Yervoy/Nivolumab May Need Stronger Survival Data To Be First Choice In Melanoma

Bristol’s combo demonstrates similar response rate as PD-1 alone, but with much better survival rates in a small melanoma study presented at ASCO. Due to toxicities, including one death, some say combination would need to shore up survival benefit to become first choice in frontline therapy.

CHICAGO – The combination of Bristol-Myers Squibb Co.’s CTLA-4 inhibitor Yervoy (ipilimumab) and PD-1 inhibitor nivolumab will need to show very high survival rates in large studies to secure a role in frontline treatment of melanoma, in light of the significant toxicities for the combo and the strong performance of PD-1 monotherapy, said specialists at the American Society of Clinical Oncology annual meeting.

In follow-up data for the combo in 53 Stage 3/4 melanoma patients taking part in a broader Phase I trial, presented at the ASCO meeting on June 2, researchers reported an objective response rate (ORR) of 40%, for this population, half of whom had very advanced disease and half who were naïve to systemic treatment. One- and two-year survival rates were 85% and 79%. Just a few years ago, the two-year survival rate was only about 20%-25%, according to lead study author Mario Sznol, Yale School of Medicine.

“While this is a small trial, that’s very significant – significant meaning impressive – two-year overall survival data,” Sznol said during a June 2 briefing at the ASCO meeting.

The same day, Bristol-Myers Squibb highlighted survival rates for the combination of 94% at one year and 88% at two years, from a subset of 17 patients taking a 3 mg dose.

While the response rate for the combination does not appear to be significantly different than what has been achieved with anti-PD-1 monotherapy, the University of California’s Steven O’Day told the press briefing, if it holds up in larger trials, the 80% two-year survival rate is very impressive.

The “proof of the pudding will be survival,” O’Day said.

Sznol noted that the combination worked regardless of BRAF mutation status and in those who were negative for PD-L1 expression, patients who don’t typically respond as well to anti-PD-1 therapy.

The substantial activity in PD-L1-low or -negative tumors “suggests we are doing something different than anti-PD-1 alone,” he said.

However, combining the drugs definitely had a cost in toxicity relative to monotherapy in other studies. The rate of Grade 3/4 (severe/life-threatening) events for all cohorts taking the combination in the Phase I study (94 patients) was 62%, and one death occurred as a consequence of colitis.

“We feel fairly confident these adverse events can be managed with a little education and training,” Sznol said. Practitioners successfully manage toxicities in oncology all the time, including the immune-mediated adverse events associated with Yervoy.

In The Shadow Of MK-3475

Results for the combination were somewhat overshadowed by a presentation of data about Merck’s PD-1 pembrolizumab (MK-3475, formerly called lambrolizumab) as a monotherapy in a very large Phase I study of metastatic melanoma. The study included patients who had previously received Yervoy and those who were treatment-naïve.

The ORR in the study of 411 patients was 34% and was higher in those who had never had Yervoy (40%) and who were treatment-naïve (44%). Those pretreated with Yervoy had an ORR of 28%. Overall, two-thirds had some kind of benefit, such as stable disease or modest tumor shrinkage, and the survival rates at one year and eighteen months were 69% and 62% respectively.

Importantly, the drug was well-tolerated. The rate of Grade 3/4 events in the study was 12%, with the most common serious event being fatigue, occurring in 2% of patients. The 12% serious adverse event rate is higher than expected for anti-PD1 therapies, said Moffit Cancer Center’s Jeffrey Weber, discussing the results at the full presentation on June 2. The rate of immune-related serious adverse events with nivolumab monotherapy for example is about 5%. Weber speculated that the 12% rate in the Merck study could actually be a reporting error.

During the company’s investor event on the evening of June 2, however, Merck executives challenged the comparison, noting that the 12% rate reflects total Grade 3/4 events. The rate of immune-related severe adverse events is similar to what has been reported for nivolumab, according to Merck.

Given the toxicity profile, if pembrolizumab becomes available as a first-line treatment, it would clearly be preferred over Yervoy, O’Day said after the press briefing.

But the real question, he said, is whether the combination is better. Determining the answer to that will take time. It’s also not clear currently whether combining the two drugs at the same time vs. sequencing them is better from the point of view of toxicity and survival, O’Day said.

“If the [survival] data hold up with the combination, we’ll be using that upfront, but we have to really study that further,” O’Day said.

UCLA’s Antoni Ribas, lead author of the study of the Merck drug, commented after the briefing: “I think that in the near future we will be able to select patients to go to one therapy or the other based on how their tumor looks and how their immune system is already interacting with the tumor.”

Combo Also Works In Kidney Cancer

The melanoma data is the tip of the iceberg for the immune checkpoint class, and with high expectations for combinations among and across the field, attention is focused on how Bristol is capitalizing on the lead it has in marketing the only approved CTLA-4 inhibitor. Yervoy and AstraZeneca’s investigational tremelimumab are seen as potential partners for myriad immuno-oncology approaches.

In melanoma, Bristol is testing nivolumab with Yervoy against nivolumab alone or Yervoy alone in a Phase III study. And a Phase II study will evaluate nivolumab with Yervoy to Yervoy alone.

During a June 2 investor event at the ASCO meeting, the company expressed high hopes for the future of the Yervoy/nivolumab combination, not just in melanoma but also in other tumors, like renal cell carcinoma. In early data presented at the meeting in pretreated metastatic RCC, the Yervoy/nivolumab combination doubled the response rate possible with nivolumab monotherapy, execs noted.

The company now has a very good understanding of metastatic RCC and is “totally confident of moving the combination of ipilimumab and nivolumab into Phase III studies in RCC,” said Fouad Namouni, global development lead for nivolumab.

During the call, the company said that it will also be starting an adjuvant study of nivolumab in RCC.

Yervoy In Adjuvant Setting

Phase III results were presented for Yervoy in the adjuvant setting at the ASCO meeting, highlighting a potential role for the drug in a broad setting, but with notable toxicity.

Yervoy has been approved since March 2011 for inoperable, metastatic melanoma (Stage 4) in March 2011, ahead of the availability of data to support use outside refractory disease (Also see "Yervoy Cuts To The Head Of The Line: Ipilimumab Has Unrestricted Label" - Pink Sheet, 28 Mar, 2011.).

The adjuvant study, which was funded by BMS and run by the European Organisation for the Treatment of Cancer cooperative group, evaluated Yervoy against placebo in 951 Stage 3 melanoma patients, following surgery to remove all detectable disease.

Currently, about half of these patients opt to take interferon in the adjuvant setting – high-dose interferon alpha2b and pegylated interferon-alpha2b are cleared by FDA for that use – to improve their prospects, but this has limited efficacy in microscopic disease and also many side effects.

“Some opt to not receive it because of concerns around toxicity, but also the perception about the benefit it can provide,” Ronald Peck, global development lead for Yervoy, said in an interview prior to the ASCO meeting.

Those taking Yervoy had a 25% reduced risk of relapse compared to placebo.

Started in 2008, the study evaluated a 10 mg dose every three weeks and then a dose every three months, with a maximum treatment period of three years. In contrast, the dose approved by FDA is 3 mg every four weeks, with a total of four doses.

Head-to-head studies are not available, but O’Day said that the efficacy looks broadly similar to interferon. “It’s comparable, it’s not superior, so we need to be cautious,” he noted.

Benefits came at the cost of a 42% rate of Grade 3/4 side effects, including GI, liver, endocrine and dermatologic events, and a 1.1% treatment-related death rate (five fatalities). The rate of severe endocrine-related side effects was 8.5% and only 56% of those could be resolved. Due to the side effects, the discontinuation rate was high at 48.8% vs. 1.7% for placebo, researchers reported at the meeting. Patients tended to drop out in the first four months of the study, according to the company.

The adverse events fit the usual pattern with Yervoy, Peck said. All of them were related to mechanism-related immunologic activity of therapy, such as colitis, diarrhea and rash (Also see "Ipilimumab Boosts Survival, But With Adverse Events That Need Strict Oversight" - Pink Sheet, 6 Jun, 2010.)

The rate of treatment-related deaths (1.1%) is similar to what has been reported for interferon in this setting, Peck said.

A second Phase III study – ECOG 1609 – is now testing Yervoy against high-dose interferon in this patient population.

Bristol noted that the results from this study mark the third positive Phase III study since the pivotal trial release at ASCO in 2010 and support the company’s development strategy for the drug across a number of tumor types, different lines and settings.

During the June 2 investor event, Bristol execs said that the company is pleased with the results and will be discussing them with regulatory authorities.