Shilpa Gupta, MD, and Jason R. Brown, MD, PhD, discuss a recently published paper by Grivas et al. (2019) on the use of checkpoint inhibitors for maintenance therapy to prolong the benefits of frontline therapy while minimizing toxicity in solid tumors.
Considering the limited clinical benefit and cumulative toxicities experienced by patients who are administered prolonged chemotherapy,1 maintenance therapy has emerged in clinical practice to increase and sustain chemotherapy benefits.
A recent Between the Lines program hosted by CancerNetwork®, Shilpa Gupta, MD; and Jason R. Brown, MD, PhD, explored a recently published manuscript on the use of checkpoint inhibitors for maintenance therapy to prolong treatment benefit for patients with solid tumors.2
“Chemotherapy often doesn’t have long-lasting response. On the other hand, immune checkpoint inhibition [ICI] only works for a minority of patients in a number of cancers—for example, urothelial cancer,” explained Brown, a genitourinary medical oncologist at University Hospitals Cleveland Medical Center in Ohio. “If there’s a way [in which] we can enhance the response of ICI and lengthen the duration of response, that could be an amazing thing for our patients, ultimately.”
“Every tumor type is so different, and what we need to understand is, biologically, what the mechanisms are for response or resistance,” noted Gupta, director of genitourinary medical oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at Cleveland Clinic in Ohio.
Both experts detailed the utility of ICI in the maintenance therapy options for patients with solid tumors: continuous maintenance therapy and switch maintenance therapy.
In continuous maintenance therapy, combinations of chemotherapy and ICI are used for a fixed duration. After initial therapy, “treatment de-intensifies and patients continue ICI, receiving maintenance until progression or unacceptable toxicity,” Brown said. This therapeutic strategy has been effective in treating patients with lung cancers, but less so in patients with bladder cancers, he added
Phase 3 trials focusing on frontline treatment of non–small cell lung cancer (NSCLC) included KEYNOTE-189 (NCT02578680), examining pembrolizumab (Keytruda) or placebo plus pemetrexed and platinum; IMpower130 (NCT02367781), investigating carboplatin plus nab-paclitaxel (Abraxane) with or without atezolizumab (Tecentriq) for nonsquamous histology; and KEYNOTE-407 (NCT02775435), looking at pembrolizumab or placebo plus chemotherapy among patients with squamous histology.
“It’s interesting how frontline chemotherapy and immunotherapy combinations did so well in lung cancer, and the studies in bladder cancer [exploring continuous maintenance strategies vs] chemotherapy alone were negative,” Gupta stated.
Gupta then described a switch maintenance therapy strategy, which consists of frontline chemotherapy treatment for a fixed duration followed by immunotherapy if patients do not progress.
An example of success with this strategy in urothelial cancer is the phase 3 JAVELIN Bladder 100 trial (NCT02603432), in which patients with locally advanced or metastatic disease were treated with avelumab (Bavencio) after frontline chemotherapy.3 The trial met its primary end point of overall survival (OS) improvement (HR, 0.69; 95% CI, 0.56-0.86; P = .001), which led to the agent’s approval by the FDA in June 2020 as maintenance therapy for locally advanced or metastatic urothelial cancer that has not progressed on frontline platinum-based chemotherapy.4
Regarding different outcomes among maintenance strategies in bladder cancer, Gupta offered a potential explanation for why consolidation therapy is otherwise disappointing for patient survival compared with switch maintenance. “This approach is promising,” he said. “In urothelial cancer, the paradox of why the chemotherapy and immunotherapy [continuous therapy] didn’t work but chemotherapy followed by [switch] maintenance immunotherapy worked so well could be that we just need that chemotherapy lead-in to get the full benefit of immunotherapy.”
Despite these promising results, avelumab was less than successful as switch maintenance in treating patients on the JAVELIN Gastric 100 (NCT02625610) and JAVELIN Ovarian 100 trials (NCT02718417). Switch maintenance did not show a benefit for patients in either study.
However, Brown noted that success with switch maintenance was seen in the phase 3 PACIFIC trial (NCT02125461), in which patients with stage III NSCLC were treated with durvalumab (Imfinzi) after chemoradiation. With switch maintenance, significant improvement was seen in both progression-free survival (PFS; 17.2 vs 5.6 months; HR, 0.51) and OS (not reached vs 28.7 months; HR, 0.68; P = .0025) after more than 2 years of follow-up.5
Brown and Gupta turned their attention to key points to consider as maintenance therapy strategies continue to develop. Duration of treatment will be important, said Gupta, as finite vs lifelong treatment can have a profound effect on patients.
“Because ICI [agents] have such durable responses, the question is what will be the right [duration of treatment]? Six months, 1 year, 2 years?” asked Brown. “Keep in mind that the longer patients are treated, the more they’re exposed to this agent and [its] potential toxicities, including financial toxicity.”
They noted the rationale for using maintenance therapy as described by the authors of the paper. “There’s a good biological basis [for maintenance therapy], as there’s a synergy between chemotherapy and immune checkpoint inhibitors, whether it’s exposing neoantigens to make immune checkpoint inhibition more effective, recruiting lymphocytes, or even depleting some immunosuppressive types of T-reg[ulatory] cells,” Brown said.
Looking ahead, ongoing phase 3 data to support the effective use of maintenance therapy are necessary, although both Gupta and Brown emphasized the importance of seeing OS benefit in addition to the other end points investigated.
“PFS [benefit from] any therapy is useful, but if it is not translating into an OS benefit, then it makes you wonder what the advantage of using the treatment is, if we have further effective subsequent therapies available for patients,”
“OS will be the gold standard for these trials,” Brown agreed, “but it would be interesting to look into some of these other secondary end points, especially in cancers that may have long-term OS [data to see] what a useful surrogate could potentially be.”
As for next steps, Brown wants to see well-designed clinical trials that can help figure out how to integrate maintenance ICI into mainstream treatment. He also suggested that providers need a better understanding of patients’ previous treatments and the biology of their tumors because of the variation in outcomes with first-line ICI among disease types.
“Once we come to a point where patients achieve an initial good response or stable disease, and we can maintain it with intense approaches for a finite duration of time, that’s the next step to add to other possibilities,” Gupta concluded.