evidence has influenced real-world clinical practice by analyzing trends in rates of primary APR and overall survival (OS) outcomes. Methods: We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) registry, including patients diagnosed with non-metastatic SCCA between 2004 and 2020. Patients with T0 or T1N0 stage disease were excluded. Descriptive statistics were generated, and chi-square tests were used to compare characteristics between patients who underwent surgery and those who did not. Temporal trends in surgery and radiation therapy were analyzed using the Cochrane-Armitage trend test. Multivariable logistic regression was employed to identify factors associated with surgery uptake, while OS trends were analyzed using Kaplan-Meier and Cox proportional hazard models. Results: A total of 16,718 patients were included, with 33.1% requiring salvage APR following CRT. The proportion of patients requiring surgery significantly declined from 46.6% in 2004 to 31.1% in 2020 (p < 0.001). Factors associated with surgery included younger age, male gender, and non-Hispanic Black race (p < 0.001). Kaplan-Meier analysis revealed significant improvements in OS over the study period (log-rank p = 0.0002), with more recent years (2016-2020) associated with significantly better OS compared to earlier periods (2004-2007, HR = 0.77, p < 0.001). Conclusions: The significant decrease in rates of salvage APR for non-metastatic SCCA likely reflects the global impact of recent phase III trials. Meanwhile, OS rates have been steadily improving. These findings suggest improved overall knowledge regarding treatment strategies and highlight the real-world impact of clinical investigation in non-metastatic squamous cell carcinoma of the anal canal.
vaccines
2024-03-22 | Abstract 1769: Pan-cancer genomic characterization of human papillomavirus associated tumors reveals patterns of somatic alteration that associate with virus status and anatomic site
Abstract Human papilloma virus (HPV) infection causes over 600,000 human cancers yearly and accounts for nearly all cervical cancers, increasing rates of head and neck squamous cell carcinomas (HNSCC), and many anogenital cancers - all with varying clinical outcomes due to a lack of personalized care. While recent integrative genomic studies have described molecular features of individual cancer types, few studies have compared genomic changes between HPV(+) and HPV(-) cancers across anatomic sites. Here, we conducted the first pan-cancer genomic analysis of HPV-associated tumors across multiple anatomic tumor types using whole exome and transcriptome data from The Cancer Genome Atlas (TCGA) cohorts of cervical (n=254) and HNSCCs (n=514), and targeted exome sequencing of 800 cancer genes plus full length HPV16/18 genomes in a clinical cohort of squamous tumors from the head and neck (n=458), cervix (n=78), vulva (n=23), anal canal (n=5), and vagina (n=2). Somatic variant calling and filtering, followed by an integrative pathway analysis of commonly altered targets, defined the catalog of somatic mutations and copy number alterations (CNAs) that drive HPV(+) and HPV(-) tumorigenesis. Sequencing reads from viral RNA or DNA determined HPV status, and HPV type, genome structure, integration events, and viral load were characterized in a subset of samples via de novo assembly of viral aligned reads followed by copy number analysis, breakpoint identification, and the calling of structural variants. Overall HPV positivity was 50% (668 out of 1334 total), with HPV16 accounting for 96%, 89%, and 60% of all HPV(+) anogenital, head and neck, and cervical tumors respectively. Significant differences in somatic mutation frequency between HPV(+) and HPV(-) tumors were observed in the full cohort, as well as in analyses stratified by anatomic site. Interestingly, we noticed recurrently mutated “hotspots” attributable to increased APOBEC-mutagenesis in HPV(+) samples across anatomic sites (PIK3CA:E545K, FGFR3:S249C, EP300:D1399N), while hotspot mutations likely caused by tobacco smoking predominate HPV(-) HNSCC (PIK3CA:H1047R/L, CDKN2A:R80*, TP53:R282W). Focal and arm level CNAs were distinctive, including gains of 11q22 in HPV(+) cervical and HPV(-) HNSCC, and losses of 11q22 in HPV(+) HNSCC. Biological pathways commonly altered include epithelial differentiation, cell death, innate immunity, growth factor/kinase signaling, and cell cycle control. In summary, pan-cancer genomic analysis revealed distinct patterns of somatic alteration of conserved biological pathways that associate with HPV status and anatomic site. These findings improve our understanding of tumor biology unique to HPV-associated cancers and may lead to novel treatment and classification strategies to improve patient outcomes in the clinical setting. Citation Format: Jeremiah Ray Holt, Paul Little, Heejoon Jo, Xiaobei Zhao, Hyo Young Choi, Vonn Walter, Benjamin Wahle, Jose P. Zevallos, Angela Mazul, Katherine A. Hoadley, Michele Hayward, David N. Hayes. Pan-cancer genomic characterization of human papillomavirus associated tumors reveals patterns of somatic alteration that associate with virus status and anatomic site [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1769.
2023-10-23 | Characteristics of anal canal squamous cell carcinoma as an HPV-associated cancer in Japan.
The definition of the anal canal was revised in the TNM classification (8th edition). The Japanese Society for Cancer of the Colon and Rectum (JSCCR) conducted a retrospective multi-institutional study to clarify the characteristics of anal canal cancer (ACC) in Japan. The diagnoses of 1781 patients treated for ACC were squamous cell carcimoma (SCC; n = 428; 24.0%), adenosquamous cell carcinoma (n = 7; 0.4%), and adenocarcinoma (n = 1260; 70.7%). Anal carcinoma is associated with human papillomavirus (HPV) infection and is risk factor for anal SCC. Among 40 cases analyzed at Takano Hospital and 47 cases analyzed at National Cancer Center Hospital, 34 cases (85.0%) and 40 cases (85.1%), respectively were infected with HPV; HPV-16 was the most common genotype (79.4% and 82.5%). In the JSCCR retrospective multi-institutional study, the prognosis analysis by stage was performed for anal SCC cases (202 cases treated by CRT and 91 cases treated by surgery). The 5-year overall survival (OS) rates by stage did not differ between the two treatment groups to a statistically significant extent. Regarding the results of cancer treatment of patients who underwent HPV infection tests, although the 5-year OS rates by stage did not differ to a statistically significant extent due to the small number of cases, HPV-positive patients had better survival. While an HPV vaccine for anal canal SCC has already been approved internationally, HPV vaccination has already been implemented in Japan as a national immunization program for young women but not for men at present. An HPV vaccination for men is urgently needed.
2023-04-27 | Phase II Trial of MEDI0457 and Durvalumab for Patients With Recurrent/Metastatic Human Papillomavirus-Associated Cancers
Abstract Background Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. Methods Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p < 0.15; Ha: p ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. Results Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. Conclusions The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate.
2023-02-01 | Therapeutic Vaccination for HPV-Mediated Cancers
The goal of this narrative review is to educate clinicians regarding the foundational concepts, efficacy, and future directions of therapeutic vaccines for human papillomavirus (HPV)-mediated cancers.Therapeutic HPV vaccines deliver tumor antigens to stimulate an immune response to eliminate tumor cells. Vaccine antigen delivery platforms are diverse and include DNA, RNA, peptides, proteins, viral vectors, microbial vectors, and antigen-presenting cells. Randomized, controlled trials have demonstrated that therapeutic HPV vaccines are efficacious in patients with cervical intraepithelial neoplasia. In patients with HPV-mediated malignancies, evidence of efficacy is limited. However, numerous ongoing studies evaluating updated therapeutic HPV vaccines in combination with immune checkpoint inhibition and other therapies exhibit significant promise.Therapeutic vaccines for HPV-mediated malignancies retain a strong biological rationale, despite their limited efficacy to date. Investigators anticipate they will be most effectively used in combination with other regimens, such as immune checkpoint inhibition.
2022-07-19 | A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 TH1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study
Background There is a strong rational of using anti–programmed cell death protein-1 and its ligand (anti–PD-1/L1) antibodies in human papillomavirus (HPV)–induced cancers. However, anti–PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti–PD-1/L1 is therefore of interest. Combining anti–PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non–small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV + cancers. Methods Patients with HPV + cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously. Discussion Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific T H 1 CD4 T cells sustain the quality and homing of an antigen-specific CD8 + T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based T H 1 inducing vaccine (UCPVax) and an anti–PD-L1 (atezolizumab) immunotherapy in HPV + cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. Clinical Trial Registration https://www.clinicaltrials.gov/ , identifier NCT03946358.
antibodies
2026-08-05 | FDA Approval Summary: Retifanlimab for the treatment of adult patients with metastatic or inoperable locally recurrent squamous cell carcinoma of the anal canal.
On May 15, 2025, the Food and Drug Administration approved retifanlimab in combination with carboplatin and paclitaxel for treating unresectable or metastatic squamous cell carcinoma of the anal canal (SCAC), and as a single agent for second-line SCAC treatment. These approvals were based on POD1UM-303 and POD1UM-202 trials. In POD1UM-303, 308 patients with no prior systemic treatment for advanced disease were randomized 1:1 to receive retifanlimab or placebo, both combined with carboplatin and paclitaxel. The primary efficacy outcome was progression-free survival (PFS) assessed by blinded independent central review, with overall survival (OS) as a key secondary endpoint. The trial demonstrated a statistically significant PFS improvement with a hazard ratio (HR) of 0.63 (95% CI: 0.47, 0.84, p-value 0.0006). Median PFS was 9.3 months (95% CI: 7.5, 11.3) and 7.4 months (95% CI: 7.1, 7.7) in the retifanlimab and placebo arms, respectively. Interim OS results were not statistically significant (HR 0.70 [95% CI: 0.49, 1.01]), although the point estimate for OS was 29.2 months (95% CI: 24.2, NE) in the retifanlimab arm and 23 months (95% CI: 15.1, 27.9) for placebo. Second-line approval was based on POD1UM-202, a single-arm trial of 94 patients receiving single-agent retifanlimab. The independent centrally assessed overall response rate was 14% (95% CI: 8, 23). No new adverse safety signals were identified. The approval of retifanlimab as a single agent or in combination with chemotherapy provides a new therapeutic option for patients with unresectable or metastatic SCAC.
2026-07-22 | Durable Cancer Control and Extended Long-Term Survival Following Salvage Surgery for Squamous Cell Carcinoma of the Anal Canal: A Cohort Study.
Salvage surgery is the standard-of-care for patients with squamous cell carcinoma of the anal canal (SCCa) who experience isolated locoregional failure after upfront chemoradiotherapy. While perioperative morbidity and short-term survival outcomes have been described, long-term outcomes of surgical salvage are unknown. This study examines recurrence patterns and survival in a cohort of patients with extended follow-up. A retrospective chart review was performed on a cohort of consecutive patients who underwent salvage surgery at two specialized cancer centers between 1987 and 2006. Overall, disease-specific and re-recurrence-free survival (OS, DSS, RRFS) were estimated using the Kaplan-Meier method. Prognostic variables were evaluated using univariate and multivariable Cox models. Forty patients were included (29 female, 11 male; median age 56). Median follow-up was 16.5 years (IQR 15.0-20.5) for patients alive at last follow-up. Re-recurrence developed in 52% of patients, 95% of which occurred within 3 years of salvage surgery; re-recurrence was associated with a 91% risk of subsequent SCCa-specific mortality. DSS was 45% (95% CI 30-61) at 5 years, after which point conditional 5-year DSS was 100%. Approximately half of patients who undergo salvage surgery for persistent/recurrent SCCa experience durable cancer control with extended long-term survival. Emerging treatment options such as immunotherapy should be evaluated relative to this benchmark.
2026-07-22 | An evaluation of retifanlimab-dlwr with carboplatin and paclitaxel and as a single agent for squamous cell carcinoma of the anal canal.
Anal squamous cell carcinoma (SCC) is a rare cancer. Metastatic anal SCC is still a significant clinical challenge due to limited treatment options and poor outcomes. This review paper will focus on retifanlimab, a humanized monoclonal antibody targeting the programmed cell death protein 1 (PD-1) pathway, and its role in the treatment of metastatic anal SCC, both as monotherapy or in combination with chemotherapy. This review will evaluate its efficacy, safety, and place within the current therapeutic landscape. The POD1UM-303 trial is the first randomized phase III study for patients with metastatic and locally, advanced unresectable anal SCC. The results from POD1UM-303 are practice-changing, establishing retifanlimab in combination with carboplatin and paclitaxel as a new standard of care for first-line treatment in this setting. Current research includes investigating earlier integration of PD-(L)1 inhibitors with definitive chemoradiotherapy in the locally advanced setting. Further biomarker-driven studies are essential to guide treatment and improve patient selection.
2026-05-29 | Updates on Management of Anal Cancer: A New Era Has Begun.
Squamous cell carcinoma of the anal canal (SCAC) is a rare, human papillomavirus-driven malignancy with a rising global incidence and an increasingly dynamic therapeutic landscape. This review summarizes recent advances and current evidence in the management of SCAC, with a focus on immunotherapy, systemic treatment strategies, and optimization of curative-intent approaches. For locally advanced SCAC, concurrent chemoradiotherapy with fluorouracil and mitomycin C remains the standard of care, on the basis of multiple randomized trials demonstrating improved disease control and organ preservation compared with radiotherapy alone. These studies also show that treatment intensification with alternative chemotherapy, induction therapy, or radiation dose escalation does not improve outcomes. Given the curative intent, maintaining quality of life is a key consideration, and current studies are evaluating radiation dose optimization to reduce treatment-related toxicity, as well as the integration of immunotherapy to improve treatment efficacy. In metastatic SCAC, the combination of carboplatin and paclitaxel is the established first-line chemotherapy backbone. The addition of the PD-1 inhibitor retifanlimab to chemotherapy has demonstrated improved clinical outcomes and is now a preferred first-line approach. In the treatment-refractory setting, anti-PD-1 monotherapy provides modest response rates and remains a standard option for immunotherapy-naïve patients. Together, these findings summarize the current evidence base guiding the management of SCAC.
2026-05-28 | Efficacy and safety of retifanlimab across solid tumors: A systematic review and meta-analysis.
e14585 Background: Retifanlimab is a PD-1 inhibitor with demonstrated activity in several solid tumors, including FDA approved indication in squamous cell carcinoma of the anal canal (SCAC). However, its efficacy and safety across tumor types have not been systematically synthesized. Methods: We conducted a systematic review and meta analysis of prospective trials evaluating retifanlimab in solid tumors. PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and oncology conferences were searched through January 2026. Pooled ORR and CR were estimated using random effects models. Subgroup analyses were performed by tumor type, treatment line, and regimen. Results: Nineteen studies encompassing 1,113 patients across phase I-III trials were included. Tumor types included SCAC, Merkel cell carcinoma (MCC), NSCLC, HNSCC, sarcoma, and MSI-H endometrial cancer. Pooled ORR was 57.2% (95% CI, 48.6–65.9%; I² = 87%); CR rate was 26.3% (95% CI, 19.7–32.8%). First-line treatment showed significantly higher ORR than later lines (79.8% vs 39.5%). By tumor type, higher ORRs were observed in HNSCC (74.8%), NSCLC (74.7%), MCC (69.4%), and SCAC (65.4%). Safety was consistent with PD-1 inhibitor class: any-grade irAEs in 27.8%, grade ≥3 in 6.3%. Conclusions: Retifanlimab demonstrates clinically meaningful antitumor activity across multiple solid tumors, with greatest benefit in first line treatment. Consistency of efficacy and safety signals supports ongoing development. Pooled ORR by tumor type. Tumor Studies Patients ORR (95% CI) SCAC 3 402 65.4% (40.7–90.2%) MCC 2 111 69.4% (37.2–101.6%) NSCLC 2 58 74.7% (39.1–110.3%) HNSCC 2 50 74.8% (53.3–96.4%) Sarcoma 3 88 37.5% (21.8–53.2%)
oligonucleotides
2021-10-01 | Molecular characterization of squamous cell carcinoma of the anal canal
Squamous cell carcinoma of the anal canal (SCCA) is an uncommon malignancy with limited therapeutic options. Nivolumab and pembrolizumab show promising results in patients with SCCA. Human papillomavirus (HPV)-negative tumors are frequently TP53-mutated (TP53-MT) and often resistant to therapy.We present a large molecularly-profiled cohort of SCCA, exploring the underlying biology of SCCA, differences between TP53-wild type (TP53-WT) and TP53-MT tumors, and differences between local and metastatic tumors. SCCA specimens (n=311) underwent multiplatform testing with immunohistochemistry (IHC), in situ hybridization (ISH) and next-generation sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square testing was used for comparative analyses.The most frequently mutated genes included PIK3CA (28.1%), KMT2D (19.5%), FBXW7 (12%), TP53 (12%) and PTEN (10.8%). The expression of PD-1 was seen in 68.8% and PD-L1 in 40.5% of tumors. High TMB was present in 6.7% of specimens. HER2 IHC was positive in 0.9%, amplification by chromogenic in situ hybridization (CISH) was seen 1.3%, and mutations in ERBB2 were present in 1.8% of tumors. The latter mutation has not been previously described in SCCA. When compared with TP53-WT tumors, TP53-MT tumors had higher rates of CDKN2A, EWSR1, JAK1, FGFR1 and BRAF mutations. PD-1 and PD-L1 expression were similar, and high TMB did not correlate with PD-1 (P=0.50) or PD-L1 (P=0.52) expression.Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.
2012-11-29 | Genomic analysis and selected molecular pathways in rare cancers
It is widely accepted that many cancers arise as a result of an acquired genomic instability and the subsequent evolution of tumor cells with variable patterns of selected and background aberrations. The presence and behaviors of distinct neoplastic cell populations within a patient's tumor may underlie multiple clinical phenotypes in cancers. A goal of many current cancer genome studies is the identification of recurring selected driver events that can be advanced for the development of personalized therapies. Unfortunately, in the majority of rare tumors, this type of analysis can be particularly challenging. Large series of specimens for analysis are simply not available, allowing recurring patterns to remain hidden. In this paper, we highlight the use of DNA content-based flow sorting to identify and isolate DNA-diploid and DNA-aneuploid populations from tumor biopsies as a strategy to comprehensively study the genomic composition and behaviors of individual cancers in a series of rare solid tumors: intrahepatic cholangiocarcinoma, anal carcinoma, adrenal leiomyosarcoma, and pancreatic neuroendocrine tumors. We propose that the identification of highly selected genomic events in distinct tumor populations within each tumor can identify candidate driver events that can facilitate the development of novel, personalized treatment strategies for patients with cancer.
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Drug Discovery Landscape
4 orphan drug designations for Squamous cell carcinoma of the anal canal.
4 orphan drug designations for Squamous cell carcinoma of the anal canal.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
imiquimod | small molecules | FDA | 2025-12-09 | — | Delnaggar Biotech Group |
5-fluorouracil | small molecules | FDA | 2025-12-09 | — | Delnaggar Biotech Group |
Cisplatin | small molecules | FDA | 2016-09-06 | — | Privo Technologies |
ADXS11-001 | proteins | FDA | 2013-08-12 | — | Advaxis, Inc. |
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