The Expanding Reach of Immunotherapy Demands a Focus on Applications

Charu Aggarwal, MD, MPH

Both patients and providers are excited by the potential of immunotherapy as a treatment for cancer. The promise of a chemotherapy- free option that can lead to durable tumor control in patients who respond is a thrilling prospect.

“I think the premise of immunotherapy is really activating or reactivating the immune system and harnessing the power of our T cells for cancer treatment. And we know that inherently our T cells as well as our bodies are programmed to fight cancer. However, there may be inhibitory molecules that are expressed by cancer cells, which can then be inhibited by the use of these PD-1/ PD-L1 inhibitors that can potentially create the immune response again. So it’s really the premise of immune activation inherent in the immune system to fight cancer,” Charu Aggarwal, MD, MPH, explained about the rationale for immunotherapy.

Even after more than a decade, the uses of immune checkpoint inhibitors continue to expand across both solid and hematologic malignancies, further adding to the excitement over immuno-oncology.

This mechanism of action has shown potential across a multitude of cancer types. Looking specifically at immune checkpoint inhibitors, the FDA has recently approved PD-1/PD-L1 inhibitors in the treatment of urothelial, breast, renal, endometrial, esophageal, and gastric cancers. Additionally, a new chimeric antigen receptor (CAR) T-cell therapy was approved in April for the treatment of patients with large B-cell lymphoma.

As the reach of immunotherapy continues to expand, the necessity of understanding the practicalities of treatment with this class of agents gains in importance for not just oncologists but also for other practitioners and health care professionals. For example, how to handle immune-related adverse events (irAEs) seen from immunotherapy treatment in patients with cancer is an area where greater education is critically needed for professionals, especially for emergency department staff.

The upcoming 6th Annual International Congress on Immunotherapies in Cancer is specifically focused on understanding the areas of application for immunotherapy as well as managing aspects of care that come with treatment, such as immune-related toxicities.

“What I want the attendees to take out of this is practical application of how to apply chemotherapy or immunotherapy in the clinic in the context of new clinical information and new clinical trials that have been presented at recent meetings,” Aggarwal, the Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Perelman School of Medicine, University of Pennsylvania, told Targeted Therapies in Oncology™ about the meeting in an interview.

Aggarwal is a program co-chair for the congress along with Mario Sznol, MD. In addition, Aggarwal will present and lead the discussion on changes in the use of immunotherapy for the treatment of patients with lung cancers during the morning session (see AGENDA).

During the meeting, participants will have the opportunity to hear from experts in various tumor types who are well versed in the use of immunotherapy, many of whom were even involved in early clinical trials of immune checkpoint inhibitors in their respective fields.

Aggarwal, for instance, was an investigator in the phase 1 KEYNOTE-001 trial (NCT01295827) of the PD-1 inhibitor pembrolizumab (Keytruda) in the treatment of patients with advanced non–small cell lung (NSCLC). This study showed an objective response rate (ORR) of 19.4%, a median duration of response (DOR) of 12.5 months, and a median overall survival of 12.0 months. In patients with PD-L1 expression in at least 50% of their tumor cells, the ORR was 45.2%.1 This trial helped lead to the FDA approval of pembrolizumab for the treatment of patients with advanced NSCLC.

“I still have patients in long-term follow-up from that clinical trial that we started in 2012. It’s pretty incredible to be part of that experience,” she commented.

Through presentations and case discussions, these experts will attempt to answer practical questions about the use of immunotherapy based on their own experiences, such as how long to continue immunotherapy for, how to determine which patients are more likely to benefit from immunotherapy, when should immunotherapy be stopped or not in the case of toxicity, and how to manage irAEs.

Duration of Treatment

The duration of treatment for immunotherapy is one of several questions in immuno-oncology without a specific, defined answer.

A post-hoc analysis from the phase 3 KEYNOTE-006 trial (NCT01866319) of pembrolizumab or CTLA-4 inhibitor ipilimumab (Yervoy) in patients with advanced melanoma showed that 21 patients who completed the full 2 years of pembrolizumab—a typical treatment period for immunotherapy in clinical trials—achieved a complete response (CR), as compared with 23 patients who did not complete the full 2 years of treatment but did have a CR. In the patients who achieved a CR but stopped treatment before 2 years, the 24-month progression-free survival (PFS) rate was 86.4% compared with 85.4% in patients who did complete 2 years of treatment.²

Also, pooled analyses have shown that even patients who discontinued treatment with an immune checkpoint inhibitor early due to toxicity demonstrated benefit from treatment, suggesting the potential for shorter courses of treatment. In one such pooled analysis of phase 2 and 3 trials of nivolumab (Opdivo) and ipilimumab in patients with melanoma, the ORR was 58.3% in patients who discontinued treatment due to AEs in comparison with an ORR of 50.2% in patients who did not discontinue. The median overall survival was not reached in either group.³

Much of the data regarding immunotherapy cessation is reliant upon retrospective data or pooled analyses. However, prospective trials have begun opening to try to answer this question. For example, the Safe Stop trial in the Netherlands is looking at the potential of early cessation of frontline nivolumab or pembrolizumab in patients with advanced or metastatic melanoma who have achieved a confirmed CR or who have an ongoing partial response. Also, the randomized phase 3 DANTE trial in the United Kingdom is randomizing patients with unresectable stage III or IV melanoma who have received a year of nivolumab or pembrolizumab treatment to either stop treatment or to continue for another year.

Biomarkers

One significant area of research in immuno-oncology is in biomarkers to determine which patients may benefit more or less from immunotherapy. An early biomarker, PD-L1 expression, as seen in the KEYNOTE-001 trial, was subject to too much variation and thus found not to be clinically viable. As such, several accelerated approvals for immune checkpoint inhibitors based on PD-L1 positivity were recently called into question or withdrawn from the market. The indication for the PD-L1 inhibitor atezolizumab (Tecentriq) in combination with chemotherapy for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors express PD-L1, for example, was withdrawn from the US market in August (see page XX).⁴

Other biomarkers have shown promise, including tumor mutational burden (TMB), microsatellite instability high, and mismatch repair deficiency (dMMR). The PD-1 inhibitor dostarlimab (Jemperli), which was first approved for the treatment of patients with recurrent or advanced endometrial cancer with dMMR, was recently approved for the treatment of adult patients with dMMR recurrent or advanced solid tumors that have progressed on or after prior treatment.⁵ The approval was based on findings from the phase 1 GARNET trial (NCT02715284) of dostarlimab in patients with advanced solid tumors. In the study, patients with dMMR solid tumors (209/740) had an ORR of 41.6% and a CR rate of 9.1%. The median DOR was 34.7 months and 95.4% of responders maintained their response for 6 months or more.⁶

In June, the FDA granted an accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic TMB high solid tumors that have progressed after prior treatment.⁷ The approval was based on findings from the phase 2 KEYNOTE-158 trial (NCT02628067) of pembrolizumab in patients with advanced solid tumors. in the study, among 13% with TMB-high tumors (≥10 mutations/megabase), the ORR was 29% and the CR rate was 4%. The median DOR was not reached, but 50% maintained responses for at least 2 years. However, this approval was met with a bit of controversy in the field as it was based on a single-arm study.

Immune-Related Adverse Events

Several sets of guidelines have emerged in recent years to provide recommendations for the management of irAEs. For example, the Society for Immunotherapy of Cancer (SITC) recently updated their clinical practice guidelines on immune checkpoint inhibitor–related adverse events.⁸ These guidelines provide evidence- and consensus-based recommendation to assist health care professionals in the management of irAEs and decision making regarding the cessation or re-treatment of immunotherapy due to such toxicities.

The guidelines generally recommend patient education on irAEs as well as referral to a specialist in the case of grade 3 or higher toxicities or any-grade myositis, myocarditis, or neurological symptoms. Other organ-specific recommendations are also provided.

Aggarwal also noted that there is recent evidence to suggest that the development of an irAE may be associated with a better outcome.

In one analysis in patients treated with the PD-L1 inhibitor avelumab (Bavencio) in the JAVELIN trials, among 16.5% of patients who experienced an irAE, these patients had a 29% reduced risk of death compared with patients who did experience immune-related toxicity.⁹ The researchers predicted that patients who achieved a response had a higher chance of having an irAE compared with those who did not respond, but they could not predict who would or would not respond to immunotherapy.

Further research and anecdotal evidence from such experts in immuno-oncology will help to answer these and other emerging questions regarding immunotherapy applications in the future.

_REFERENCES:

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_{2. Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20(9):1239-1251. doi:10.1016/S1470- 2045(19)30388-2}

_{3. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807-3814. doi:10.1200/JCO.2017.73.2289}

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_{6. Andre T, Berton D, Curigliano G, et al. Safety and efficacy of anti– PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results from GARNET study. J Clin Oncol. 2021;39(suppl 3):9. doi:10.1200/JCO.2021.39.3_suppl.9}

_{7. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 16, 2020. Accessed September 21, 2021. https://bit.ly/39ptsJV}

_{8. Brahmer JR, Abu-Sbeih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6):e002435. doi:10.1136/jitc-2021-002435}

_{9. Kelly K, Manitz J, Patel MR, et al. Efficacy and immune-related adverse event associations in avelumab-treated patients. J Immunother Cancer. 2020;8(2):e001427. doi:10.1136/jitc-2020-001427}