Experts say the combining intralesional therapies with immunotherapy is a strategy that has potential to expand into medical practices outside of the oncology realm.
Pairing intralesional therapies with immunotherapy agents has the potential to expand their use to nononcologists, especially if new formulations of the agents prove beneficial. Their expanded use could result in more patients gaining access. However, the skill set required by the nononcology professional would require signficant revision and overhaul.
“I used to inject IL-2 as well as Bacillus CalmetteGuérin vaccine,” Jeffrey Weber, MD, PhD, told Targeted Therapies in Oncology (TTO) in an interview. “We’ve also injected interferon,” he continued. “With those agents, delivering drug to a localized tumor could be carried out by a nononcologist as long as they were familiar with it, felt comfortable with it, and felt comfortable managing the adverse effects.”
Weber pointed out that some dermatologists deliver imiquimod, a topical immune response modifier, to patients with melanoma in situ. “But that’s their bread and butter and that’s for local therapy,” Weber said.
Historically, early immunotherapies such as interleukin-2 (IL-2) and interferon-α were delivered through subcutaneous injection. Interferon-α, in particular, was prescribed by dermatologists and their patients were trained to give themselves the daily injection.
In the United States, dermatologists don’t usually administer systemic therapy for cancer. Their education does not involve inpatient-type oncologic therapy, and their training does not extend to the administration of infusions of immunotherapy or chemotherapy in general.
“Systemic therapy is really the bailiwick of the medical oncologist, a surgeon, urologist, or an ear, nose, and throat specialist if, for example, the tumor affects the head and neck,” said Weber, who is deputy director at the Laura and Isaac Perlmutter Comprehensive Cancer Center and professor of medicine at the New York University Grossman School of Medicine in New York.
Not all immunotherapies, though, have to be delivered through infusion, and which could open the door for nononcologists to prescribe. Cemiplimab-rwlc (Libtayo) originally received its FDA approval as an infusion treatment for patients with metastatic cutaneous squamous cell carcinoma (CSCC) or patients with locally advanced CSCC who are not candidates for curative surgery or curative radiation.1,2
In April 2019, however, a trial evaluating an intralesional formulation of the agent in patients with recurrent CSCC prior to surgical resection was launched (NCT03889912). The phase 1 study is expected to be completed in August 2020, and its primary end points are safety and tolerability using this mode of delivery in 36 patients with the disease. Secondary end points include objective response rate, pathologic complete response rate, and major pathologic response rate in CSCC index lesions in patients with recurrent CSCC.
Patients receive intralesional injections of cemiplimab every week for 12 weeks in a 3+3 dose-escalation design with cohort expansion. To be included in the study, patients must have a history of recurrent resectable CSCC, measurable disease in the index lesion, and have an ECOG performance status score of 0 or 1. Exclusion criteria include ongoing or recent evidence of significant autoimmune disease that required prior treatment with systemic immunosuppressive treatments and prior treatment with a PD-1 or PD-L1 inhibitor.
For approved drugs, a direct injection alone, in the absence of subsequent or simultaneous immunotherapy with checkpoint inhibitors, would not be optimal, Weber said. The additional benefit of systemic immunotherapy could increase the impact of intralesional treatment to overcome resistance to the immunotherapy.
Clinical trial data combining intralesional therapy and PD-1 inhibitor therapy may further support Weber’s claim and open the door for delivery of intralesional therapies in the community setting. The ongoing phase 1b/3 MASTERKEY-265/KEYNOTE-034 trial (NCT02263508) is examining the combination of therapies that target complementary and nonredundant cancer immunity pathways that could result in synergistically improved antitumor responses.3
In previously reported results of the phase 3 OPTiM trial (NCT00769704), the intralesional oncolytic immunotherapy talimogene laherparepvec (Imlygic) significantly improved the durable response rate compared with subcutaneous granulocyte–macrophage colony-stimulating factor.4 The investigators reported that the objective response rate was higher in the talimogene laherparepvec arm as compared with the control arm, and the greatest efficacy was demonstrated in patients with earlier-stage (IIIB, IIIC, or IVM1a) melanoma.
MASTERKEY-265 is evaluating talimogene laherparepvec in combination with pembrolizumab (Keytruda) in patients with unresectable stage IIIB to IV melanoma.3 The primary end point is incidence of dose-limiting toxicities. Secondary end points include immune-related response criteria, duration of response, and progression-free survival.
Patients participating in the trial had to be treatment naive, have injectable lesions, and have no clinically active evidence of brain metastasis.
In the trial, 21 patients received up to 4 mL of talimogene laherparepvec in subcutaneous/nodal lesions, with the first dose at 105 plaque-forming units/mL, followed 3 weeks later with a dose of 108 plaque-forming units/mL every 2 weeks. Pembrolizumab at 200 mg was administered at the third dose of talimogene laherparepvec. Treatment continued until disease progression or intolerance to therapy. The response rate reported in the phase 1b portion of the trial was 66.7% in patients with unconfirmed tumor assessment (95% CI, 43.0%-85.4%) and 57.1% in patients with confirmed tumor assessment (95% CI, 34.0%-78.2%). In patients with unconfirmed tumor assessment, 6 (28.6%) had a complete response, 8 (38.1%) had a partial response, 1 (4.8%) had stable disease, and 6 (28.6%) had progressive disease. For patients with confirmed tumor response, 5 (23.8%) had a complete response, 7 (33.3%) had a partial response, 3 (14.3%) had stable disease, and 6 (28.6%) had progressive disease.
Treatment-related adverse effects (AEs) occurred in all patients. Overall, 33% of patients reported grade 3/4 AEs with no reports of grade 5 events. The most common AEs reported were fatigue (62%), pyrexia (52%), and chills (48%).
“There’s probably not a huge penetration of [talimogene laherparepvec] as monotherapy into the oncology market, but if the MASTERKEY-265 trial is positive for progression-free survival and overall survival, I think a lot of physicians would be enthused about local injection and an anti–PD-1 agent,” Weber said. “The results could be practice changing.” This would be 1 of the first trials to show that the activity of PD-1 blockade could be augmented without adding significant toxicity.
Although talimogene laherparepvec is injected directly into tumors in the skin and lymph nodes, it is manufactured using a form of the herpes virus.5 Depending on the community clinic’s policies about safe handling procedures, administration may require a separate room for giving talimogene laherparepvec with stringent preparation and cleaning requirements. This level of regulation may not be feasible in a community setting and lends itself to an academic setting.
“There are some medical oncologists who are willing to inject into cutaneous or subcutaneous lesions,” Mario Sznol, MD, professor of medicine (medical oncology) and co-director of Cancer Immunology at Yale Cancer Center in New Haven, Connecticut, told TTO. “But I think most medical oncologists are busy enough in clinics.”
Preparation time, training, and setting up a separate room for administration can be challenging and even physically unfeasible given a medical practice’s priorities. “If medical oncologists [in the community setting] decide to administer, most will limit injections to those near the surface that they can easily palpate and feel,” said Sznol.
Vinod E. Nambudiri, MD, MBA, and colleagues recently published a study in the Journal of the American Academy of Dermatology discussing the use of talimogene laherparepvec in the dermatology setting.6 The appeal of its use among dermatologists and dermatologic surgeons is its implementation as first-line therapy in patients with injectable and unresectable stage IIIB to IVM1a melanoma.7
Further, National Comprehensive Cancer Network Clinical Practice Guidelines note that patients with 1 or more cutaneous, subcutaneous, nodal, or aggregation of lesions greater than 10 mm in diameter can be treated with talimogene laherparepvec because it is useful in recurrent locoregional disease unamenable to surgery, but not yet requiring systemic therapy.8
The authors concluded that with a “standardized clinical approach and training, dermatologists can pave the way in using T-VEC [talimogene laherparepvec] and future oncolytic virus therapies in appropriate clinical scenarios.”
In some intralesional studies, toll-like receptor agonists require tumoral injections, which are delivered by interventional radiologists who use ultrasound to guide delivery. “It would be unusual for a medical oncologist to do their own ultrasound and then do their own injections,” said Weber, especially when a referral to the interventional radiology department only requires completing a form.
At most academic institutions, there is a cooperative interaction between surgeons and medical oncologists or medical oncologists and interventional radiologists to coordinate both the administration of the intralesional or intratumoral therapy together with systemic therapy, Sznol said.
Whereas most discussions involving intralesional therapies focus on patients with melanoma, patients with hepatocellular carcinoma (HCC) are also treated by interventional radiologists and usually come before an academic institution’s multidisciplinary tumor board, said Steven C. Rose, MD, an interventional radiologist and professor of radiology at the University of California (UC) San Diego.
The board can include hepatologists, medical oncologists, interventional and diagnostic radiologists, transplant and oncologic surgeons, and radiation oncologists. Depending on the disease setting, interventional radiologists have numerous treatment options to consider.
“For limited disease that is located in a good location and that constitutes 1 to 2 tumors of up to 3 millimeters in diameter, we would probably use a thermal agent, such as microwave ablation,” Rose told TTO. “In advanced disease, we might opt for a chemoembolization or transarterial bead embolization,” he continued.
Interestingly, Rose said that in HCC, it’s rare to have the patient referred from a medical oncologist, at least at UC San Diego Health. “The vast majority of patients are referred through the hepatology department for underlying liver disease. Cancer is usually subsequently discovered and then at that point, the case comes to the multidisciplinary board,” he said.
Because of the complexity of treating HCC, Rose recommends that these patients should be presented to the multidisciplinary tumor board. “It’s important to have input from many disciplines because every patient is different in terms of underlying liver disease. We need to know how compromised the liver is, in terms of function, size, number, and distribution of lesions,” Rose said. “The appropriate place for making those types of therapeutic decisions would be the multidisciplinary tumor board.
For treating physicians, nurse practitioners, advanced practice nurses, physician assistants, and pharmacists, the Society for Immunotherapy for Cancer offers a certificate program in cancer immunotherapy, said Sznol, who is the current president of the organization.9
The purpose of the certificate program is to provide an identifiable designation for health care providers who can safely and effectively participate in administration of immunotherapies and manage patients treated with these approaches.
“The courses are open to those with advanced degrees who are not practicing clinicians, but they will not be eligible for certification,” Sznol said.
Although early forms of immunotherapy were administered subcutaneously, and in the case of interferon-α, were self-administered by patients, today’s versions are much more complex with toxicities that require special management and knowledge. Their use in combination with intralesional therapies could pave the way for greater use of the combination in the community setting.
“The administration of immunotherapies is evolving and community oncologists are actively using them,” said Sznol. “Intralesional therapies, if they are effective, could make their way into community practices.”
1. FDA approves first treatment for advanced form of the second most common skin cancer. News release. CDER Office of Communications. September 28, 2018. Accessed May 17, 2020. https://bit.ly/3bIzVhM
2. Libtayo (cemiplimab-rwlc). Prescribing information. Regeron Pharmaceuticals, Inc. and Sanofi-Aventis US LLC; Approval September 2018. Accessed May 18, 2020. https://bit.ly/2Ymdudt
3. Long GV, Dummer R, Ribas A, et al. Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec and pembrolizumab for unresectable stage IIIb-Iv melanoma. J Clin Oncol. 2016;34(suppl 15):9568. doi: 10.1200/JCO.2016.34.15_ suppl.9568
4. Andtbacka RHI, Collichio F, Harrington, KJ et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte- macrophage colony-stimulating factor in unresectable stage III–IV melanoma. J Immunotherapy Cancer. 2019;7(1):145. doi:10.1186/s40425-019-0623-z
5. Imlygic. Prescribing information; BioVex, Inc. Approved 2015. Accessed May 18, 2020. https://bit.ly/2zcLRem
6. Haitz K, Khosravi H, Lin JY, Menge T, Nambudiri VE. Review of talimogene laherparepvec: a first-in-class oncolytic viral treatment of advanced melanoma J Am Acad Dermatol. [Published online ahead of print, January 28, 2020.] 2020;S01909622(20)30123-7. doi:10.1016/j.jaad.2020.01.039
7. Rehman H, Silk AW, Kane MP, Kaufman HL. Into the clinic: talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer. 2016;4:53.
8. National Comprehensive Cancer Network guidelines. Clinical Practice Guidelines in Oncology. Melanoma, version 3.2020. Accessed May 18, 2020. https://bit.ly/3dYgpzi 9. Society for Immunotherapy of Cancer. Certificate in cancer immunotherapy. Accessed May 18, 2020. https://bit.ly/2zNz6XS.