Jordyn Sava is an assistant editor for Targeted Oncology. 

Jordyn Sava

In June 2022, the FDA granted 3 approvals, including the FoundationOne companion diagnostic (CDx) to identify patients with 

 fusion–positive non–small cell lung cancer (NSCLC) and 

 fusion–positive cancers, dabrafenib (Tafinlar) plus trametinib (Mekinist) for adult and pediatric patients with unresectable or metastatic solid tumors, and lisocabtagene maraleucel (liso-cel; Breyanzi) for patients with large B-cell lymphoma (LBCL).

Along with multiple approvals, the FDA granted 2 fast track designations, 3 approvals, 3 new drug applications, 6 orphan drug designations, 1 supplemental biologics license application, and 1 breakthrough therapy designation across various disease types.

The FDA withdrew its approval for umbralisib (Ukoniq) for the treatment of marginal zone and follicular lymphoma due to safety concerns and data which suggested that the oral inhibitor of PI3K-δ and CK1-ε may be associated with an increased risk of death in patients. Additionally, the phase 1/2 NUV-422-02 trial examining NUV-422 in solid tumors was halted after some patients treated with NUV0422 developed uveitis, a form of inflammation in the eye.

Here is a look back at all of the FDA happenings from June 2022.

FDA Withdraws Approvals for Umbralisib in Marginal Zone and Follicular Lymphoma

On June 2, 2022, the FDA withdrew its approval for umbralisib, which had previously been approved for marginal zone lymphoma and follicular lymphoma.

FDA Grants Fast Track Status to PDS0101 Plus Pembrolizumab for Recurrent/Metastatic HPV16+ HNSCC

Fast track designation was granted by the FDA to the combination of PDS0101 and pembrolizumab (Keytruda), an investigational regimen for the treatment of patients with recurrent or metastatic HPV16-positive head and neck squamous cell carcinoma, also on June 2, 2022.

Omidubicel Developer Seeks FDA Approval to Treat Blood Cancers in Need of Transplantation

A rolling submission of a biologics license application was submitted to the FDA on June 3, 2022, seeking approval of omidubicel for the treatment of patients with blood cancers in need of an allogeneic hematopoietic stem cell transplant.

FDA Approves FoundationOne CDx for ROS1 Fusion–Positive NSCLC and NTRK Fusions

On June 10, 2022, the FDA granted approval to the FoundationOne CDx which will be used to identify patients with ROS1 fusion–positive NSCLC or NTRK fusion–positive cancers who may benefit from entrectinib (Rozlytrek).

FDA Accepts sBLA for Pembrolizumab in Stage IB, II, or III NSCLC

The FDA accepted a new supplemental biologics license application for pembrolizumab used to treat patients with stage IB (≥4 cm), II, or III NSCLC following complete surgical resection, on June 13, 2022.

NDA for Momelotinib Submitted to the FDA for Myelofibrosis

A new drug application has been submitted to the FDA on June 17, 2022, for the ACVR1, ALK2, JAK1 and JAK2 inhibitor, momelotinib, which is in development for the treatment of patients with myelofibrosis.

FDA Grants ODD to Paxalisib for Rare Pediatric Brain Cancer

On June 20, 2022, the FDA granted an orphan drug designation to paxalisib (GDC-0084), for the treatment of patients with atypical rhabdoid or teratoid tumors (AT/RT) in rare and aggressive childhood brain cancer.

FDA Grants Orphan Drug Designation to QXL138AM for Pancreatic Cancers

Also on June 20, 2022, the FDA granted an orphan drug designation to QXL138AM, a first in class masked immunocytokine, for the treatment of patients with pancreatic cancer.

FDA Grants Fast Track Status to Dianhydrogalactitol for Newly-Diagnosed Glioblastoma

The FDA also granted a fast track designation to dianhydrogalactitol (VAL-083) on June 20, 2022, for the treatment of patients with newly-diagnosed unmethylated glioblastoma.

FDA Clears IND Application for Novel HSF1 Inhibitor in Patients With Advanced Cancers

The FDA provided clearance to an investigational new drug application for NXP800 to be assessed as a possible treatment for patients with various advanced cancers on June 21, 2022.

FDA Grants Orphan Drug Designation to PT217 for Small Cell Lung Cancer

Also on June 21, 2022, the FDA granted an orphan drug designation to the first-in-class bispecific antibody, PT217, as a potential treatment option for patients with small cell lung cancer.

FDA Approves Dabrafenib/Trametinib Combo for 

V600E–Mutated Unresectable, Metastatic Solid Tumors

On June 23, 2022, the FDA granted accelerated approval to dabrafenib plus trametinib for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors who harbor a 

 V600E mutation, have progressed after previous treatment, and who have no satisfactory alternative treatment options.

FDA Grants Orphan Drug Designation to MB-106 for Waldenstrom Macroglobulinemia Treatment

The FDA granted orphan drug designation to MB-106, for the treatment of patients with Waldenstrom macroglobulinemia, on June 23, 2022.

FDA Grants Orphan Drug Designation to VBI-1901 for Patients Treatment of Glioblastoma

VBI-1901, a bivalent gB/pp65 immunotherapeutic vaccine candidate, was also granted orphan drug designation by the FDA on June 23, 2022, for the treatment of patients with glioblastoma.

FDA Approval Sought for Elacestrant in ER+/HER2- Advanced or Metastatic Breast Cancer

A new drug application was submitted to the FDA seeking approval of elacestrant for the treatment of patients with ER-positive/HER2-negative advanced or metastatic breast cancer on June 24, 2022.

FDA Approves Liso-Cel for Second-Line Treatment of R/R LBCL

On June 25, 2022, the FDA granted approval of the CD19-directed chimeric antigen receptor (CAR) T cell therapy, lisocabtagene maraleucel for the treatment of adult patients with LBCL, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

FDA Halts Phase 1/2 Trial Evaluating NUV-422 in Solid Tumors

A partial clinical hold was placed by the FDA on the phase 1/2 NUV-422-02 trial examining NUV-422 in solid tumors, including high grade glioma, hormone receptor–positive advanced breast cancer, and metastatic castration-resistant prostate cancer on June 28, 2022.

FDA Grants Breakthrough Therapy Designation to Talquetamab for R/R Myeloma

On June 29, 2022, the FDA granted breakthrough therapy designation to talquetamab for the treatment of adult patients with relapsed or refractory multiple myeloma, who have previously received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

FDA Grants Orphan Drug Designation to PT886 for Pancreatic Cancer

The FDA granted orphan drug designation on June 30, 2022 to PT886, for the treatment of patients with pancreatic cancer.

FDA Warns About Possible Increased Risk of Death and Side Effects With Duvelisib

On June 30, 2022, the FDA warned that treatment with duvelisib (Copiktra) may lead to increased risk of death and serious side effects vs other medicines in patients with leukemia and lymphoma.

Articles

A look back at all of the FDA happenings of June 2022.

A Look Back at FDA News from June 2022

The FDA warns that treatment with duvelisib (Copiktra) may lead to increased risk of death vs other medicines in patients with leukemia and lymphoma, according to results from a clinical trial of duvelisib.

Duvelisib was also found to be associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood.

The FDA recommends that patients should talk to their health care providers about the risks vs benefits duvelisib while health care professionals should consider these risks and benefits compared to other treatments. They should also advise patients of the possible increased risk of death and higher risk of serious adverse events while taking this drug.

duvelisib was approved by the FDA in 2018

 for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or relapsed/refractory follicular lymphoma. Both indications were patients who previously received at least 2 therapies.

The approval was based on findings from the phase 3 DUO trial (NCT02004522) and the phase 2 DYNAMO study (NCT01882803).

In DUO, duvelisib was shown to reduce the risk of disease progression or death by 60% vs ofatumumab (Arzerra) in patients with relapsed/refractory CLL/SLL who had received at least 2 prior lines of therapy. The median progression-free survival was 16.4 months with duvelisib compared to 9.1 months with ofatumumab (HR, 0.40). In the DYNAMO study, duvelisib demonstrated an overall response rate (ORR) of 42% in patients with follicular lymphoma.

The phase III DUO study randomized 319 patients with CLL/SLL in a 1:1 ratio to duvelisib at 25 mg twice daily until disease progression or unacceptable toxicity, or ofatumumab at 300 mg on day 1, followed by 7 weekly infusions and 4 monthly infusions of 2000 mg.

The FDA based its approval on a subset of these patients with CLL/SLL who had received ≥2 prior lines of therapy. The subset included 95 patients randomized to duvelisib and 101 patients who received ofatumumab. This median patient age across this subset was 69 years (range, 40-90), 88% had an ECOG performance status of 0 or 1, and 59% were male. At baseline, 22% of patients had a detected 17p deletion and 52% had 1 or more tumors ≥5 cm. Over half (54%) of this group had received ≥3 prior treatment lines, with the remaining 46% having received 2.

The median duration of treatment exposure for the duvelisib arm was 13 months (range, 0.2-37). Patients were exposed to ofatumumab for a median duration of 5 months (range, <0.1 to 6). The ORR was 78% with duvelisib versus 39% with ofatumumab.

FDA warns about possible increased risk of death and serious side effects with cancer drug Copiktra (duvelisib). News release. FDA. June 30, 2022. Accessed July 1, 2022. https://bit.ly/3y8ZJkp

Duvelisib shows possibility of increased risk of death and serious side effects vs other medicines in patients with leukemia and lymphoma.


The FDA has granted orphan drug designation to PT886 for the treatment of patients with pancreatic cancer, according to Phanes Therapeutics, Inc.

Earlier this month, PT886 received an investigational new drug (IND) application by the FDA.

orphan drug designation was granted by the FDA to another one of the company's products, PT217, 

for the treatment of patients with small cell lung cancer, and an IND clearance for PT199.

"PT886 has the potential to be a transformative treatment option for pancreatic cancer patients whose current standard of care is severely limited," said Ming Wang, PhD, MBA, founder and chief executive officer of Phanes Therapeutics, in a press release. "This orphan drug designation comes in the same month with our recent IND clearance for PT886, which we are rapidly progressing into the clinic. These important milestones the company has achieved in Q2 this year follow the March IND clearance for PT199, an anti-CD73 monoclonal antibody for the treatment of multiple solid tumors."

PT886 is a first-in-class, bispecific antibody which works to target claudin 18.2 (CLDN18.2) and cluster of differentiation 47 (CD47). The drug is being developed for use in patients with pancreatic, gastric, and gastroesophageal cancers.

The goal of the bispecific antibody is to block the CD47-SIRPα interaction, stimulate phagocytosis of tumor cells by macrophages, and deliver robust effects mediated by the functional Fc of the bispecific antibody.

Findings presented at the 2022 American Association for Cancer Research meeting showed PT886 to have high affinity monovalent binding to cell surface CLDN18.2 and low affinity monovalent binding to cell surface CD47.

 By doing so, PT886 can preferentially bind to tumor cells which overexpress CLDN18.2 and CD47, and reduce its binding to normal cells exclusively express CD47.

However, PT886 exhibits higher activity to tumor cells expressing CLDN18.2 and close to no activity toward normal cells that do not express CLDN18.2. This was shown in a phagocytosis assay as PT886 stimulates stronger phagocytosis in the presence of CLDN18.2 binding in vitro.

Along with targeting CLDN18.2 and CD47, PT886 has a fully functional Fc to directly recruit the tumor cell killing activities of NK cells and macrophages. The anti-tumor activity of PT886 was potent and demonstrated in vivo in a pancreatic cancer xenograft model. Here, treatment with PT886 resulted in a complete tumor clearance at doses as low as 1 mg/kg.

In NHP studies, PT886 also demonstrated a good safety profile. These data support the phase 1 clinical trial of the bispecific antibody planned for 2022.

Phanes therapeutics' PT886 granted orphan drug designation for the treatment of pancreatic cancer by the FDA. News release. Phanes Therapeutics. June 30, 2022. Accessed July 1, 2022. 

Phanes Therapeutics announces FDA IND clearance for PT886, an anti-claudin18.2/anti-CD47 bispecific antibody being developed for patients with gastric, gastroesophageal junction, and pancreatic cancers. News release. Phanes Therapeutics, Inc. June 15, 2022. Accessed July 1, 2022. 

Li J, Jia H, Ramsey E, et al. PT886, an anti-claudin18.2/anti-CD47 bispecific antibody constructed with the PACbody࣪ and SPECpair࣪ technology platforms, exhibits robust anti-tumor activity in a pancreatic cancer xenograft model. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 4260.

PT886 was granted orphan drug designation by the FDA for the treatment of patients with pancreatic cancer.

Expanded data from the phase 1b C-800 study (NCT03860272) of botensilimab (AGEN1181) plus balstilimab (AGEN2034) in patients with microsatellite stable (MSS) colorectal cancer (CRC) demonstrate the combination to offer strong durability and superior efficacy compared with previously reported data, according to Agenus.

The combination elicited an objective response rate (ORR) of 24% (95% CI, 14%-39%) among 42 evaluable patients at a median follow-up of 5.8 months (range, 1.6-24.4), including a 24% partial response rate. Additionally, 49% of patients achieved stable disease with the regimen and 27% experienced disease progression.

At the time these findings were shared by Anthony El-Khoueiry, MD, at the 2022 ESMO World Congress on Gastrointestinal Cancers as part of a late-breaking oral presentation, the median duration of response (DOR) had not yet been reached with the doublet. However, the disease control rate (DCR) reported was 73% (95% CI, 58%-84%).

“These data reinforce the strong therapeutic potential of botensilimab, when used in combination with balstilimab, in cold tumors such as MSS CRC,” stated Steven O’Day, MD, chief medical officer at Agenus, in the press release. “Thus far, botensilimab has demonstrated activity in 9 cold and treatment-resistant cancers, and we plan to initiate a robust, global phase 2 program, including in MSS CRC, later this year.”

The open-label, multicenter, phase 1, looked to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of a novel fragment crystallizable (Fc)-engineered immunoglobulin G1 anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) human monoclonal antibody, botensilimab, in combination with an anti-programmed cell death protein-1 (PD-1) antibody, balstilimab.

 Maximum tolerated dose was assessed in patients with advanced solid tumors, and the study aimed to find the recommended phase 2 dose of the doublet.

Eligibility in the first-in-human trial was open to adult patients with a histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumor refractory to standard treatment. Patients must have had a measurable disease on imaging based on RECIST 1.1, a life expectancy of 3 months or greater, an ECOG performance status of 0 or 1, adequate organ, bone marrow reserve function, hematological, liver, and renal function, and no history of prior or concomitant malignancy that requires other active treatment. Inclusion in the CRC cohort was open to patients with metastatic disease and MSS status per local assessment.

The study enrolled a total of 41 evaluable patients with metastatic MSS CRC who received botensilimab at 1 mg/kg (n = 7) or 2 mg/kg every 6 weeks in combination with balstilimab at 3 mg/kg (n = 34) every 2 weeks.

Patients were heavily pre-treated, with a median of 4 prior lines of therapy (range 2-10), with 12% of patients receiving 2 prior lines, 32% who received 3 prior lines, 22% who received 4 prior lines and 35% who received 5 or more prior lines. Among those 41 patients, 34% had received prior immunotherapy. The median age of patients enrolled in the MSS CRC cohort was 57 years (range, 36-82). A total of 59% were female, 59% had an ECOG performance status of 1, and 34% received prior immunotherapy. Further, 51% of patients had tumors harboring a 

mutation, and 5% of patients had tumors which harbored 

Findings revealed that 80% of objective responses were ongoing at the time of the data cut-off and 30% objective responses exceeded 1 year.

In the patient sub-populations, an objective response was seen in 5 patients with RAS mutations for a 24% overall response rate and 81% disease control rate in this population. Other trials examining PD-1 combinations have reported only rare responses in this population (≤1% response rate). Additionally, in patients with metastases historically resistant to immunotherapy, including patients with malignant pleural effusions, soft tissue, peritoneal, retroperitoneal, and bone metastases, responses were observed.

Additionally, data showed that those without active liver metastases (n = 24) experienced positive responses with the combination with the combination achieving an ORR of 42% (95% CI, 25%-61%), and a DCR of 96% (95% CI, 80%-99%).

In regard to safety, any-grade treatment-related adverse effects (TRAEs) were experienced by 76% of patients, all of which were grade 1 or 2 in (51%) or grade 3 (24%). Botensilimab was shown to be well tolerated with no grade 4 or 5 TRAES demonstrated. The rates of gastrointestinal and skin toxicities ended up being comparable to those reported with first-generation CTLA-4 inhibitors.

Of the gastrointestinal toxicities reported with the combination, the most common consisted of diarrhea or colitis (grade 1/2, 29%; grade 3, 10%), nausea (grade 1/2, 17%), and vomiting (grade 1/2, 10%). Constitutional toxicities seen in patients included fatigue (grade 1/2, 20%; grade 3, 2%), decreased appetite (grade 1/2, 22%), chills (grade 1/2, 17%), and pyrexia (grade 1/2, 12%; grade 3, 2%). Additionally, hepatic toxicities included increased alanine aminotransferase (grade 1/2, 12%) and increased aspartate aminotransferase (grade 1/2, 7%; grade 3, 2%).

Musculoskeletal effects observed in patients included arthralgia (grade 1/2, 10%; grade 3, 2%) and myalgia (grade 1/2, 12%), while skin toxicities included pruritus (grade 1/2, 10%) and rash (grade 1/2, 10%). No hypophysitis was reported in patients given the combination, and it was noted that pneumonitis as a result of the combination was rare.

In 46% of patients, investigator-assessed irAEs of any grade occurred, and 17% experienced grade 3 irAEs. A total of 10% of patients ended up discontinuing treatment with botensilimab due to a TRAE, while 10% discontinued both agents.

Overall, the doublet demonstrated deep objective responses and showed evidence of durability in this patient population. The combination was well tolerated and had a differentiated safety profile along with showing enriched responses in patients who did not have active liver metastases.

A global phase 2 dose-randomized trial examining patients with MSS CRC is expected to be launched within the year.

“Colorectal cancer is the second leading cause of cancer-related death worldwide, with roughly 95% classified as microsatellite stable and historically unresponsive to immunotherapy. Treatment-resistant MSS CRC patients lack effective options, with standard of care offering only a 1-2% response rate and a median expected survival ranging from 6 to 7 months,” said Anthony El-Khoueiry, MD, phase 1 program director at the USC Norris Comprehensive Cancer Center, Keck Medicine of USC, in the press release. “The combination of robust response rate, durability, and tolerability demonstrated by botensilimab and balstilimab supports further development of the combination in MSS CRC, as well as more broadly, in other cold and treatment-resistant tumors.”

Agenus shows unprecedented activity for botensilimab/balstilimab combination in microsatellite stable colorectal cancer at ESMO World GI Congress. News release. Agenus. June 29, 2022. Accessed June 30, 2022. https://bit.ly/3OOvt56

Bullock AJ, Grossman JE, Fakih MG, et al. Botensilimab, a novel innate/adaptive immune activator, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancers; June 29-July 2, 2022; Barcelona, Spain. Abstract LBA-09. https://bit.ly/3NM4rdT

Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Accessed June 30, 2022. https://clinicaltrials.gov/ct2/show/NCT03860272

Botensilimab and balstilimab use in patients with microsatellite stable colorectal cancer showed  strong durability and superior efficacy, according to expanded data from the phase 1b C-800 study 

Botensilimab Plus Balstilimab Shows Remarkable Activity in MSS CRC

 Evaluation of RMC-6236 in Subjects With Advanced Solid Tumors Harboring Specific Mutations in KRAS

 
Contact: inquiries@RevMed.com or (650) 779-2300

The first patient has been dosed in the phase 1/1b monotherapy clinical trial (NCT05379985) of RMC-6236, for the treatment of patients with advanced solid tumors driven by a variety of 

 mutations, according to an announcemnet by Revolution Medicines, Inc.

RMC-6236 is an oral, potent, tri-complex RAS(ON) inhibitor which works to uniquely target a variety of RAS(ON) variants responsible for many cancers.

The study’s first patient to be given RMC-6236 has pancreatic cancer with a 

“Beginning clinical evaluation of the first compound from our broad portfolio of RAS(ON) Inhibitors marks a significant milestone in our efforts to serve unmet needs of patients with 

-addicted cancers,” said Mark A. Goldsmith, MD, PhD, chief executive officer and chairman of Revolution Medicines, in the press release. “To our knowledge, RMC-6236 is the first oral, direct RAS inhibitor to be deployed against a tumor harboring the 

 variant, and it ushers in a wave of groundbreaking RAS(ON) Inhibitors we expect to advance.”

The multicenter, open-label, dose-escalation, dose-expansion phase 1/1b trial is examining RMC-6236 in patients with advanced solid tumors who harbor selected KRASG12 mutations, including 

Adult patients aged 18 years and older with histologically confirmed advanced solid tumor with 

 p.G12V mutations identified through DNA sequencing are eligible for enrollment in the trial. Patients must have received prior standard therapy appropriate for their tumor type and stage, an ECOG performance status of 0-1, and adequate organ function.

Those with any advanced solid tumor type with specific 

 mutations can be enrolled into phase 1, the dose-exploration portion of the trial and administered RMC-6236 orally. The dose-expansion portion may continue with 1 or more groups of patients who have a single histotype/genotype receiving oral RMC-6236.

Main objectives of the study are to evaluate safety and tolerability of RMC-6236 in this patient population and to inform the recommended phase 2 dose and schedule. The primary end points include incidence of severity of treatment-emergent adverse events (AEs) and serious AEs, as well as number of patients with dose-limiting toxicity.

Additionally, secondary end points of the study consist of overall response rate, duration of response, disease control rate, time to response, progression-free survival, maximum observed blood concentration, time to reach maximum observed blood concentration, area under blood concentration time curve, and elimination half-life of RMC-6236.

“RMC-6236 is a compelling drug candidate with the potential to demonstrate broad utility across many 

 cancer variants, particularly those harboring 

 mutations. We are enthusiastic about its potential both to display first-in-class single agent activity as an inhibitor of mutant 

 and to be deployed as a RAS companion inhibitor in combination with mutant-selective RAS(ON) Inhibitors we have in development,” added Steve Kelsey, MD, president, research and development at Revolution Medicines, in the press release.

Revolution medicines advances first RAS(ON) inhibitor into clinic, dosing first patient in phase 1/1b trial of RMC-6236. News release. Revolution Medicines, Inc. June 28, 2022. Accessed June 29, 2022. https://yhoo.it/3yrwCu4

Evaluation of RMC-6236 in subjects with advanced solid tumors harboring specific mutations in KRAS. ClinicalTrials.gov. Accessed June 29, 2022. https://www.clinicaltrials.gov/ct2/show/NCT05379985?term=RMC-6236&draw=2&rank=1

A phase 1/1b monotherapy clinical trial of RMC-6236 for the treatment of patients with advanced solid tumors driven by a variety of RAS mutations has dosed its first patient.

First Patient Dosed in Study of RMC-6236 in KRAS-Driven Advanced Solid Tumors

The treatment of patients with early disease anal carcinoma has not changed much from the 1980s due to the fact that chemotherapy and radiation has continued to show high cure rates in this patient population.

Between 1990 and 2010, both incidence and mortality of the rare malignancy have increased, underscoring the need for more therapies. According to Charles J. Schneider, MD, FACP, who spoke about the subject in an interview with Targeted Oncology™, the incidence of occurrence has increased by about 2.7% per year with an increasing mortality in the space at roughly 3.1% year after year.

Schneider also explained that a preventative strategy for patients with anal carcinoma is the human papillomavirus (HPV) vaccination. As more children aged 12 years and older are vaccinated, a potential for decreased rates of this cancer and mortality rate occur.

Additionally, immunotherapy and targeted therapy has come front and center for treating patients with anal carcinoma with the advancements of nivolumab (Opdivo) and pembrolizumab (Keytruda). These 2 PD-1 inhibitors have become the standard of care for patients with advanced disease who are resistant to chemotherapy in advanced disease

During the interview, Schneider, a clinical professor of Medicine at the Abramson Cancer Center at Perelman Center for Advanced Medicine, provided an overview of the treatment landscape for anal carcinoma, and ongoing research.

What did you discuss at the NCCN 2022 Annual Conference regarding new approaches for the treatment of patients with anal cell carcinoma?

I was a co-presenter with Cathy Eng ,MD, FACP, FASCO, and I gave the first portion of the presentation, which was split into 2 parts.

The first part was focused on the tumor and immune environment, which is pretty unique in anal cancer. It is mostly driven by the HPV and facilitated to some extent by the human immunodeficiency virus [HIV] in patients who are HIV positive. A lot of that first part was focused on how these viruses facilitated in causing cancer.

Then the second half was a very comprehensive review, historically, of all the important trials that have led us to standard of care, both in localized disease and advanced disease. After that, Eng gave an update on current clinical trials.

What does the current landscape look like for this patient population?

The incidence and mortality is rather low, but despite the cancer being a rare malignancy, both incidence and mortality has been increasing between 1990 up until about the year 2010 with incidents increasing by about 2.7% per year and mortality by about 3.1% per year.

Hopefully, the HPV vaccination in children ages 12 and older will eventually lead to a plateau of that rising incidence and mortality and hopefully a decrease, but that's going to take a while since the HPV effect takes years on the canal.

In what ways has the management and care of these patients changed over the past decade?

Our treatment for early disease, and this sounds kind of horrible, but it really has not changed much at all since the 1980s. The reason is because nothing has been found to be better than the chemotherapy and radiation that we use for early-stage disease with very high cure rates. The only thing new really and local disease, I'd say two things. The first is that more patients are being treated now with an oral chemotherapy drug as a substitute for 1 of the 2 [intravenous] drugs with radiation with comparable cure rates. Then the second is that we are investigating immunotherapy as a component of treatment for localized disease as well, for advanced disease.

Immunotherapy and targeted therapy has come to the forefront. You know, especially with the PD-1 inhibitors of a drug called nivolumab (Opdivo) and a drug called pembrolizumab (Keytruda), which had become our standard of care for patients who were resistant to chemotherapy in advanced disease.

What unmet needs still need to be filled in this space?

The first thing is, although it sounds counterintuitive, patients who are not infected with HPV, [HPV-negative] and have anal cancer that's not induced by that virus have a much worse prognosis. We need to make advances in that patient population. About 80% of anal cancers are caused by high-risk HPV infection, either HPV16 or HPV18. The other 20% are not induced by HPV and those patients have a much worse prognosis. That's the first group.

Then in the second group, the incidence is much higher in African American men and that may have to do with lack of surveillance or other factors that need to be addressed. Other risk groups such as cigarette smokers, and immunosuppressed patients, especially organ transplant patients, and also women with either cervical dysplasia or cervical cancer, both of those are related to HPV. We need to do a better job in identifying those high-risk groups and using public health interventions in efforts to step that up in those populations.

Is there any ongoing research currently examining patients with anal cell carcinoma?

We have a lot of research ongoing. For instance, we just completed accruing nationally to a trial through the Eastern Cooperative Oncology Group that assigned patients after receiving potentially curative and intensive chemotherapy radiation for early disease, assigning them to either observation, which is our standard of care vs 6 months of immunotherapy using the drug nivolumab. That's an exciting trial that's been completed, and we're just waiting for results. We are hoping that adding immunotherapy to the treatment paradigm for early-stage disease will improve survival in that group even higher.

Second is localized disease. There's an ongoing trial that's looking at lowering the amount of radiation given which would reduce toxicity from radiation to the area to the pelvis, while still hopefully maintaining high cure rates. In advanced disease, there are many trials that are looking at different immunotherapy drugs, and also adding immunotherapy to chemotherapy, which would be the logical next step.

What does the future look like for the space?

I think the future is going to hinge on immunotherapy bench research and research on targeted drugs that may change the immune environment in anal cancer or specifically target anal cancer cells. I think the future looks bright in a cancer that's rare but still increasing in incidence and mortality. It is important that we make further advances.

The only thing I would say to patients and families is to please participate in trials because that's really the only avenue that we have to improve standard of care and improve survival of anal cancer and any other cancer.

In an interview with Targeted Oncology, Charles J. Schneider, MD, FACP, provided an overview of the treatment landscape for anal carcinoma, and ongoing research.
