Experts Explore Landscape Advancements for Cancer Immunotherapy Month

The modern science of immunotherapy continues to expand, and it has rapidly become a primary choice for managing multiple disease types. As numerous approvals across cancer settings and emerging approaches are explored in clinical research, new findings presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting in June continue to encourage investigators.

“The evolution of immunotherapy in cancer is a story that’s more than a century old,” Sandip P. Patel, MD, a medical oncologist and associate professor of medicine at the Moores Cancer Center at UC San Diego Health in California, said in an interview with Targeted Therapies in Oncology.

William B. Coley, MD, a surgeon at Memorial Sloan Kettering Cancer Center in New York, New York, observed that in the past patients were getting skin infections after sarcoma surgery, some of which were very severe.¹ These were “a clot in remission, not only for the resected lesion, but elsewhere as well. This led to Coley’s [toxins], which was a concoction of likely multiple cytokines used for decades as a treatment. [It’s likely that its] purity couldn’t be refined, and so ultimately it fell out of favor,” Patel said.

Eventually, IL-2 was tested with some success in patients with metastatic melanoma or clear cell renal cell carcinoma, but in the past, solid tumors were less likely to respond to immunotherapy than hematologic cancers. IL-2 was used at a high dose with durable remissions for certain patients, although it had high toxicities such as sepsis.

“The patients were receiving multiple doses in the intensive care unit. It was a very intricate and potentially an often toxic intervention that only worked in a subset of patients,” Patel explained.

Even though immunotherapies were being used in hematologic cancers, they weren’t being investigated for solid tumors until James Allison, PhD, published his observation of the CTLA-4 immune checkpoint blockade and Tasuku Honjo, MD, PhD, discovered PD-1 checkpoint pathways, for which they were jointly awarded the Nobel Prize in Physiology or Medicine in 2018.²

“Even with the first-in-human trials, we did see some activity,” Julie Brahmer, MD, a professor of oncology at Johns Hopkins’ The Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, said in an interview with Targeted Therapies in Oncology.“That was very exciting to see. We saw our first hints in solid tumors outside of melanoma or kidney cancer in some early trials as well, [which] led to expansion and testing in other malignancies. In 2014 and 2015, when some of the first PD-1 antibodies were approved for use for non–small cell lung cancer [NSCLC], that really opened the door to expansion.”

Over the past decade, these immune checkpoint inhibitors for PD-L1, PD-1, and CTLA-4 have found a place in managing multiple hematologic cancers and solid tumors. “It has really been a transformational therapy,” Patel said.

Currently, there are FDA-approved checkpoint inhibitors for most solid tumors, filling an unmet need where chemotherapy was the standard of care for decades, according to Brahmer. For hematologic malignancies, checkpoint blockades and chimeric antigen receptor (CAR) T-cell therapy are being investigated, and many are already approved. Patients with leukemia, melanoma, lymphoma, and other cancers have indications for immunotherapy.

“It’s truly an amazing change to see over a relatively short period of time,” Brahmer said. “Basically, over the past decade, this has significantly changed for our patients. I think this gives patients hope, and it’s very attractive to patients to use their own immune system to fight cancer, their cancer.”

One of the most important aspects of newer trials is the use of immunotherapy in early-stage disease, either as neoadjuvant or adjuvant treatment.

At the 2021 ASCO meeting, presentations covered several disease types with results for adjuvant and neoadjuvant immunotherapy. One of the main populations with new data is patients with NSCLC.

The neoadjuvant dual checkpoint blockade of nivolumab (Opdivo) plus ipilimumab (Yervoy) versus nivolumab plus chemotherapy versus chemotherapy alone was investigated in the CheckMate 816 trial (NCT02998528), which “is of particular interest in thoracic oncology,” Patel said.

The outcomes from the nivolumab plus chemotherapy arm versus the chemotherapy-alone arm from this phase 3 trial showed that nivolumab and chemotherapy did not affect the feasibility, extent or completeness, or timing of surgery compared with chemotherapy.³ Patients given the combination experienced increased depth of pathological response and had significantly improved pathologic complete response (pCR). The investigators concluded that this regimen is a potential option for patients with stage IB to IIIA disease in the neoadjuvant setting.

“I think the neoadjuvant therapy in multiple tumor types will help move the field [to] where we can do a scientific deep dive in these tumors [and explore] microenvironment data about the genomics of the cancer. That’s where we think it’ll give us a better insight in where to move forward, even in the metastatic disease,” Brahmer said.

Additionally, in the adjuvant setting for NSCLC, the primary results of the IMpower010 study (NCT02486718) were presented at this meeting.⁴ Participants with resected stage IB to IIIA disease received atezolizumab (Tecentriq) versus best supportive care after adjuvant chemotherapy. The trial met its primary end point of disease-free survival (DFS) benefit with adjuvant atezolizumab in all randomized patients (median DFS, 42.3 vs 35.3 months; HR, 0.79; 95% CI, 0.64-0.96). This benefit included those with PD-L1 tumor cells of 1% or more, with the median DFS not reached compared with 35.3 months with best supportive care (HR, 0.66; 95% CI, 0.50-0.88).

“There [have also] been studies in bladder cancer in the adjuvant space with anti–PD-L1 directed therapies,” Patel said. “The fundamental goal of these therapies is to stimulate your own immune system to fight the cancer. This may be well suited for the curative intent setting, and I think we’re seeing more publications and presentations utilize these therapies in earlier-stage disease.”

In terms of hematologic cancers, data on melanoma were presented at 2021 ASCO. There were multiple presentations on nivolumab plus relatlimab (BMS-986016), an anti–LAG-3 antibody. The first presentation looked at this combination in a single-arm study as neoadjuvant therapy for stage III or oligometastatic stage IV melanoma (NCT02519322).⁵ Nivolumab and relatlimab demonstrated a high pCR rate of 59% and near pCR of 7%, for a major pathologic response of 66%.

The other melanoma data involving relatlimab in combination with nivolumab were from the phase 3 RELATIVITY-047 study (NCT03470922).⁶ Patients with previously untreated advanced melanoma were randomized to the combination versus nivolumab monotherapy. The median progression-free survival (PFS) by blinded independent review was 10.1 months compared with 4.6 months, respectively (HR, 0.75; 95% CI, 0.6-0.9; P=.0055). Nivolumab plus relatlimab had a 12-month PFS rate of 47.7% versus 36.0% with nivolumab alone.

“In thoracic oncology, TIGIT [T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains] is probably the hottest area of immune checkpoint blockade,” Patel said.

Multiple trial designs for anti-TIGIT monoclonal antibodies were presented at ASCO: AdvanTIG-202, a phase 2 trial of ociperlimab plus tislelizumab versus tislelizumab alone in previously treated metastatic or recurrent cervical cancer (NCT04693234); AdvanTIG-203, a randomized phase 2 trial of ociperlimab and tislelizumab compared with tislelizumab plus placebo in patients with advanced or recurrent esophageal squamous cell carcinoma and PD-L1 expression (NCT04732494); and AdvanTIG-302, a phase 3 study looking at tislelizumab in combination with ociperlimab versus pembrolizumab (Keytruda) in PD-L1 positive previously untreated, locally advanced, unresectable or metastatic NSCLC (NCT04746924).

The phase 1 AdvanTIG-105 study (NCT04047862) was the only trial of ociperlimab plus tislelizumab with data reported.⁷ It was a dose escalation of the combination in patients with advanced solid tumors. All doses of ociperlimab plus tislelizumab were well tolerated, and the recommended phase 2 dose was 900 mg of ociperlimab and 200 mg of tislelizumab every 3 weeks.

“Some of the newer data of combinations of immunotherapy, such as TIGIT with PD-1 or PD-L1 antibody, are things that are on our radar. As the data mature in different tumor types, I think that will be exciting,” Brahmer said.

Even though immunotherapy has made large strides recently, it is not without challenges. The more severe toxicities associated with it, such as hypothyroidism, rash, and fatigue, need to be discussed with patients beforehand.

“Understanding the rare immune-related adverse events, how to diagnose, mitigate them, and treat with immunosuppression, I think is key in helping patients on the cancer journey,” Patel said. “Especially now that there’s a potential of longer-term remissions for many of these patients.”

Brahmer also feels it’s crucial to increase education, alert patients and their caregivers to these potential problems, and manage toxicities beyond using steroids or prednisone. If the patient experiences dose-limiting or treatment-stopping toxicities, their immune system needs to be under control before they can continue with their treatment plan.

Another issue with immunotherapy is what to do when patients become resistant. “We all have patients who don’t respond at all to immunotherapy,” Brahmer said. “Trying to figure out the nuances of resistance is so important now. I think that’s the barrier. We had all this success, and we continue to have success pushing the envelope. But now it’s trying to figure out ways around resistance. It’s so complicated, and it’s so different for each patient.”

By monitoring the patient’s immune responses and figuring out how to provide patients with precision oncology that is individualized for each patient, it may be feasible to fight resistance. Clinical trials will be able to shed light on how to fight this resistance.

“One thing to highlight, particularly for patients as well as providers, is that it’s so important to be part of clinical trials like that because…we’re seeing benefit for that particular patient. But we’re also able to get so much information that we can use to modify therapy in the future,” Brahmer concluded.

_References:

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_{4. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500}

_{5. Amaria RN, Postow MA, Tetzlaff MT, et al. Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma. J Clin Oncol. 2021;39(suppl 15):9502. doi:10.1200/JCO.2021.39.15_suppl.9502}

_{6. Lipson EJ, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503}

_{7. Frentzas S, Meniawy T, Kao SC, et al. AdvanTIG-105: phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors. J Clin Oncol. 2021;39(suppl 15):2583. doi:10.1200/JCO.2021.39.15_suppl.2583}