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Flare Phenomenon or Pseudoprogression

During ICI Therapy in RCC: Potential Value of

Treatment Beyond First Progression

 

Saby George, MD

Associate Professor

Department of Medicine

Roswell Park Cancer Institute

Buffalo, New York

 

 

 

 

 

 

A consistent theme emerging from recent studies across tumor types is that a fraction of patients will potentially benefit from treatment beyond progression in terms of tumor shrinkage as well as overall survival advantage suggested by the hazard ratios from Kaplan Maier analysis. New guidelines for patient assessment after first progression are evolving as the concept of pseudoprogression underscores the pitfalls in relying on RECIST criteria alone. Careful consideration by treating physicians after informed consent to continue beyond progression is the appropriate strategy and is supported by mounting evidence in the literature. This review highlights the translational impact of pivotal studies such as CheckMate 025 and other evidence from pooled and subgroup analyses.

 

A dramatic shift in the treatment paradigm for renal cell carcinoma (RCC), characterized by the introduction of newer agents such as immune checkpoint inhibitors, has ushered in new thinking on the management of the disease. These newer agents such as nivolumab for the treatment of advanced RCC in patients who have received prior antiangiogenic therapy provide a unique mechanism of action as opposed to many of the traditional targeted therapies for mRCC.1 Although the era of targeted therapy resulted in significant improvements in objective response rate and progression-free survival (PFS), the limitations of such strategies soon became apparent because the majority of patients eventually experience treatment resistance and disease progression.2,3 As a result, the focus turned toward the need for novel treatment options and within the last 5 years, immune checkpoint inhibitors  have shown durable responses and have improved OS for a broad range of patients.

The wider use of immune checkpoint inhibitors has dramatically reshaped the debate—not only on how such therapies can more effectively be applied but on the need to address many questions and uncertainties, including the criteria used to measure response and the duration of therapy needed to optimize outcomes. As part of this review, we will focus on these issues, including the extent to which standard criteria, such as the Response Evaluation Criteria in Solid Tumors (RECIST) still need to be adhered to or reexamined in the light of emerging data suggesting whether RECIST-defined first progression after immunotherapy is a valid endpoint for determining whether such treatment needs to be discontinued.  And if RECIST-defined first progression is accepted as a compelling argument for discontinuing immune checkpoint therapy, would many patients have benefited from treatment beyond progression (TBP)? Although there is compelling evidence in recent literature clearly favoring TBP, there is still controversy over the  practice that is becoming the standard of care. A review of the literature, including recommendations from the FDA on this question, will help put these issues in context.

In its mechanism of action, nivolumab, for example, offers a useful guide to understanding the rationale for using checkpoint inhibitors. This agent is a fully human IgG4 programmed cell death 1 PD-1) immune checkpoint inhibitor antibody that selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. This interaction is the mechanism that normally leads to immune tolerance.4 We have abundant data supporting the use of nivolumab vs antiangiogenic therapy. In the CheckMate 025 trial, evaluating 821 patients with mRCC who had received earlier treatment with antiangiogenic regimens, the use of nivolumab produced a significant survival advantage aver everolimus (25 vs 19.6 months) and this checkpoint inhibitor also had a more favorable side effect profile.5 Treatment with immunomodulatory agents such as nivolumab has been controversial because of the issue of “tumor flare” (Figure 1). This phenomenon, also referred to as pseudo-progression, refers to what appears to be an increase in tumor burden or the appearance of new lesions that may be observed prior to a clinical response in patients receiving immunotherapy.6 The cause of tumor flare is thought to be caused by transient immune cell infiltration into the tumor or continued tumor growth that can occur while the immune system is priming for an antitumor response, according to Wolchok et al.6 The key concept in understanding the phenomenon has been suggested by other authors: namely, the time required to achieve an effective immune response may be longer than what is typically seen for response times when targeted therapies are used in RCC.2

 

Figure 1. Potential Mechanism for Tumor Flare Associated With Immunotherapy.

 

Revisiting the RECIST Criteria

The standard for evaluating response has been the RECIST criteria. In early 2017, the RECIST working group developed a guideline of a modified RECIST 1.1 for immune-based therapeutics.7 Patterns of response based on RECIST criteria include complete response (total remission of all target and non-target lesions, including the lack of appearance of new lesions; to be confirmed no less than 4 weeks after the first assessment); partial response (a decrease of at least 30% in the total tumor burden compared to baseline; to be confirmed after at least 4 weeks); stable disease (the change of the total tumor burden is reduced of less than 30% when compared with baseline or increased less than 20% compared to baseline or nadir); unconfirmed progressive disease (increase in the total tumor burden of at least 20% compared to nadir/ baseline; further confirmation at imaging is needed to rule out PP); progressive disease (increase in the total tumor burden of at least 20% when compared to nadir confirmed by a further progression after 4–8 weeks or appearance of new lesion).8  As new reports present emerging data on TBP, the RECIST criteria have become the center of controversy as to whether they should be followed for treatment guidelines. When treatment response to immunotherapy is assessed by these criteria, tumor flare occurring with an agent like nivolumab will be viewed as disease progression. When it is considered as progression, discontinuation of treatment before the potential clinical benefit of a check point inhibition is realized will yield diminishing results. Thus, it is important to determine whether patients receiving immunotherapy may still realize benefit if treated beyond RECIST-defined progression.

Evidence for the appearance of pseudoprogression has been documented in immunotherapy studies in which treatment is associated with an initial tumor flare but reduced tumor burden and shrinkage have been reported later. When nivolumab therapy
was used in melanoma and non-small-lung cancer trials a subgroup of patients treated beyond first progression showed an uncommon pattern of benefit relative to another group not treated beyond first progression.9-11

 

Pivotal Trials Verifying TBP

Several analyses, including results from Phase 2 and 3 trials and subgroup data, are providing a more accurate picture of clinical benefit derived from TBP. In a study by George et al,12 the authors presented a subgroup analysis of a blinded, randomized, multicenter, phase 2 trial to further delineate the potential for reduction in tumor burden after RECIST-defined first progression (Figure 2). This subgroup analysis continued the line of investigation in the initial assessment when some patients had sustained reductions or stabilization in the size of their target lesions.13 The analysis is important for several reasons: 1) it further elucidates the hypothesis that immunologic treatment may induce infiltration of immune cells and inflammation of the tumor, thereby increasing tumor size as measured objectively by imaging; (2) the transient growth of tumor during this time may result in a decrease in RECIST-defined PFS but not necessarily OS; and (3) it calls attention to the hypothesis that RECIST-defined progression may not necessarily be a marker for biologic disease progression, at least during this initial phase. This leads to proposed immune-related response criteria (irRC) that could be used to better characterize patterns of response observed with immunotherapies.6

 

Figure 2. Tumor Burden Change From First Progression. Tumor burden change in target lesions from first progression in patients treated beyond progression. The horizontal dashed reference line indicates the 30% reduction consistent with a Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response. Plus signs indicate patients who had at least 20% increase in target lesions at time of first progression. One patient did not have tumor sum of diameters values available prior to progression because 1 of the target lesions became nonmeasurable, and therefore is not shown in the Figure.

 

 

In the subgroup analysis by George et al, 154 of 168 patients were randomized to nivolumab in the Checkmate-010 trial; 36 were treated beyond progression, 26 were treated beyond first progression for 6 weeks or less, and 92 were not treated beyond first progression.12 Of the 36 treated beyond first progression, 25 demonstrated reductions in tumor burden or stabilization in the size of target lesions after first progression. Thus, the analysis offers compelling evidence that sustained reductions in tumor burden or stabilization in the size of target lesions can be achieved if nivolumab treatment is continued after initial disease progression in mRCC is observed.

 

CheckMate 025 Confirms Value of TBP

If one were looking for Phase 3 results to further delineate the value of TBP then CheckMate 025 provides significant data from a large pivotal study. From this landmark study by Escudier et al,14 a subgroup analysis addressed similar questions on treatment in 406 nivolumab-treated patients, 316 of whom had progressed by RECIST criteria. Treatment beyond progression was defined as treatment for at least 4 weeks after first progression The key “take-away” messages from CheckMate 025 are:

  • Patient TBP with nivolumab had additional clinical benefit: 13% of patients
    experienced a subsequent benefit of at least a 30% decrease or more in tumor
    burden.
  • The reduction in tumor burden was found in patients who initially responded and then
    progressed as well as in patients with stable disease or progressive disease as their
    best overall response—perhaps explained by tumor flare.
  • There were key differences in disease characteristics at first progression in patient
    TBP vs those who were not treated beyond progression. These characteristics
    included better Karnofsky performance status, lower incidence of new bone lesions,
    higher overall response rate, shorter time to response, and improved QOL.

 

FDA Pooled Analysis Offers Skeptical View
of TBP But It Has Limitations

Skeptics who remain unconvinced of the value of TBP point toward data from an FDA pooled analysis that concluded continuation of TBP beyond progression in the product labeling should not be recommended because the clinical benefit remains to be proven.15 In this pooled analysis, (which should not be confused with CheckMate025) although more than half of patients with unresectable or metastatic melanoma with RECIST-defined progression received continued anti-PD-1 antibody treatment beyond progression, only a modest number of these patients (95 [14%] of 692) seemed to have subsequent decreases in their target lesion tumor burden that reached the level of a response (≥30% decrease) in this analysis. Extrapolating from these results, the FDA analysis differs from the conclusions reached in the study by Escudier et al. The FDA paper suggests that the overall clinical benefit of treatment beyond progression with anti-PD-1 antibodies remains unclear. The report further suggests the survival of patients given such treatment seems to be similar in the chemotherapy group and the anti-PD-1 antibody group in the comparative trial. Furthermore, the number of patients with a delayed response during treatment beyond progression with anti-PD-1 antibodies was apparently low relative to the total population in the pooled analysis.

However, does this mean the FDA definitively recommends that TBP should unequivocally be followed as a policy? Not necessarily. The report  acknowledges that the risks of continued treatment beyond progression should be balanced with the small potential of a subsequent reduction in tumor burden or prolonged disease stability. It notes that further evaluation is needed to identify patients who might benefit from continued treatment with the inclusion of various biomarkers and other criteria.

What remains to be considered, however, are significant differences between the FDA-sponsored report and results from Escudier et al which put the interpretation of the FDA findings into doubt. The FDA analysis excluded patients who responded to treatment and then progressed and excluded patients with nontarget expression even if there was a reduction in target lesions (based on personal communication with author Bernard Escudier).15 In a similar vein, the data from Escudier are based on all patients who were treated beyond progression. Thus, these data are more inclusive and provided a landmark analysis for a significant survival advantage derived from TBP compared to not treated beyond progression.

 

A Case Report on TBP in RCC

Although the literature is still sparse on the use
of TBP in mRCC, other papers have provided additional evidence supporting such strategy.
In a case report  by Rebuzzi et al,16 for example, reviewed results from an advanced renal cell carcinoma patient treated with nivolumab who developed clinical benefit and delayed radiological response after initial progression. These authors performed a review of the literature on immunotherapy beyond progression in advanced solid tumors; 12 clinical trials were identified and showed that selected patients have subsequent response and survival benefit receiving immunotherapy beyond progression.

Offering a corroborating perspective in their review of the literature, Atkins et al17 provided an analysis on the future use of checkpoint inhibitors, including the potential value of treatment beyond progression, the potential use in earlier lines of care in combination with other agents. They also identify biomarkers that could help to guide patients selection and enable individualization of therapy.

 

Reexamining the RECIST Criteria and the Need

for a Paradigm Shift in Assessment Guidelines

An overarching theme to virtually all of the studies examining the issue of treatment beyond progression is the focus on RECIST criteria and the need to reevaluate practical implications of their use. As Wolchok suggest in their report, increasing clinical experience indicates that traditional response criteria may not be sufficient to fully characterize activity in the new era of targeted therapies and/or biologics. The RECIST criteria were initially published nearly 20 years ago and the guidelines were updated 10 years ago.6 The criteria have become so much a part of practice and have guided the methods used in clinical trials. What can replace them? The precepts embodied by the RECIST criteria suggest why new thinking needs to be considered. For example, for cytotoxic agents, the guidelines assume that an early increase in tumor growth and/or the appearance of new lesions signal progressive disease. Thus, for cytotoxic agents, the term “progression” became synonymous with drug failure and cessation of the current treatment is recommended once PD is detected.

In contrast to the rationale for discontinuing the use of cytoxic agents, the calculus for immunotherapeutic agents is markedly different. With chemotherapy, for example, stable disease (SD) is often transient and not considered indicative of true antitumor activity.6 With immunotherapy SD may be viewed as an indicator of a meaningful therapeutic effect. Wolchok et al also provide a valuable backdrop with which to analyze whether the traditional RECIST criteria need to be revisited. In studies with cytokines, cancer vaccines, and monoclonal antibodies (such as ipilimumab) complete response, partial response (PR), and SD have been shown to occur after an increase in tumor burden characterized as PD by the RECIST criteria.

A pivotal point in the evolution of new criteria occurred when approximately 200 oncologists, immunotherapists and regulatory experts met in a series of workshops in 2004 and 2005. The result of these workshops was a new line of thinking about immunotherapeutic agents in cancer.18 Wolchok et al present novel criteria, called immune-related response criteria (irRC) that can better capture the response patterns observed with some immunotherapies. Among the criteria suggested in this report:

  • An increase in tumor burden or the appearance of new lesions points toward the
    need for appropriate followup at a subsequent point to confirm progressive disease.
  • Treatment should be continued as tumors may begin to shrink during this interval.
  • Patients treated with immune therapy whose performance status is stable and whose
    laboratory values have not significantly deteriorated, as well as those with moderate
    tumor growth on physical exam or radiographic imaging, should be considered for
    repeat confirmation scans. These scans should be done before progressive disease
    is defined and the immunotherapeutic agent is discontinued.

 

It is our practice generally to continue immunotherapy beyond the first progression, if patients are tolerating the drug and are found to have clinical benefit (after explaining the potential flare phenomenon). If progressive disease is observed a second time then immunotherapeutic agents should be discontinued. The key message is that TBP refers to treatment beyond first progression; because the tail of the survival curve does not support continued immunotherapy after a second progression, we recommend discontinuation of immunotherapeutic agents.

 

Conclusion

The criteria for the continued use of immune checkpoint inhibitors beyond progression are changing as recent analyses begin to show a translational impact on clinical practice. The concept of tumor flare or pseudoprogression is increasingly important to consider in patient assessment. Based on data from pooled analyses and other reports in a broad range of tumors, including RCC, the traditional RECIST criteria have been reexamined and, if followed, may not provide patients with the potential clinical benefit they could receive with continuation of treatment beyond first progression.  A new set of guidelines, the immune-related response criteria, need further prospective evaluation to determine the extent to which their application could be associated with sustained benefit and improved overall survival. This topic also underscores the unmet need to develop radiographic bio-marker studies to better assess early tumor changes after the introduction of immune checkpoint inhibitors. Such imaging modalities should ideally include tracking T-cell infiltration of tumors/ tumor metabolism/tumor microenvironment in parallel to the RECIST based assessments. Although it is not possible to conduct a prospective trial to definitively address many questions regarding TBP, if there are adequate resources to address this in a prospective trial, a randomized discontinuation trial would provide important perspectives.

 

References

1. Raman R, Vaena D. Immunotherapy in metastatic renal cell carcinoma: a comprehensive review. Biomed Res Int. 2015;2015:367354.

2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. Version 1.2016. NCCNWebsite. http://www .nccn.org/professionals/physician_gls/f_guidelines .asp. Accessed September 16, 2016.

3.  Escudier B, Porta C, Schmidinger M, et al; ESMO GuidelinesWorking Group. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii49-iii56.

4. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA. 2007;104(9): 3360-3365.

5. Motzer RJ, Escudier B, McDermott DF, et al. CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.

6. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-7420.

7. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–14. [PubMed] [Google Scholar]

8. Pardoll, Drew M. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

9. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1030.

10. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4): 320-330.

11. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135.

12. George S, Motzer RJ, Hammers HJ, et al. Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016;  Sep 1;2(9):1179-86.

13. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33(13):1430-1437.

14. Escudier B, Motzer RJ, Sharma P, et al. Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur Urol. 2017; 2:368-376.

15. Beaver JA, Hazarika M, Mulkey F, et al. Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2018;229-239.

16. Rebuzzi SE, Bregni G, Grassi M, et al.  Immunotherapy beyond progression in advanced renal cell carcinoma: a case report and review of the literature. Immunotherapy. 2018 Sep;10(13):1123-1132.

17. Atkins MB, Clark JI, Quinn DL. Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions. Ann Oncol. 2017;28;7:1484-1494.

18. Hoos A, Parmiani G, Hege K, et al. A clinical development paradigm for cancer vaccines and related biologics. J Immunother. 2007;30:1–15  KCJ

 

Copyright © 2019

 

Vol 17, No 3    2019

The Official Journal of the Kidney Cancer Association

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In the subgroup analysis by George et al, 154 of 168 patients were randomized to nivolumab in the Checkmate-010 trial; 36 were treated beyond progression, 26 were treated beyond first progression for 6 weeks or less, and 92 were not treated beyond first progression.12 Of the 36 treated beyond first progression, 25 demonstrated reductions in tumor burden or stabilization in the size of target lesions after first progression. Thus, the analysis offers compelling evidence that sustained reductions in tumor burden or stabilization in the size of target lesions can be achieved if nivolumab treatment is continued after initial disease progression in mRCC is observed.