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HemOnc Today Melanoma and Cutaneous Malignancies 2016
The HemOnc Today Melanoma and Cutaneous Malignancies meeting in New York City on March 18 and 19 hosted about 1,000 melanoma specialists. Several sessions were staged as debates on management issues of high general interest. Among them were key clinical aspects of systemic or locoregional use of immunotherapies.
The BRAF-Positive Patient: How Should a Clinician Decide?
Presenting the cases for either immunotherapy or molecularly targeted therapy as frontline treatment for advanced BRAF-mutant melanoma, Dr. Atkins said that survival curves for the two options cross over at a little past two years. While BRAF inhibitor survival is superior at first, later CTLA-4 inhibition with ipilimumab is better, reaching a steady plateau sustained past five years.
In the column favoring immunotherapies is their ability to produce treatment-free tumor responses. BRAF inhibitors don’t share that capacity. A study by Schadendorf et al. showed a 21% three-year overall survival (OS) for ipilimumab,1 which compared favorably with Dr. Atkins’ trial of high-dose interleukin-2 (IL-2) with an OS of 11% at more than five years, and median OS with BRAF inhibition of approximately 26 months (median progression-free survival [PFS], approximately 10–13 months). While combined BRAF/MEK inhibition has produced the best outcomes in normal lactate dehydrogenase (LDH) patients, the benefit is strongest in patients with elevated LDH, more advanced disease (M1c versus IIIC/M1a/M1b) and greater tumor burden (three or more disease sites).2 Immunotherapy, however, works as well against BRAF V600 mutant melanoma as it does against wild-type tumors. Other confirmatory studies demonstratied survival benefit regardless of NRAS mutation status. The same immunity to BRAF mutation status was shown by Postow et al. in the CheckMate 069 trial of nivolumab with or without ipilimumab (complete responses [CRs] were reported in 22% of patients).3
BRAF inhibitors also work as well in patients with or without prior immune therapy. In a study by Ribas et al., the objective response rate (ORR) of about 53% with vemurafenib was observed regardless of prior IL-2 treatment.4 However, there were no tumor responses among 34 patients when single-agent immunotherapy with ipilimumab was given following MAPK inhibition,5 and median OS was five months. (All surviving patients at a year were back on MAPK inhibitors.)
“Patients progressing on BRAF inhibitors appear unlikely to respond to ipilimumab,” Dr. Atkins said. A trial comparing ipilimumab/BRAF inhibitor sequencing confirmed that observation.6 The implication is that starting with immunotherapy “offers a chance for long-term benefit without compromising benefit from subsequent BRAF inhibition,” he said.
Combining ipilimumab with the programmed death-1 (PD-1) inhibitor nivolumab prolonged median PFS from 6.9 months to 11.5 months and reduced ipilimumab toxicity.7 Ipilimumab monotherapy’s grade 3–4 serious adverse event rate was 55%; combined with nivolumab, it was 16%.
Dr. Atkins said that antitumor activity is similar between the BRAF inhibitors and the newer monotherapies; durability, however, is greater for the immunotherapies.
The Keynote-006 trial, showing superior one-year OS for the PD-1 inhibitor pembrolizumab (74.7% versus 58.2% for ipilimumab) with longer PFS (5.5 months versus 2.8 months for ipilimumab) and a nearly tripled ORR (33.7% versus 11.9%), lends further support for front-line immunotherapy.8
There is a case, Dr. Atkins said, for the molecularly targeted therapies. The BRAF/MEK inhibitor combination produces responses in most patients, and in the subgroup of patients with M1a/b disease, high response, median OS, and CR rates are observed. For patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib, three-year OS was 68% in stage IIIC/M1a/M1b patients and 62% in patients with LDH less than or equal to the upper limit of normal9 and with fewer disease sites.10
Two further factors favoring frontline BRAF/MEK inhibitor therapy arise from the observation of PD-1 pathway blocker responses after the development of BRAF/MEK inhibitor resistance, and from experience that toxicity may be worse after immunotherapy. Optimal ipilimumab/nivoluma–dabrafenib/trametinib sequencing is being assessed in the EA6134 trial, Dr. Atkins said.
Intralesional and Regional Therapy Debate
Intralesional Monotherapy: Is There a Role?
Dr. Ross outlined the spectrum of intralesional therapy targets, including 1) stage IIIB/C regionally metastatic in-transit disease with or without nodal disease; 2) stage M1a (distant skin, soft tissue, and nodal metastases); and 3) the second situation with low-volume visceral disease. Intralesional therapy is very well-tolerated and addresses the fact that, in patients with advanced regional and injectable stage IV lesions, uncontrolled disease can be very morbid, painful, and disfiguring. “You can deliver a high concentration of drug very easily, providing a very good palliation of symptoms—and durable control may be curative,” he said.
It is likely, as well, that intralesional therapies can provide a priming mechanism for a host-immune response. In essence, the three intralesional therapies cited by Dr. Ross (talimogene laherparepvec [T-VEC], PV-10, and coxsackievirus A21), each through differing mechanisms, selectively invade and lyse tumor cells, leading to the release of tumor-derived antigens and potentiating a systemic T-cell–mediated antitumor response.
Dr. Ross cited clinical trial evidence from T-VEC and PV-10. In the OPTiM phase 3 trial of T-VEC, objective overall responses were reported in 26.4% of patients. Among responders, the complete response (CR) rate was 41%. Fifty percent or higher lesion decreases were reported in 17% of uninjected visceral lesions. The risk of developing visceral or bone metastasis was reduced by 59% compared to the granulocyte-macrophage colony-stimulating factor control.
In the 80-patient phase 2 study of PV-10, a chemoablative agent, the CR rate was 24% in injected lesions and 24% in uninjected “bystander” lesions, with a disease control rate (DCR) of 71%. Responses in bystander lesions correlated highly with responses in injected target lesions.
A group showing the strongest responses to several intralesional therapies is patients with stage IIIB/C melanoma. For them, response rates have compared favorably (T-VEC, 52%; PV-10, 49%) to those of the approved systemic immunotherapies (ipilimumab, less than 30%; pembrolizumab, 27–39%; nivolumab, 34–40%). Grade 3–4 adverse event rates, however, are far lower with the intralesional therapies (T-VEC less than 2% versus ipilimumab’s 19%).
The roles for intralesional monotherapy in advanced melanoma are as treatment of unresectable lesions and, potentially, as neoadjuvant therapy before surgery to activate the immune system.
Dr. Andtbacka underscored the superiority of intralesional therapies combined with systemic therapies (i.e., checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab). He listed three factors: 1) intralesional therapies do not add toxicity; 2) they may enhance the effect of checkpoint inhibitors; and 3) response rates with the combinations are better than with either treatment alone.
The best change from baseline in target lesion volume in the CheckMate 067 trial of nivolumab plus ipilimumab was –51.9% for the combination, –34.5% with nivolumab alone, and +5.9% with ipilimumab alone. The 40% grade 3–4 adverse event rate with the combination, however, is a concern, according to Dr. Andtbacka. “There clearly are patients who are not candidates for this combination,” he said.
In the phase 1B trial of ipilimumab plus T-VEC among 18 patients, the DCR was 72%, with durable responses in 44% and complete regression of uninjected nonvisceral and visceral lesions in 39% (52% had 50% or more regression).
Dr. Andtbacka concluded that “the future of oncolytic immunotherapy is in combination with other therapies,” based on his comparison of response rates in advanced unresectable stage III/IV melanoma between monotherapies (ipilimumab, 6–15%; pembrolizumab, 27–38%; nivolumab, 34–40%; T-VEC, 26%) and combination therapies (nivolumab plus ipilimumab, 52%; T-VEC plus ipilimumab, 50%; T-VEC plus pembrolizumab, 56%).
Conference Chairman and Moderator Sanjiv Agarwala, MD, wrapped up the debate stating, “Intralesional therapy is here to stay.” In the course of taking polar positions on intralesional monotherapy, the debaters effectively affirmed their own and Dr. Agarwala’s position.
Debate on Combination Checkpoint Blockade
Combination Checkpoint Blockade: The New Standard For All Patients
Dr. O’Day began by listing factors supporting combinations of checkpoint blockade immunotherapy as the standard in metastatic melanoma, such as high disease control rates; rapid deep responses; improved response rates; longer progression-free survival (PFS); and good estimated overall survival (OS), approaching 70% at three years.
By comparison, the traditional cell-directed therapies are characterized by short responses with little impact on survival. The new therapies produce durable tumor responses with early disease control and symptom management, and offer patients time without symptoms or treatment and often long-term survival.
Response rates with ipilimumab, the CTLA-4 blockade agent that was the first agent in decades to show an OS benefit in advanced melanoma, have been far surpassed by nivolumab and pembrolizumab, the new programmed death-1 (PD-1) blockade agents. In the phase 3 CheckMate 067 trial, objective response rates (ORRs) were 19% for ipilimumab, 44% for nivolumab, and 58% for the combination of nivolumab and ipilimumab. Complete responses were reported in 2.2% for ipilimumab, 8.9% for nivolumab, and 11.5% for the nivolumab/ipilimumab combination. Similarly, median PFS was 2.9 months for ipilimumab, 6.9 months for nivolumab, and 11.5 months for the combination.
The combination, however, had increased grade 3–4 adverse events at 55.0%, compared with 27.3% and 16.3%, respectively, for ipilimumab and nivolumab. No treatment-related deaths were reported in the nivolumab/ipilimumab arm (0.3% each for the ivolumab and ipilimumab arms).
While adverse events led to discontinuation of therapy in 29.4% of patients receiving the ipilimumab/nivolumab combination, the ORR among discontinuing patients was nearly 70%. “Those responses are still durable, so with coming off therapy, while it shortens treatment, the opportunity for long-term survival is still there,” Dr. O’Day said. “If patients are educated and prepared for side effects and communicate about them rapidly, early intervention reverses almost all of them,” he added.
Resolved: Ipilimumab Plus Nivolumab Not Suitable for All Metastatic Melanoma Patients
Toxicities with checkpoint inhibitor combinations were at the center of Dr. Weber’s position. “You can talk about a zero death rate in a very tightly controlled, well-put-together randomized phase 3 trial, but when it comes to treatment in the community, where physicians have less experience, it’s going to be a different scenario.”
“The toxicity of combination therapy suggests that those over 75 to 80 years of age or with significant comorbidities should be treated with single-agent PD-1 [programmed death-1] or a PD-1 combination other than ipilimumab,” he said. Among patient populations unlikely to tolerate combination (but appropriate for single-agent nivolumab or pembrolizumab) are patients with prior grade 3–4 ipilimumab therapy-related adverse events and patients with prior allografts or a history of hepatitis or controlled human immunodeficiency virus infection, he added.
Other candidates for checkpoint monotherapy other than ipilimumab include the roughly 40% of melanoma patients with “hot” programmed death ligand 1 (PD-L1)-positive tumors with an “inflammatory signature” who are likely to benefit from PD-1 abrogation. Also, BRAF-mutated melanoma patients with low to normal lactate dehydrogenase (LDH) will likely respond as well to targeted BRAF plus MEK inhibitors like dabrafenib and trametinib that have demonstrated a 30% overall survival plateau as they will to ipilimumab plus nivolumab. The BRAF plus MEK combination, importantly, is much less toxic. For high LDH BRAF-mutated patients, a brief induction with BRAF plus MEK followed by ipilimumab plus nivolumab might be preferred because the BRAF plus MEK combination induces a T-cell influx into tumors and converts a “cold” tumor to a responsive “warm” tumor, Dr. Weber said.
Dr. Weber noted a promising future combination—pembrolizumab with an indoleamine 2,3-dioxygenase (IDO) inhibitor—that has demonstrated a 53% objective response rate, similar to ipilimumab/nivolumab but with significantly less toxicity.
“Therefore, ipilimumab plus nivolumab combination therapy is not indicated for all metastatic melanoma patients,” he concluded.
Dr. O’Day, in a post-debate interview, pointed out that combinations of a PD-1 agent with ipilimumab at lower doses, or with a third intralesional therapy such as T-VEC or PV-10, may also prove successful.
He emphasized, too, that among ipilimumab side effects, while the pituitary cases (hypophysitis) generally require lifelong replacement therapy, a “hassle” factor for the patient, the more important colitis and liver toxicities are generally reversible. “I completely agree with Dr. Weber,” he said, “that the combinations with ipilimumab should be given through experienced hands. There needs to be a big commitment from the patient and the family to communicate information about side effects.”
- Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015;33(17):1889–1894.
- Long GV, Stroyakovskiy D, Gogas H, et al. Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. J Clin Oncol 2015;33(15)(suppl):abstract 102.
- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372(21):2006–2017.
- Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. J Clin Oncol 2011;29(15)(suppl):abstract 8509.
- Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014;120(11):1695–1701.
- Ascierto PA, Minor D, Ribas A, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 2013;31(26):3205–3211.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373(1):23–34.
- Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372(26):2521–2532.
- Long GV, Weber JS, Infante JR, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol 2016;34(8):871–878.
- Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol 2015;33(34):4023–4031.