Experts Explore Immunotherapy Frontier in Melanoma

Omid Hamid, MD

Treatment options are expanding in the setting of metastatic melanoma. In January, the National Comprehensive Cancer Network (NCCN) revised its melanoma treatment guidelines to include pembrolizumab and nivolumab, along with ipilimumab, among the preferred systemic options for patients with advanced or metastatic disease.¹ These immunotherapy advances are among the emerging treatment approaches that make it an exciting time for patients with melanoma and their physicians, according to experts who participated in a recent OncLive Peer Exchange program.

Led by moderator Omid Hamid, MD, the panel of clinical and research experts discussed the evolving treatment of metastatic melanoma during a Peer Exchange session entitled “Updates on the Treatment of Malignant Melanoma.”

An increased understanding of tumor pathology and immunology has led to seven new melanoma drug approvals since 2011, including the recent approvals of the PD-1 inhibitors nivolumab and pembrolizumab. In addition, several completed and ongoing trials show promise that these immunotherapies will improve survival for patients with melanoma. The integration of immunotherapy is still evolving, and the panel discussed several key issues related to its current and future use.

Who Will Respond?

Although much progress has been made with immunotherapy, there are still no definite predictors for response to agents that inhibit PD-1 or its ligand PD-L1. Richard W. Joseph, MD, described a retrospective study of patients on pembrolizumab.² The researchers “quantified to baseline tumor size in every patient and found out that that was the number one independent prognostic factor, both for survival as well as for response.”

Richard W. Joseph, MD

Questions remain whether PD-1 or PD-L1 expression should be used as a predictive marker for nivolumab and pembrolizumab. Howard L. Kaufman, MD, FACS, explained that even though “there are increasing data coming out to suggest that PD-L1 expression is associated with the higher response rate...the corollary is that even though the response may be lower in the PD-L1-negative [tumors], there are still some patients who will respond.”³

Howard L. Kaufman, MD, FACS

Assessing Response and Progression

With several immunotherapies available for the treatment of malignant melanoma, oncologists are challenged with assessing treatment response. Anna C. Pavlick, DO, explained that there can be a “lot of angst when you have to decide, is someone having true progression or is someone having what we know as pseudo-progression, which is essentially an inflammatory response, an immunologic response to the therapy around the tumors where things look worse but the patient is actually responding.” It is not uncommon for patients to have new lesions develop and other lesions get larger before responding to therapy, Robert H.I. Andtbacka, MD, CM, explained. For instance, in the phase III OPTiM study⁴ looking at talimogene laherparepvec (TVEC), an intralesionally administered oncolytic vaccine, almost half of patients who ultimately achieved a durable response had growth of their initial melanoma beforehand, said Andtbacka, who helped lead the study.

Other situations that challenge response assessment with immunotherapy include late responders and responders who have persistent lesions. With persistent lesions, a PET scan can verify the patient’s response and isolated persistent lesions can even be treated with surgery or radiotherapy.

Pavlick explained that when assessing how a particular patient is faring on therapy, the patient’s condition is the most important factor, with imaging results and laboratory values being secondary. For example, she said that if a patient appears to be stable or improving but the scan looks worse, she typically tracks the patient for another 6 to 8 weeks to assess disease progression. Joseph added that if the patient was taking a PD-1 inhibitor, he would repeat the scan in 12 weeks, unless there is clinical deterioration.

Hamid added that he would continue therapy in a patient who has stable disease on immunotherapy because these patients have overall survival similar to that of patients who achieve a classic complete remission. Achieving stable disease appears to be meaningful, especially with immunotherapy. This will be important information for oncologists treating cancers other than melanoma. Andtbacka explained that if patients with prolonged stable disease want to discontinue therapy, he follows them with CT or PET scans every 3 months. It is not uncommon, he remarked, to go back and operate and find that there is only fibrosis there and no active tumor. Importantly, Kaufman added, there doesn’t appear to be cross-resistance among immunotherapies; thus, a patient who doesn’t respond to one immunotherapy may respond to another.

Anna C. Pavlick, DO

Treatment Duration

The optimal duration of therapy with nivolumab and pembrolizumab remains an unanswered question that is an important goal for randomized trials. According to Joseph, patients in clinical trials have stayed on these agents indefinitely. However, many patients who have achieved complete remission seek to discontinue therapy at some point. Pavlick stressed that the overall effect of constantly stimulating the immune system must be considered.

Joseph noted that he has stopped PD-1 inhibitor therapy successfully, but that late relapses have been reported anecdotally. Joseph added that the risk of discontinuing treatment seems to be low because patients can be retreated with the PD-1 inhibitor at recurrence. Kaufman confirmed that some patients will respond to immunotherapy again when retreated. This has been seen with ipilimumab and interleukin-2 (IL-2). However, until more is known, his preference is to try a different therapy in a patient whose disease progresses after PD-1 inhibitor therapy.

Managing Toxicities

Pavlick observed that although the toxicities with PD-1 inhibitors are not benign, they appear to be more easily managed than the toxicities with other immunotherapies she is accustomed to administering.

“PD-1 is probably the easiest drug I’ve ever administered as an oncologist,” remarked Joseph.

While rash, thyroid-related problems, and fatigue are common side effects, they are not dose-limiting. Pneumonitis is more of a concern for patients with lung cancer who receive PD-1 inhibitor therapy; however, oncologists still need to be highly suspicious of pneumonitis when a patient on a PD-1 inhibitor presents with respiratory symptoms, shortness of breath, cough, or difficulty breathing.

Robert H. I. Andtbacka, MD, CM

Combining Immunotherapies

There is a scientific rationale for combining immunotherapies with one another and with other types of therapy for the treatment of advanced melanoma, with the ultimate goal of improving efficacy while maintaining tolerability. While the combination of the BRAF inhibitor dabrafenib with ipilimumab proved far too toxic, the clinical trial results for nivolumab with ipilimumab were very impressive. In fact, preclinical studies in mice have shown the additive potential for triple immunotherapy with CTLA-4, PD-1, and PD-L1 blockade, said Kaufman. He added that it remains unclear as yet what the toxicity profile would be for that combination. However, with some of the less toxic agents, TVEC and granulocyte-macrophage colony-stimulating factor (GM-CSF), it might be possible to think about three- and four-drug combinations.

The most mature data of combined immunotherapies in melanoma are from a study looking at ipilimumab with nivolumab.⁵ However, other immunologic agents are now being combined; for example, TVEC with ipilimumab or pembrolizumab, and ipilimumab with GM-CSF.^6-9 The trial of ipilimumab and GM-CSF9 actually showed a decrease in some of the toxicities over monotherapy, particularly gastrointestinal toxicities, said Kaufman.

Whether it is two or three agents being combined, it will be important to understand how to combine them to achieve greater responses with the least amount of toxicity for patients. “If we can increase response rates,” said Hamid, “maybe we can increase the long-term durability of responses and long-term survival advantage.” Pavlick commented that “you’re getting more efficacy when you combine them, but you’re also getting more toxicity, and I think that’s my biggest concern.” She said that with combined ipilimumab and nivolumab, a large percentage of patients will develop profound, rapid-onset diarrhea, similar to the way it presents with ipilimumab, and it needs to be managed early.

Role of Radiation

Radiation therapy is taking on an increased role based on evidence of an abscopal effect in combination with immunotherapy. An abscopal effect is a phenomenon in the treatment of metastatic cancer where localized treatment of a tumor causes not only shrinkage of the treated tumor but also shrinkage of distant tumors. According to Joseph, it is reassuring that the addition of radiation therapy can improve tumor response without adding further toxicity. Joseph described a case that exemplifies the additive effect of combining ipilimumab and radiation therapy in which a patient with a large lung metastasis had a much better response with the combination than what would be expected with either treatment alone. Concurrent stereotactic radiotherapy and ipilimumab are used in patients with brain metastases as well, explained Andtbacka. It is ideal to start immunotherapy as early as possible to try to achieve the abscopal effect. Hamid commented that the combination has resulted in significant responses in patients with melanoma who also have brain metastases.

Multidisciplinary Approach Necessary

Oncologists who treat patients with melanoma are collaborating with other physicians more often as therapeutic options and their associated toxicities continue to expand. The involvement of surgeons, interventional radiologists, pathologists, and others is necessary from diagnosis through treatment.

In addition, recognizing and managing the varied dermatologic, gastrointestinal, and endocrine toxicities may require additional specialties. Patients require and deserve a multidisciplinary approach based on the growing complexity involved in treating melanoma, noted Andtbacka.

References

1. NCCN Clinical Practice Guidelines Melanoma Version 2.2015. Published January 1, 2015. Accessed March 24, 2015.
2. Joseph RW, Elassaiss-Schaap J, Wolchok JD, et al. Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol. 2014;32(suppl 5s; abstr 3015).
3. Kefford R, Ribas A, Hamid O, et al. Clinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol. 2014;32(suppl 5s; abstr 3005).
4. Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol. 2013;31(suppl; abstr LBA9008).
5. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32(suppl 5s; abstr LBA9003).
6. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01740297. Accessed March 25, 2015.
7. Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J Clin Oncol. 2014;32(suppl 5s; abstr 9029).
8. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02263508.Accessed March 25, 2015.
9. 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).