Society for Immunotherapy of Cancer

New Guidelines Outline Management of Immunotherapy Side Effects

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Emerging patterns suggest checkpoint inhibitors may cause problems in several organ systems

The Society for Immunotherapy of Cancer (SITC) has released new consensus recommendations on the recognition and clinical management of immune-related side effects from cancer immunotherapy.

The authors, members of the SITC Toxicity Management Working Group, noted that immunotherapy has become a pillar in the treatment of cancer, with clinical trials showing that checkpoint inhibitors can provide long-term benefit with generally manageable side effects. However, emerging patterns suggest that checkpoint inhibitors may cause unwanted side effects in a number of organ systems.

“We have, in a comprehensive fashion, organized thoughts on the proper screening, diagnosis, management, and handling of treatment interruptions or cessations with immune checkpoint inhibitors,” Igor Puzanov, MD, director of the Early Phase Clinical Trials Program and co-leader of the Cancer Center Support Grant Experimental Therapeutics Program at Roswell Park Cancer Institute in Buffalo, NY, told MedPage Today. “The recommendations provide an online reference point for practicing oncologists to find quick reference if they have a patient with a particular toxicity.”

New immunotherapy agents are being approved at a rapid pace, and patients have new treatment options, but “many of these agents have side effects we haven’t seen before. We’re seeing effects on the skin, lungs, gastrointestinal and endocrine systems, joints, heart and other organs, and some of these are only just beginning to be described,” he continued. “Clinicians need guidance on how to recognize early signs, how to treat adverse effects, and when to refer to a disease specialist.”

Puzanov is one of the four co-leaders of the multidisciplinary Working Group, which SITC convened to meet for a full-day workshop to develop the document to standardize the management of immune-related adverse events. Medical oncologists, surgeons, disease specialists, scientists, pharmacists, nurses, and others with relevant expertise met to develop guidance on managing adverse effects from immune checkpoint inhibitors.

The recommendations state that when caught early, most side effects from checkpoint inhibitors are mild to moderate and can be treated with drugs that temporarily suppress the immune system. “We focused on ensuring that clinicians recognize and know how to manage these emerging side effects so patients can continue to take advantage of the benefits of immunotherapy,” said Puzanov.

Serious and occasionally life-threatening immune-related adverse events have been reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by checkpoint inhibitor. Immunotherapy-related immune-related adverse events typically have a delayed onset and prolonged duration compared with adverse events from chemotherapy. Effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies, he said.

The recommendations follow an earlier effort by the European Society for Medical Oncology, which issued the first comprehensive Clinical Practice Guidelines for the management of toxicities from immunotherapy in May 2017. The SITC effort, however, is unique, Puzanov said, because it included representatives from pharmaceutical companies, who provided information derived from large databases of toxicities of immunotherapy.

“From the information in the databases, we also learned what we don’t have. We may ask about symptoms, but not recognize that fatigue or dyspnea may hide cardiac toxicity. A patient may actually have cardiomyopathy and be coded as [having] fatigue and dyspnea.” Puzanov noted that reports of fatal cardiac side effects from immune checkpoint inhibitors began appearing in the literature around 2016.

“Immune checkpoint inhibitors are coming to the community where practicing oncologists work. [Checkpoint inhibitors] have a different set of side effects than chemotherapy or targeted therapy. Physicians who treat cancer patients — hospitalists, emergency room physicians, and specialists — need to be aware of these side effects.”

For example, he noted, if a patient on chemotherapy develops shortness of breath and fever, the recommended treatment is antibiotics and supportive care. “If a patient on immunotherapy develops these symptoms, they could be due to cytokine storm, and the patient could develop pneumonitis. The patient may still develop pneumonia, but it may be pneumonitis. This can be confusing.”

Some side effects, like pneumonitis, come on early after immunotherapy, while others, like cardiac events, may come later. “Once we know the problem, we can properly treat the patient.”

Puzanov said he hopes clinicians will refer to the online consensus recommendations in real-time when they see patients: “If a patient presents with fever from immunotherapy, the clinician can look at the recommendations and decide whether this is an infection from the drug itself, and then start the patient on corticosteroids.”

The new recommendations are a “living document, and the plan is to update them accordingly as immune checkpoint inhibitors evolve and new drugs and combinations become available.

The next step for SITC is to issue a comprehensive handbook that provides more information on individual drugs and side effects with more references, he said, adding that SITC leaders will also be involved in the development of ASCO and NCCN guidelines.

“Immune checkpoint inhibitors are a whole new therapeutic ballgame,” said Puzanov. “They have changed the way we practice and treat cancer patients, but have also brought new challenges with novel toxicities. We need to conduct prospective trials with these agents to dig into the etiology of side effects. That will help us recognize which patients have the potential to develop toxicities at baseline when we give them immune checkpoint inhibitors.”

Survival Bump in Bladder Cancer with Keytruda

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But no outcome advantage for Tecentriq in metastatic urothelial cancer

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  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Patients with recurrent urothelial cancer lived longer when they received pembrolizumab (Keytruda) instead of chemotherapy as second-line treatment, according to long-term follow of a randomized trial.

After a median follow-up of 28 months, patients treated with pembrolizumab had a median survival of 10.3 months versus 7.3 months for those who received chemotherapy. Both 12- and 24-month survival was significantly better in the group treated with the immunotherapeutic drug, according to Joaquim Bellmunt, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

 PD-L1 expression status did not influence response to treatment with pembrolizumab or the survival benefit, they reported here at the Genitourinary Cancers Symposium.

“Pembrolizumab is the first immunotherapy to demonstrate superior survival over chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based therapy,” Bellmunt said. “This study provides level 1 evidence that supports the use of pembrolizumab as a standard of care for this patient population.”

Data from the trial, known as KEYNOTE 045, provided the basis for approval of pembrolizumab for advanced urothelial carcinoma, irrespective of PD-L1 status, in the U.S., Europe, and Japan, he added. The 2-year follow-up data remained consistent with the data that supported the approval.

A different PD-1/PD-L1 inhibitor failed to demonstrate an advantage over chemotherapy for PD-L1-positive locally advanced/metastatic urothelial cancer that progressed or relapsed after initial platinum-based chemotherapy. As previously reported, patients treated with atezolizumab (Tecentriq) had a median overall survival (OS) of 11.1 months versus 10.6 months for investigator’s choice of chemotherapy. An intention-to-treat (ITT) analysis of all treated patients, irrespective of PD-L1 status, yielded a similar result, reported Thomas Powles, MD, of Barts Cancer Institute in London.

The pembrolizumab results should increase confidence in second-line use of the drug, said invited discussant Robert Jones, MD, PhD, of the University of Glasgow in Scotland.

“This helps our patients make an informed decision about whether or not to accept this treatment,” said Jones. “The results remain in keeping with the possibility of a long immunotherapy [survival] tail. None of these data support a role for second-line cytotoxics after failure of platinum in preference to a checkpoint inhibitor.”

The pembrolizumab data affirmed findings initially reported at the 2016 Society for Immunotherapy of Cancer, followed by publication in the New England Journal of Medicine. At that point, after a median follow-up of 14 months, the median OS was 10.3 versus 7.4 months for the pembrolizumab and chemotherapy arms, respectively.

KEYNOTE 045 involved 542 patients whose disease had progressed or relapsed after first-line platinum-based chemotherapy. Almost half the patients had two or more high-risk characteristics.

The patients were randomized to pembrolizumab or the investigators’ choice of three different chemotherapy options: paclitaxel, docetaxel, or vinflunine. The trial had coprimary endpoints of OS and progression-free survival (PFS), as assessed in the ITT population and according to PD-L1 status (using ≥10% PD-L1 expression in tumor cells, lymphocytes, and macrophages to define positivity).

The initial results in favor of pembrolizumab represented a 27% reduction in the survival hazard (P=0.0022). The updated data reflected a 30% reduction in the survival hazard (95% CI 0.57-0.85, P=0.00017). The 12-month survival was 44.4% with pembrolizumab and 29.8% with chemotherapy, and the 24-month survival was 27.0% versus 14.3% with pembrolizumab and chemotherapy, respectively.

“By 24 months, 60% of patients in the chemotherapy arm had received an immunotherapeutic agent, including those who received pembrolizumab at crossover,” said Bellmunt.

Subgroup analysis demonstrated a consistent survival advantage for patients treated with pembrolizumab.

Analysis by PD-L1 status showed a median OS of 8.0 months with pembrolizumab and 4.9 months with chemotherapy in the PD-L1-positive patients (n=124) and 10.8 versus 7.7 months in the PD-L1-negative group.

Median PFS did not differ significantly between treatment groups after 14 or 28 months of follow-up (2.1 vs 3.3 months) although the proportion of patients who remained progression free at 12 months (18.4% vs 9.5%) and 24 months (12.5% vs 2.5%) favored pembrolizumab.

Objective response rate was twice as high with the PD-1 inhibitor than with chemotherapy (21.1% vs 11.0%).

Pembrolizumab was associated with a more favorable adverse-event profile, as patients treated with chemotherapy had more fatigue, diarrhea, asthenia, anemia, constipation peripheral sensory neuropathy, peripheral neuropathy, decreased neutrophil count, neutropenia, and alopecia. Immune-related adverse events occurred more often with pembrolizumab: hypothyroidism, pneumonitis, hyperthyroidism, and colitis.

Investigators in the atezolizumab study, known as IMvigor211, performed extensive exploratory analyses to gain insight into the negative result. They found a correlation between DNA damage response (DDR) mutations tumor mutational burden (TMB). Additional analysis showed no association between DDR and efficacy. However, they identified a significant benefit of atezolizumab in the small subgroup of patients (about 100 of 931) who had high TMB and tested positive for PD-L1 expression (IC 2/3): median OS of 17.8 versus 10.6 months, representing a 50% reduction in the hazard ratio (95% CI 0.29-0.86).

In his review of the two trials, Jones concluded that neither provided compelling evidence of a biomarker to predict response to PD-1/PD-L1 inhibition.