Immune Checkpoint Inhibitors as Switch or Continuous Maintenance Therapy in Solid Tumors: Rationale and Current State - Episode 1
Drs. Gupta and Brown review 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.
Shilpa Gupta, MD: Hello, I’m Dr. Shilpa Gupta. I’m a GU medical oncologist at the Cleveland Clinic. It is a pleasure to join Dr. Jason Brown, a GU medical oncologist at University Hospital also based in Cleveland. They are right across from us. We are really excited to participate in this discussion for the featured article on “Immune Checkpoint Inhibitors as Switch or Continuation Maintenance Therapy in Solid Tumors,” and we’ll discuss the rationale and current state. This paper was published by Dr. Petros Grivas, et al, in 2019. I’ll let Dr. Brown take over from here. Thank you.
Jason R. Brown, MD: Thank you for that introduction, Dr. Gupta. I’m looking forward to discussing this paper with you.
To discuss the background of this paper, chemotherapy use is limited in many tumor types due to toxicity. For example, in urothelial cancer, we can only give platinum-based therapy for at most six cycles. Therefore, maintenance therapy is a strategy to prolong the benefits of frontline therapy while minimizing toxicity. There are different maintenance therapy options which we’ll get into a little bit more in this discussion of this paper. These are continuation, switch, and consolidation maintenance treatments. Finally, this paper describes the options and summarizes several clinical trials using these strategies.
There are several strategies for maintenance-based immune checkpoint inhibition for clinical trials. The first is a continuation maintenance strategy that has actually been shown to be quite effective in lung cancer. In this strategy, patients are first treated with chemotherapy combined with immune checkpoint inhibition for a fixed duration, for example in lung adenocarcinoma when patients receive carboplatin, pemetrexed, and pembrolizumab. After initial treatment for a fixed number of cycles, this treatment deintensifies and patients continue immune checkpoint inhibition, receiving maintenance until progression or unacceptable toxicity. Ultimately, upon progression, they’ll be re-treated either with the prior chemotherapy if they responded for a long enough time or potentially starting a new regimen. We’ve seen that this has worked quite well in some cancers like lung cancer. However, in bladder cancer, it has not been as effective.
Shilpa Gupta, MD: Jason, it is really interesting how the frontline chemo and immunotherapy combination did so well in lung cancer and the studies in bladder cancer comparing the combination of chemotherapy alone were negative. That brings us to the point of switch maintenance strategy. What it means is that frontline chemotherapy is offered to patients for a fixed duration as standard practice. If patients do not progress after that, then they are switched to immunotherapy, single agent, for maintenance and this is continued until progression or unacceptable toxicity.
As we have seen, the recent phase III JAVELIN Bladder 100 trial showed that maintenance with avelumab after frontline platinum-based chemotherapy in metastatic urothelial cancer patients resulted in significant overall survival benefit and was approved by the FDA [Food and Drug Administration] in June of 2020. That’s really a classic example of where we are using it in the urothelial cancer field. There’s another phase II trial led by the Hoosier Network with Dr. Galsky at the lead investigator, which also showed benefit of maintenance pembrolizumab after platinums compared to placebo. But it was a phase II trial and not a registrational trial. It’s really great to see the maintenance immunotherapy pan out in urothelial cancer. And there’s a lot of trials going on using this approach in ovarian cancer where patients who have BRD alterations are switched to maintenance with PARP [poly-ADP ribose polymerase] inhibitors as opposed to immunotherapy. There are also trials going on in lung cancer where they are switched to maintenance with chemo or immunotherapy versus standard of care or placebo.
This approach is really a very promising approach, and I want to add that in urothelial cancer, the paradox of why chemo and immunotherapy combination didn’t work but chemo followed by maintenance immunotherapy worked so well could be that we just need that chemo lead-in to get the full benefit of immunotherapy. Have you discussed the consolidation strategy?
Jason R. Brown, MD: That’s a great point, Shilpa. Maintenance immunotherapy following chemotherapy has really shown a great impact. We discussed strategies that work for metastatic cancers, but this immune checkpoint inhibition-based maintenance has also worked for some localized or locally advanced cancers which brings us to the consolidation strategy. In this strategy, patients receive first-line chemotherapy or definitive chemoradiation, for example in stage III lung cancer. They stop the initial therapy after a fixed number of cycles and switch to immune checkpoint inhibition. For example, durvalumab has shown to be positive in the PACIFIC trial in lung cancer. They receive a fixed duration of immune checkpoint inhibition consolidation, and ultimately upon progression, depending on how long it takes to progress, they can be re-treated with prior chemotherapy or start a new regimen.
In bladder cancer, we see something somewhat similar following initial treatment in the adjuvant setting. There are some patients who receive neoadjuvant chemotherapy and then ultimately get cystectomy, and if they have residual disease, there’s actually been shown to be some benefit of nivolumab. Initially, this was shown in a phase II trial and further phase III trials are pending.
Shilpa Gupta, MD: Totally agree. That’s a great point.
Jason R. Brown, MD: This table shows a number of studies of established maintenance agents. Many of these are in non-small cell lung cancer, as we mentioned earlier, which is one of the first cancers that really showed the benefit of this. In terms of switch maintenance, as well as continuation, chemotherapies have worked well in this cancer, for example pemetrexed. For switch maintenance, as Shilpa mentioned earlier, in ovarian cancer niraparib has been shown to have benefit, as have other PARP inhibitors as well, including olaparib and rucaparib.
Shilpa Gupta, MD: You know, as is highlighted here, there’s a lot of switch maintenance with checkpoint inhibitors approach being used across a variety of solid tumors like lung cancer, both non-small cell lung cancer and small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer. And urothelial cancer, the good news is that the JAVELIN Bladder 100 already resulted last year and has made avelumab maintenance the current recommended standard of care, based on level 1 evidence from the phase III trial. So that’s already in use in the real world. Certainly the approach also extends to folks who are getting definitive chemoradiation, like in the PACIFIC trial we’ve set the standard for durvalumab maintenance after stage III non-small cell lung cancer patients complete their chemo and radiation. And there’s an ongoing trial, RTOG 3505, which is looking at similar patient population testing nivolumab versus placebo. So these are really strategies to improve outcomes in these difficult-to-treat diseases.
Jason R. Brown, MD: Yeah, absolutely, Shilpa. That’s a great point that this is really shown to be effective in certain cancers. However, not to play devil’s advocate, but in some other cancers, unfortunately the results haven’t been as successful in terms of switch maintenance. For example, one of the studies mentioned on here, the JAVELIN Gastric 100, ended up ultimately being a negative study with avelumab maintenance. So a lot of it may depend on what cancer we’re treating with, as well as what treatment the patient received prior to getting switch maintenance as well.
Shilpa Gupta, MD: Yeah, that’s a great point. Every tumor type is so different, and biologically what are the mechanisms for response or resistance is really, we need to understand.
Jason R. Brown, MD: Here we present a table with a number of phase III trials of continuation maintenance with immune checkpoint inhibition. This is great that we have so many trials, especially these large trials, looking into this question. Many of these were in lung cancer, for example KEYNOTE-189 and IMpower130. But there are also some other trials here in ovarian cancer as well as the urothelial carcinoma trial, Imvigor130 which unfortunately was a negative trial showing that chemoimmunotherapy up front didn’t have as much benefit as the switch maintenance therapy that we discussed earlier in bladder cancer.
Transcript edited for clarity.