Is IL-2 Still Indicated for Melanoma and RCC? What a Question to Ask!

Drs. Amin and White ask, “Is Interleukin-2 (IL-2) still indicated for the therapy of renal cell carcinoma (RCC) and melanoma in an era of targeted therapies?”[1] What a question! There has never been a referendum on IL-2. True, in the era of paradigm-shifting therapies, IL-2 may be overlooked at times, but it must not be excluded from the conversation. As demonstrated at the recent American Society of Clinical Oncology (ASCO) 2013 meeting, the field of immunotherapy is moving at an accelerated pace. The initial euphoria from those “eureka” moments with ipilimumab (Yervoy)[2] and then vemurafenib (Zelboraf)[3] in 2011 were quickly succeeded by the next ones with the programmed death protein 1 (PD-1)[4] and PD ligand 1 (PD-L1)[5] antibodies less than 2 years later. However, the notion that immune checkpoint inhibition with PD-1– and PD-L1–targeted agents would rapidly become the standard of care may have lasted only 1 year, since it is currently being challenged by combinatorial therapies. Wolchok et al presented startling data on an ipilimumab-nivolumab combination[6] that boasted significant response rates, with rapidity, depth, and durability of response that may possibly surpass other single-agent experiences. At the same time, lambrolizumab[7] and MPDL3280A[8,9] both demonstrated promising single-agent benefit in many solid tumors.

Unfortunately, the time from discovery to yesterday’s news has continued to shorten, as all of the therapies just mentioned are now being rapidly moved to combinatorial evaluation. Amidst the excitement generated by these novel therapies, it is an error to overlook the fact that the longest experience with durable response and survival in metastatic melanoma and RCC belongs to IL-2. Unfortunately, this rate of benefit is small and without clear indication of which patients will benefit. Enter the need for biomarker analysis.

The future holds the possibility of higher response rates, more durable responses and-just as important-less morbidity and fewer immune-related adverse events. These benefits will not derive solely from combination therapy. The first step must be to gain an understanding of predictive markers of response to proposed therapies. Unfortunately, we lack markers for almost all therapies used to date. We must continue to look for these predictive markers.[10] Immunohistochemical staining of PD-L1 on tumor tissue, once thought to be the predictive marker for response to PD-1/PD-L1[11] immune checkpoint blockade, has not yet been fully validated. Biomarker discovery for IL-2 was the unrealized goal of the renal cell SELECT trial. The Cytokine Working Group and others are ensuring that IL-2 continues to have a voice in this discussion through the ongoing work of the melanoma SELECT trial and through combinatorial therapy with ipilimumab, vemurafenib, aflibercept (Zaltrap), and axitinib (Inlyta). An IL-2 and vaccine combination already has shown a significant improvement in overall clinical response, progression-free survival, and median overall survival, compared with IL-2 alone. Fortunately, there is still more to be discovered with IL-2.[12]

Moreover, immune therapy is not only for melanoma and renal cell carcinoma anymore. Therefore, it is unwise to overlook any immune-mediated therapy, as it may be beneficial in some setting. This belief has been amplified in the wake of the rebirth, at ASCO 2013, of the use of granulocyte-macrophage colony-stimulating factor (GM-CSF), in combination therapy. Maintenance therapy with IL-2 and GM-CSF after high-dose IL-2[13] showed a longer duration of response compared with previous reports, and this trended toward statistical significance. The authors of this study noted that this combination may help to prolong partial responses, possibly leading to conversion to complete response. In melanoma, ipilimumab plus GM-CSF significantly improved overall survival over ipilimumab alone.[14] No significant differences in toxicity were observed. Surprisingly, a trend toward improved ipilimumab tolerability was noted in the GM-CSF arm. These startling data with a “forgotten” immunotherapy were in direct contrast to initial forays into combination therapy with the new targeted agents, which have been fraught with toxicity. Combinations of BRAF inhibitors and immune checkpoint inhibitors have shown hepatotoxicity significant enough to prematurely close trials.[15] We must consider all combinations while concurrently elucidating the appropriate predictive biomarkers.

Drs. Amin and White have done a comprehensive job of identifying the right path to take. It is only a matter of time until we unlock tolerable combinations with high and durable response rates that can be amplified with patient selection through appropriate biomarker analysis. Among our options are immune checkpoint inhibitors, targeted agents, antiangiogenic agents, radiation,[16] and most definitely IL-2. The field is moving fast, and triple-combination trials have already begun.[17] If we continue to be mired in a discussion of the role of stand-alone IL-2, it is clear that we have missed the point. Treatment techniques have moved past this antiquated debate. We find ourselves at the precipice of major discovery with these therapies, in combinatorial and/or sequential fashion. Our patients are waiting for answers.

Financial Disclosure: Dr. Hamid has served as a speaker for and consultant to, and has received research funding from, Genentech; has received research funding from MedImmune; has served as a speaker for and consultant to, and has received research funding from, Bristol-Myers Squibb; and has served as a consultant to, and has received research funding from, Merck.

References:

REFERENCES

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2. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.

3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364:2507-16.

4. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65.

5. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54.

6. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 June 2. [Epub ahead of print]

7. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N Engl J Med. 2013 June 2. [Epub ahead of print]

8. Hamid O, Sosman JA, Lawrence DP, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol. 2013;31(suppl):abstr 9010.

9. Cho DC, Sosman JA, Sznol M, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2013;31(suppl);abstr 4505.

10. Yorio JT, Fox PS, Wayne R, et al. Assessment of absolute lymphocyte count (ALC) as a predictor of progression-free survival (PFS) and overall response rate (ORR) in metastatic melanoma (MM) patients (pts) treated with high-dose interleukin-2 (HD IL-2). J Clin Oncol. 2013;31(suppl):abstr 9096.

11. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65.

12. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 Peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119-27.

13. Chu MB, Fesler M, Armbrecht E, et al. Maintenance interleukin-2 (IL-2) and sargramostim (GM-CSF) following high-dose IL-2 (HD IL-2) therapy for metastatic melanoma. J Clin Oncol. 2013;31(suppl):abstr e20049.

14. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (ipi) versus ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl):abstr CRA9007.

15. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. [correspondence] N Engl J Med. 2013;368:
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16. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925-31.

17. NCT01767454: Dabrafenib +/- trametinib in combination with ipilimumab for V600E/K mutation positive metastatic or unresectable melanoma. Available from: http://clinicaltrials.gov/show/NCT01767454. Accessed June 20, 2013.