SITC Poised to Expand Toolkit of Immunotherapy Guidelines

James L. Gulley, MD, PhD

The Society for Immunotherapy of Cancer (SITC) is developing a growing menu of guidelines with treatment algorithms for specific cancer types to help practicing oncologists navigate the appropriate use of this emerging modality.¹

So far, SITC has published consensus statements for the administration of immunotherapeutic agents for prostate cancer, head and neck squamous cell carcinoma (HNSCC), cutaneous melanoma, bladder carcinoma, non—small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and the hematologic malignancies of multiple myeloma, lymphoma, and acute leukemia.

Updates are in the works for RCC and the 3 hematologic malignancies. Additionally, SITC experts are weighing recommendations for handling adverse events (AEs) associated with immune checkpoint inhibitors and cytokine- related toxicities and for managing AEs from immune effector cell-related therapies. The guidelines discuss immune checkpoint inhibitors (ICIs) and other recently approved immunotherapies as well as immunomodulatory drugs and agents with immune effects.

The breadth of the guidelines “reflects the wide array of different cancers for immune checkpoint inhibitors and other immunotherapies that are currently approved,” said James L. Gulley, MD, PhD, vice chair of the SITC Cancer Immunotherapy Guidelines Oversight Committee, in an interview with OncologyLive.^®

“Immunotherapy has fundamentally changed the way we approach and treat patients with metastatic cancer, and that is because of the rapid, deep, and durable responses that we see,” added Gulley, who is also chief of the Genitourinary Malignancies Branch at the National Cancer Institute in Bethesda, Maryland. “Our goal in creating the guidelines was to provide expert guidance in a very new area in cancer immunotherapy, to give more certainty to the treating physician.”

The guidelines also are available as a distilled pocket guide version that “allows physicians to have the condensed knowledge of a panel of experts right at their fingertips,” said Ashish M. Kamat, MD, MBBS, chair of the SITC Cancer Immunotherapy Guidelines Oversight Committee, during an interview. “The information from the guidelines [is] a critical resource,” said Kamat, who is also the Wayne B. Duddlesten Professorship in Cancer Research, professor of urology and cancer research at The University of Texas MD Anderson Cancer Center in Houston.

Prostate Cancer

Published in in December 2016, the guidelines for prostate carcinoma address the use of sipuleucel-T (Provenge). Indicated for patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), sipuleucel-T is currently the only FDA-approved immunotherapy for mCRPC, although pembrolizumab (Keytruda) has also been approved for a subset of patients with solid tumors, including mCRPC, whose cancers are microsatellite instability-high (MSI-H) or mismatch repair deficient.

“One of the most important takeaways, for me, is to use sipuleucel-T earlier in patients, before they have symptoms, and not to use it alone in symptomatic or very aggressive disease,” Gulley said. “This recommendation is based on the consensus of the group that it takes a while for the clinical benefit of this approach to work.”

Several agents, including sipuleucel-T, are approved for the second-line treatment of prostate cancer for patients whose disease has become refractory to initial androgen-targeting therapies. Consequently, the rationale for therapy selection after recurrence of disease hinges on the clinical status of the patient and the extent, site(s), and pace of the disease.

The subcommittee members unanimously recommended that patients with prostate cancer that has become refractory to initial androgen therapy be treated with sipuleucel- T prior to radiotherapy or chemotherapy.

All panel members indicated that they do not routinely combine sipuleucel-T with other agents, but the majority (58%) indicated that they had done so in the past. The subcommittee agreed that it would be reasonable to evaluate the androgen pathway—targeted agents discussed during the consensus meeting (bicalutamide, nilutamide, enzalutamide [Xtandi], and abiraterone acetate [Zytiga]) as well as zoledronic acid and denosumab (Xgeva) in combination with sipuleucel-T.

Head and Neck Squamous Cell Carcinoma

Physicians who treat patients with HNSCC have rapidly adopted immunotherapies, sparking awareness of the need for clear guidance that addresses the nuances of handling these agents. SITC’s most recent guideline for HNSCC, published in July 2019, addresses trial findings that support the use of these drugs, appropriate patient selection, therapy sequence, response monitoring, AE management, and biomarker testing.

The FDA did not require biomarker testing for use of nivolumab (Opdivo) and pembrolizumab in patients with recurrent or metastatic (R/M) HNSCC that has progressed on or after platinum therapy. However, most patients will progress on platinum-based therapies; therefore, patient selection tools are critical to determine who will benefit from treatment with ICIs, the SITC guidelines note. PD-1 expression, tumor mutational burden, and immune gene signatures have been evaluated as biomarkers in HNSCC.

The approval of pembrolizumab for tumors that express PD-L1 with a combined positive score ≥1 included the first mandated biomarker testing for patients with R/M HNSCC tumors. Unresectable or metastatic MSI—H HNSCC tumors are relatively infrequent (1%-3%), which led a large majority of the subcommittee (88%) to not recommend routine MSI testing.

Defining when and in what settings biomarker testing is necessary was of critical importance in developing the HNSCC guidelines, said Robert L. Ferris, MD, PhD, chair of the SITC Cancer Immunotherapy Guidelines Head and Neck Cancers Subcommittee, during an interview.

Robert L. Ferris, MD, PhD

Notably, no eligibility restrictions exist for the use of the approved ICIs nivolumab and pembrolizumab for patients with R/M HNSCC. However, most subcommittee members indicated that their decision to recommend immunotherapy would be influenced by the presence of R/M disease (89%), previous platinum therapy (78%), and patient performance status (56%).

Cutaneous Melanoma

The treatment landscape for melanoma has witnessed continuous change since 2011. A series of therapeutic approvals prompted SITC to update its inaugural guideline for immunotherapy in cutaneous melanoma, which was published in 2013. A total of 11 new therapies were approved either as monotherapies or in combination with other agents between 2011 and the publication of version 2.0 of the guideline in May 2018. Meanwhile, pembrolizumab was cleared for the adjuvant treatment of patients with melanoma with involvement of lymph nodes following complete resection in February 2019, shortly after SITC’s update was published.²

Stage II

The panel acknowledged that determining risk stratification for patients with melanoma can be challenging, in part because of changes in the American Joint Committee on Cancer staging system and new data that draw on a variety of histologic and molecular assays for risk assessment. Patients with tumors >4 mm in depth, with or without ulceration, or tumors >2 to 4 mm with ulceration were identified as those with high-risk stage II disease.

To date, no data justify the use of ipilimumab (Yervoy), nivolumab, pembrolizumab, or BRAF-targeted therapy in patients with stage II melanoma, they said. There was a limited consensus for interferon-α2b (IFN- α2b) as adjuvant therapy for patients with high-risk disease (10%).

Stage III

A total of 5 immunotherapy agents were deemed potentially appropriate for use in the stage III setting: IFN-α2b, ipilimumab, pembrolizumab, nivolumab, and the oncolytic virus talimogene laherparepvec (T-VEC; Imlygic).

The panel recommended that clinicians treating patients with stage III disease also perform and review a diagnostic work-up, assess tumor staging information, complete whole body imaging and performance status assessment, and determine nodal status on the basis of physical examination and sentinel lymph node biopsy (SNB) with or without subsequent completion lymphadenectomy if the SNB is positive. The group noted that clinicians should take these 4 steps before making a treatment decision.

Stage IV

Panel members recognized several systemic treatment options for patients with unresectable stage IV melanoma, including immunotherapy with high-dose IL-2, ipilimumab, nivolumab, pembrolizumab, and T-VEC if accessible lesions are present, combination ipilimumab and nivolumab, clinical trial participation, and cytotoxic chemotherapy. For patients with BRAF-mutated tumors, the subcommittee unanimously agreed that clinicians should consider immunotherapy before targeted therapy in patients with good performance status because of the potential for durable responses with immunotherapy. However, the combination of BRAF and MEK inhibitors also can be considered for patients with the mutation.

They wrote that although “there [are] little data available to support optimal sequencing of targeted therapy and immunotherapy in this setting…two retrospective studies have suggested enhanced clinical benefit from immunotherapy administered prior to BRAF-targeted therapy in those patients who required both.”

Bladder Carcinoma

When SITC first published recommendations for bladder carcinoma, the guideline focused mainly on the intravesical instillation of bacille Calmette-Guérin (BCG), a live, attenuated strain of Mycobacterium bovis that constitutes the standard treatment approach to bladder cancer.

“When it comes to immunotherapy for cancer in general, the oldest immunotherapy has actually been around since the 1970s: It’s BCG,” said Kamat. Other systemic immunotherapy agents had yet to enter the mainstream of the bladder carcinoma armamentarium, but that has been evolving quickly. Today, 5 ICIs are approved: the PD-L1 inhibitors atezolizumab (Tecentriq), durvalumab (Imfinzi), avelumab (Bavencio), and the PD-1 inhibitors pembrolizumab and nivolumab.

Ashish M. Kamat, MD, MBBS

“The whole field rapidly changed with a plethora of studies maturing, which showed that immunotherapy agents have a role in first- and second-line therapy in more advanced disease states,” Kamat added. “Furthermore, data also emerged— and continue to emerge—to suggest that [immunotherapy] is useful in patients with earlier disease in the nonmetastatic, neoadjuvant, and even non—muscle-invasive phases.”

This, Kamat said, is proof that the guidelines are “living, breathing documents” that, like the field, are subject to continuous change.

Immunotherapy with BCG is currently the treatment of choice for urothelial carcinoma in situ because of its capacity to reduce the risk of recurrence and progression of non—muscle invasive bladder cancer after transurethral resection. Guideline panel members agreed that BCG also should be considered as a primary option for patients with non–muscle-invasive bladder cancer deemed intermediate risk (multiple and/or recurrent low-grade Ta tumors) or high risk (T1, high-grade and/or carcinoma in situ).

Overall, group members supported the use of BCG in carcinoma in situ of the bladder as their preferred treatment approach. BCG induction and maintenance for 3 years per the SWOG schedule was deemed the optimal therapy. A combination of BCG and mitomycin was recommended as the second-best option, and the least preferred treatment was a trial of mitomycin alone initially, with BCG reserved for those patients whose tumors do not respond to chemotherapy.

Most subcommittee members recommended BCG in intermediate- risk bladder cancer and unanimously discouraged its use in low-risk patients. The panel further agreed that all high- and intermediate- risk patients should receive maintenance BCG for 3 years and 1 year or more, respectively.

For ICI therapy, the guidelines note that any of the 5 approved agents may be considered for patients with locally advanced or metastatic disease after prior chemotherapy. The guidelines, which were published in 2017, also include recommendations for administering atezolizumab and pembrolizumab in the firstline setting for patients who are not eligible for cisplatin therapy; however, in 2018, the FDA limited first-line use of these agents to cisplatin- ineligible patients with positive PD-L1 expression scores or those who are not able to receive any platinum-containing therapy regardless of PD-L1 status.3

All members of the bladder carcinoma panel advocated for risk stratification as a basis for deciding therapy. Kamat highlighted the guidelines’ emphasis on risk stratification as “the most important” recommendation of the set.

“It’s about going back to the basics. Perfect risk stratification is essential because bladder cancer is such a complex disease in the sense of classification, nomenclature, grading, and staging,” Kamat said. “Getting patients to be appropriately stratified so they can get the therapy that’s [right] for their particular disease is one of the biggest challenges that we’ve faced with bladder cancer immunotherapies.”

Non—Small Cell Lung Cancer

The approval of ICIs has led immunotherapy to supplant cytotoxic chemotherapy in some settings as the standard of care for patients with advanced/metastatic NSCLC. “The adoption of immunotherapy in routine clinical practice for NSCLC has come exceptionally quickly,” panel members wrote.

SITC developed the guideline set in response to the need for uniform standards to guide the use of these agents in the oncology community, define the role of PD-L1 biomarker testing in determining patient eligibility for treatment, and measure and monitor response to ICIs. The guidelines additionally provide recommendations on contraindications to treatment with ICIs and the management of immune-related AEs.

Analysis of PD-L1 expression by an immunohistochemistry-based test should be routine for all patients with newly diagnosed advanced NSCLC, the panel members agreed. In addition to PD-L1 testing, CT of the chest, abdomen, and pelvis was the most highly recommended test (88%), followed by thyroid function tests (81%).

The panel unanimously agreed that pembrolizumab monotherapy is the preferred first-line therapy for patients with PD-L1— positive, tumor proportion score (TPS) ≥50, squamous metastatic NSCLC. Similarly, 100% of the panel supported the use of pembrolizumab with pemetrexed (Alimta) and carboplatin in patients with nonsquamous (NSq), advanced NSCLC with PD-L1 TPS <50% and no actionable mutations. For patients with NSq, metastatic NSCLC and ≥1 EGFR, ALK, or ROS1+ mutation, the committee recommended the use of targeted therapies over pembrolizumab and chemotherapy.

When writing the guideline panel wrote that they would “prospectively consider” combination pembrolizumab and chemotherapy as a first-line option for patients with advanced, squamous cell NSCLC and “supports its use in appropriate patient subgroups if and when FDA approval is official.” The FDA cleared pembrolizumab for use with carboplatin and either paclitaxel or nab-paclitaxel as a first-line option for patients with metastatic squamous NSCLC in October 2018.²

The stock of immunotherapies has grown since SITC’s publication of the guideline in July 2018. In April 2019, single-agent pembrolizumab was indicated for the firstline treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, as well as patients with metastatic NSCLC, whose tumors express PD-L1 (TPS ≥1%) with no EGFR or ALK alterations.²

In December 2018, atezolizumab was also approved in combination with bevacizumab (Avastin), paclitaxel, and carboplatin for the first-line treatment of metastatic NSq NSCLC without EGFR or ALK mutations.⁴ In August 2018, pembrolizumab plus pemetrexed and platinum received a green light as a triplet therapy for the first-line treatment of patients with metastatic, NSq NSCLC and no actionable mutations.²

References

1. SITC cancer immunotherapy guidelines. Society for Immunotherapy of Cancer website. sitcancer.org/research/cancer-immunotherapy-guidelines. Accessed December 4, 2019.
2. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-limits-use-tecentriq-and-keytruda-some-urothelial-cancer-patients. Updated July 5, 2018. Accessed December 4, 2019. 3. Keytruda [prescribing information]. Kenilworth, NJ: Merck; 2019.
3. Keytruda [prescribing information]. Kenilworth, NJ: Merck; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s040lbl.pdf.
4. Tecentriq [prescribing information]. San Francisco, CA: Genentech; 2018. www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf.