ESMO 2024: What Is the Role of Rechallenge with the Same Class of Agents in Advanced Disease?

(UroToday.com)  The 2024 ESMO annual meeting included a session on addressing uncertainties in the management of urothelial and renal cell carcinomas, featuring a presentation by Dr. Yohann Loriot discussing the role of rechallenge with the same class of agents in advanced disease. Dr. Loriot notes that this is an old question revisited with the coming of new drugs. When discussing re-treatment and re-challenge, it is important to define these scenarios. These include a fixed duration of treatment (ie. adjuvant therapy), a toxicity event, or progressive disease:

There is biological rationale for re-treatment and re-challenge. Once targeted therapy is discontinued and the patient switches to a different interval therapy or drug holiday, external pressure changes, allowing other tumoral clones to arise and proliferate. This process may result in a reversion of resistance due to the growth of sensible tumor clones, resulting in a de novo response to targeted therapy. There are several factors associated with re-treatment/re-challenge benefit:

1. The number and location of metastatic sites (ie. liver metastases)
2. Response to a prior course of therapy
3. The length of interval until re-challenge
4. The type of treatment administered during the re-challenge (ie. monotherapy versus combination therapy)

Dr. Loriot notes that the role of re-challenge has been studied mainly for immunotherapy in both urothelial and kidney cancer. Of note, this is an old question for chemotherapy in urothelial carcinoma, but this is a relevant question given that we now have newer therapies (e. FGFR inhibitors and antibody drug conjugates).

Dr. Loriot then focused on re-challenge among patients with progressive disease during treatment (with or without intervening therapy). Re-challenge is never as good as the first time, and re-challenge modalities should depend on mechanism of resistance to immune checkpoint inhibitors. But, what are these mechanisms of resistance? Jenkins et al. [1] note three potential mechanisms of resistance, including (i) formation of tumor reactive T-cells, (ii) activation of effector T-cell function, and (iii) formation of effector memory T-cells:

One of the potential strategies to overcome resistance to immune checkpoint inhibitors is to employ combination therapies. As follows is a list of potential combinations:

• Single/dual immune checkpoint inhibitor therapy
• Immune checkpoint inhibitor + immune stimulating agents
• Immune checkpoint inhibitor + metabolic inhibitors
• Immune checkpoint inhibitor + targeted therapies
• Immune checkpoint inhibitor + epigenetic modifiers
• Immune checkpoint inhibitor + chemotherapy
• Immune checkpoint inhibitor + radiation

 Immune checkpoint inhibitor combinations are a cornerstone of therapy in metastatic RCC, so the question has been asked: Could rechallenge with immune checkpoint inhibitors improve clinical outcomes in later lines of therapies? Preliminary retrospective studies suggest there may be efficacy. Data from Ravi et al. [2] notes that most patients discontinued first line immune checkpoint inhibitor secondary to disease progression, with an overall response rate in the re-challenge setting of 23%. Re-challenge did not lead to higher risk of immune side effects, and the greatest benefit was seen among patients who had previously responded to their first course of immune checkpoint inhibitor:

Moreover, preliminary results were also encouraging in a prospective phase 1/2 trial of lenvatinib + pembrolizumab in RCC [3]. Objective response rate was 62% in immune checkpoint inhibitor pretreated patients:

When assessing retreatment of RCC patients with PD1/CTL4 inhibitors after prior PD(L)1 inhibitors, complete responses are very rare and progression free survival is short. Thus, patients with symptomatic, progression disease may not be suitable candidates for dual immune checkpoint inhibitor blockade as salvage therapy:

Dr. Loriot then discussed CONTACT-03, which assessed atezolizumab + cabozantinib versus cabozantinib alone among patients with metastatic RCC that have had radiographic progression on or after prior immune checkpoint inhibitor therapy. The trial design for CONTACT-03 is as follows:

This was a negative study, with no difference in progression free survival by blinded independent central review in the intention to treat population between the two groups (HR 1.03, 95% CI 0.83-1.28):

Dr. Loriot notes that there are several unaddressed questions with regards to immune checkpoint inhibitor re-challenge:

1. Could this lack of benefit with an anti-PD-L1 agent be generalized to other immune checkpoint inhibitor re-challenge strategies? For example, PD1 inhibitor versus PD-L1 inhibitor
2. Is the immediate post-immune checkpoint inhibitor setting the most appropriate for an immune checkpoint inhibitor re-challenge? For example, immediate post immune checkpoint inhibitor versus intervening 1-2 lines of therapy versus adjuvant
3. Do prior response patterns to immune checkpoint inhibitors influence response to immune checkpoint inhibitor re-challenges? For example, complete response versus partial response versus stable disease

The second trial discussed by Dr. Loriot for re-challenge in the setting of disease progression during immune checkpoint inhibitor treatment was presented by Dr. Toni Choueiri at ESMO 2024, the TiNivo-2 trial:

Again, this was a negative trial. With a median independent radiology review-assessed progression free survival of 5.7 months for tivozanib + nivolumab and 7.4 months for tivozanib (HR 1.10, 95% CI 0.82-1.43), the study did not meet its primary endpoint:

Dr. Loriot notes that clearly re-challenge is different in RCC as opposed to the melanoma field whereby primary resistance to PD-1 inhibitors can be reversed in some patients with the combination of CTLA-4 and PD-1 inhibition. Importantly, these questions are also relevant in urothelial carcinoma, where most patients receive immune checkpoint inhibitors in the first line setting and a significant subset in the adjuvant setting. With regards to re-challenge after disease progression during immune checkpoint inhibitor treatment in urothelial carcinoma, there are retrospective studies that indicate a very low response rate of <10% and very few prospective studies are available.

For patients that receive therapy after previously having treatment held secondary to toxicity (ie. re-challenge after immune related adverse events without disease progression), there are multiple studies demonstrating a link between manageable, non-fatal immune related adverse events and improved outcomes. Immunosuppressive treatment of immune related adverse events does not necessarily reduce the antitumor efficacy of these treatments. In this setting, studies show an objective response rate on second line immune checkpoint inhibitor therapy of 14% in RCC and 21% in urothelial carcinoma. The rate of subsequent grade 3-4 immune related adverse events after re-challenge is ~30%, with ~50% receiving corticosteroids. Importantly, immune checkpoint inhibitor re-challenge after moderate to severe immune related adverse events is associated with durable response in a subset of patients.

For patients having re-treatment after therapy completion without intervening therapy, a pooled analysis of pembrolizumab re-treatment after completion of 2 years of pembrolizumab (KEYNOTE-052, KEYNOTE-361, KEYNOTE-045) showed a median progression free survival of 28 months after first line immune checkpoint inhibitor versus 9.5 months after second line immune checkpoint inhibitor:

Dr. Loriot posed the following question: Will these results be relevant for patients that relapse after immune checkpoint inhibitor treatment for early stage urothelial carcinoma or renal cell carcinoma? The following table highlights examples of phase 3 trials with immune checkpoint inhibitors in the perioperative setting in urothelial carcinoma:

Dr. Loriot then discussed re-challenge with other classes of therapies, highlighting re-treatment after a fixed duration of therapy and re-challenge after progressive disease. For these treatments, mechanisms of resistance to chemotherapy are still unclear. Retrospective studies have reported some level of efficacy of platinum re-challenge in patients previously treated with cisplatin-based chemotherapy in the peri-operative setting. Importantly, the interval between the two courses of therapies matters, but to date this has been poorly defined.

Patients eligible for a chemotherapy re-challenge, based on low level evidence and more on expert opinion, include:

• Relapse since the last cycle of chemotherapy > 12 months
• Good performance status
• Lymph node only disease

Most clinical trials in the first line metastatic setting allowed patients previously treated with perioperative chemotherapy if relapse occurs > 12 months after the last cycle of therapy.

For urothelial carcinoma, the new armamentarium includes new PD1(L)1 inhibitors, but also targeted therapies (erdafitinib) and antibody drug conjugates (enfortumab vedotin, sacituzumab govitecan, and HER2 ADCs such as trastuzumab deruxtecan). Patients who are ineligible for these therapies or who subsequently progress may still be considered for further cytotoxic chemotherapy, with some reports suggesting tumor sensitization to chemotherapy after the use of immune checkpoint inhibitors. Dr. Loriot notes that the benefit of re-challenge with an antibody drug conjugate is unclear, with several mechanisms of action, including:

• Insensitivity to the payload
• Decrease in antigen binding
• Impaired internalization
• Lysosome alteration

Nectin-4 expression seems to be dynamic, and the level of Nectin-4 expression may be associated with response in some reports. However, what is the role of reduced target expression at acquired resistance? And, should we test for antigen expression at the time of re-challenge? There is a lack of data of antibody drug conjugate re-challenge in the context of progression on antibody drug conjugate, and re-challenge with enfortumab vedotin seems feasible after antibody drug conjugate discontinuation secondary to adverse events.

Finally, the role of re-challenge with erdafitinib is unclear. In 1/3 of patients there are secondary mutations, however should we offer re-challenge after ctDNA testing to exclude secondary FGFR3 mutations? New FGFR3 inhibitors (TYR 300, LOXO 435) targeting resistant mechanisms are being investigated.

Dr. Loriot concluded his presentation discussing the role of rechallenge with the same class of agents in advanced disease with the following take-home points:

• The role of drug rechallenge is unclear regardless of the type of drug
• Re-challenge after completing immune checkpoint inhibitor might be appropriate. But is there an optimal treatment-free interval?
• Re-challenge after stopping immune checkpoint inhibitor for side effects might be appropriate. But there is a risk of toxicity recurrence and should be discussed at multidisciplinary tumor board and with the patient
• Re-challenge with immune checkpoint inhibitor after progression is not appropriate as of today (with level 1 evidence in RCC). Perhaps a biopsy should be performed to identify who may benefit and what kind of combination should be offered
• Re-challenge with other drugs should be avoided if an alternative exists (low level of evidence)

Presented by: Yohann Loriot, MD, PhD, Medical Oncology Department, Gustave Roussy, Université Paris-Saclay, Paris, France. 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024. 

References:

1. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018 Jan;118(1):9-16.
2. Ravi P, Mantia C, Su C, et al. Evaluation of the safety and efficacy of immunotherapy rechallenge in patients with renal cell carcinoma. JAMA Oncol. 2020 Oct 1;6(10);1606-1610.
3. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naïve or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): A phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958.
4. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): A multicenter, randomized, open-labl, phase 3 trial. Lancet 2023 Jul 15;402(10397):185-195.