PD-1 Progress May Shorten The Life Of Other Drugs

With PD-1 immunotherapy continuing to make gains in melanoma, will Yervoy and targeted BRAF/MEK combos from Novartis, Roche and Array BioPharma get relegated to second-class status?

The latest round of immunotherapy data presented at ASCO unseat Yervoy monotherapy from its pioneering position in treatment-naive metastatic melanoma, experts say, and could also mean that targeted BRAF/MEK combinations will finally lose the battle for the front line in this indication.

Results from Bristol-Myers Squibb Co.’s CheckMate 067 study, which tested its CTLA-4 inhibitor Yervoy (ipilimumab) in combination with the company’s PD-1 inhibitor Opdivo (nivolumab) against Yervoy monotherapy or Opdivo monotherapy in first-line melanoma, had a high profile at the recent American Society of Clinical Oncology annual meeting (Also see "Opdivo/Yervoy Data Show Role For Checkpoint Combos; ASCO Debates Biomarkers" - Pink Sheet, 1 Jun, 2015.).

The combination performed best in terms of response rate and median progression-free survival, though the improvements came at the cost of a very much higher rate of Grade 3 and higher side effects (55% vs. 16.3% for Opdivo and 27.3% for Yervoy). Overall survival data are not yet mature. Nevertheless, the data helped build the case that combination use or Opdivo alone might yield better options than Yervoy.

FDA accepted a filing for the combination in June and a swift approval is likely, even ahead of the Sept. 30 user fee date. Yervoy is also under review for a monotherapy indication in adjuvant melanoma.

Yervoy is no longer the standard of care for first-line melanoma, Atkins says.

Discussing the CheckMate 067 results at ASCO, veteran immunotherapy researcher Michael Atkins, Georgetown-Lombardi Comprehensive Cancer Center, declared that Yervoy is no longer the standard of care for first-line melanoma. The results, he said, clearly show that Opdivo plus Yervoy is superior to Yervoy alone, and that Opdivo is superior to Yervoy monotherapy, he said. It’s also likely that the Yervoy/Opdivo combination is superior to Opdivo alone; “however it behooves us to wait for the critical survival data before making this statement definitive,” he said.

Two PD-1 inhibitors are already approved for relapsed metastatic melanoma, Merck & Co. Inc.’s PD-1 inhibitor Keytruda (pembrolizumab) and Bristol’s Opdivo, and National Comprehensive Cancer Network guidelines have already incorporated PD-1 inhibitors as preferred options for first-line melanoma, regardless of the presence of BRAF mutations.

The focus on immunotherapy at ASCO eclipsed presentations for therapies targeted at people with BRAF mutations, which are present in 40%-50% of melanomas. BRAF inhibitors have demonstrated very high response rates, withering tumors quickly, and approval for use with MEK inhibitors had generated high levels of excitement.

Updated data from pivotal trials were presented at the meeting for BRAF/MEK combinations from Roche– Zelboraf/cobimetinib – and Novartis AG’s Tafinlar/Mekinist (Also see "GSK Overall Survival Data Clinches Role For BRAF/MEK Combo In Melanoma" - Pink Sheet, 24 Oct, 2014.). Array BioPharma Inc. presented Phase Ib/II data for its encorafenib/binimetinib BRAF/MEK combo, which it thinks has a differentiated safety profile, with lower rates of pyrexia and photosensitivity.

Key Efficacy Results For BRAF/MEK Combos
Trial	ORR	PFS	OS
COMBI-d Phase III study of Novartis’ Tafinlar/Mekinist vs. Tafinlar (n=423)	69% for combo vs. 53%	11 months vs. 8.8 months (HR 0.67).	25.1 months for combo vs. 18.7 months; one-year OS for combo 74%, two-year OS 51%
coBRIM Phase III study of Roche’s Zelboraf/cobimetinib vs. Zelboraf (n=495)	69.6% for combo vs. 50%	12.25 months vs. 7.2 months (HR 0.58)	Trend toward OS benefit, OS at 9 months 81%; final analysis at end-2015
Phase Ib/II single-arm study of Array’s encorafenib/binimetinib (n=97)	74.5%	Median 11.3 months	Not available

Another Changing Of The Front-Line Guard

There are no head-to-head data testing PD-1 inhibitors against BRAF/MEK, so cross-trial comparisons and drug profiles will be used to guide practice.

Investigators presenting results from Novartis’ COMBI-d study, showing the combination improved survival vs. BRAF alone, proclaimed Tafinlar/Mekinist as the targeted therapy standard of care for first-line treatment of BRAF+ melanoma patients

And, in a June 2 note on Novartis, UBS Securities analyst Alexandra Hauber concluded that while the “major buzz at the meeting” was around immuno-oncology, the survival data from COMBI-d are “very competitive with I-O.”

The median overall survival for the combination was 25.1 months, and the one-year OS rate was 74%, which is the exact same as the one-year survival rate for Keytruda in the KEYNOTE-006 study, Hauber observed. A plateau in the survival curve seen with BRAF/MEK was “intriguing,” but may be due partly to post-progression treatment with immunotherapy, she acknowledged.

Melanoma Research Foundation Executive Director Tim Turnham was also impressed with OS in the 25-month range and said that he believes that that there is still room for a personalized approach, taking into account, for example, whether a patient has had prior auto-immune disease. Everyone’s enthused about immunotherapy, he said, but there still is a role for BRAF/MEK. “We just have to be careful to remember the full spectrum of things in the armamentarium,” Turnham said.

PD-1 Has Upper Hand

Yervoy was groundbreaking upon approval for metastatic melanoma in 2011, as was Zelboraf, approved for BRAF mutant-positive patients the same year. There was much discussion at the time about which should be used first, as the immunotherapy had long-lasting effects but the BRAF inhibitor had bigger, faster responses (Also see "Front-Line Of Melanoma Market Could Be Marketing Battle" - Pink Sheet, 13 Jun, 2011.). And it wasn’t long before it was discovered that in BRAF+ patients, BRAF combined with MEK could provide longer responses with better management of certain side effects of interest, introducing a new standard of care (Also see "GSK’s Mekinist/Tafinlar Combo Pushes The Price Bar" - Pink Sheet, 9 Jan, 2014.).

GlaxoSmithKline PLC’s introduction of the BRAF/MEK combo Tafinlar and Mekinist has put a damper on sales for Zelboraf, which saw a decline of 12% in 2014 (see table). Roche’s combination of Zelboraf with the MEK inhibitor cobimetinib, partnered with Exelixis Inc., is now under FDA review with an Aug. 11 user fee date.

Sales For New Melanoma Drugs: Trajectories Subject To Change
Sponsor & Drug	FDA approval	2014 Sales	Change vs. 2013	Q1 2015 Sales	Change vs. Q1 2014
Bristol’s Yervoy	March 2011	$1.3 billion	+36%	$325 million	+20%
Roche’s Zelboraf	August 2011	$325 million	-12%	$59 million	-25%
GSK’s Tafinlar*	May 2013	$211 million	+ >100%	Not reported	Unavailable
GSK’s Mekinist*	May 2013	$106 million	+ >100%	Not reported	Unavailable
Merck’s Keytruda	September 2014	$55 million	N/A	$83 million	N/A
Bristol’s Opdivo**	December 2014	$1 million (8 days on market)	N/A	$40 million	N/A
*Tafinlar/Mekinist combination approved in January 2014. Novartis now owns rights to both drugs. **Opdivo received a second approval in lung cancer in March 2015

Attention more recently has shifted to programmed death checkpoint immunotherapies, which are far better tolerated than Yervoy. In the first-line CheckMate 067 study including Opdivo and the KEYNOTE-006 study of Keytruda the Grade 3-5 adverse event rates for monotherapy in first-line melanoma were under 17%.

Response rates for the three BRAF/MEK combinations are high at about 70%, but the all-cause Grade 3/4 event rate has been in the 50% range in some pivotal studies.

In an interview at the meeting, Steven O’Day, director of immuno-oncology at the John Wayne Cancer Institute, suggested that one possible outcome is that the PD-L1 biomarker could be used to determine who gets more aggressive treatment with the combination of Opdivo/Yervoy vs. Opdivo alone. In CheckMate 067, patients who had high PD-L1 expression did as well with Opdivo monotherapy as with the combination.

For patients who are BRAF+, the first choice would be immunotherapy, which works well regardless of mutation status, and not targeted therapy, in his view.

“The durability of these immune responses – particularly this new combination data – would suggest that we are going to heavily weight to starting if at all possible with immunotherapy and [using] the BRAF/MEK combination therapies as salvage treatments down the road,” O’Day commented.

An exception would be the small group of patients that truly need a response very quickly. Those patients will still be offered BRAF and MEK drugs up front. But, by and large if there is a little bit of time to work, because of the durable, long-term responses being seen, “most melanoma experts want to start with the immune drugs first,” O’Day said.

In addition to durability of response, he also thinks the adverse event profiles favor use of PD-1 over targeted therapy.

Memorial Sloan Kettering oncologist Paul Chapman agrees that the adverse event profiles favor PD-1. Chapman also noted that the shift toward using immunotherapy first regardless of mutation status is already happening in the academic setting and the growing awareness of PD-1 means the transition is likelier to happen in the community, with BRAF/MEK moving to a second-line role.

In the community setting, there was more reluctance to use Yervoy due to the toxicities and challenges of managing treatment, Chapman and other experts agree. Kantar Health survey data support anecdotal commentary about greater use of Yervoy by academic compared to the community oncologists. The consultancy estimates that across the board, about one-quarter of BRAF+ patients receive BRAF/MEK for first-line melanoma (see sidebar).

In an interview after the meeting, Atkins said that he expects academic centers will shift to the Yervoy/Opdivo combination for first-line melanoma through research protocols, until the combination is approved, and community oncologists will favor PD-1 inhibitors in first-line melanoma.

It’s unclear whether it would be better in mutation-positive patients to try BRAF/MEK first followed by Yervoy/Opdivo after progression, or Yervoy/Opdivo followed by BRAF/MEK at the time of progression. During the ASCO plenary, Atkins said that a study funded by the National Cancer Institute will soon get under way to test these regimens head-to-head.

Another unanswered question is whether BRAF/MEK could be folded into a triplet combination with PD-1/L1, as a means of boosting duration of response.

Genentech has a Phase I study ongoing of Zelboraf, cobimetinib and its PD-L1 inhibitor atezolizumab (MPDL3280A) ongoing in V600E mutation-positive advanced melanoma. A separate Phase I study is evaluating atezolizumab and cobimetinib in combination across solid tumors, including advanced melanoma.

In the “grand scheme of things” Roche’s PD-L1 inhibitor will likely be the “anchor” of its future melanoma sales, possibly with Zelboraf or a Zelboraf/cobimetinib combo added to it, Morningstar analyst Karen Anderson commented.

“Pure BRAF/MEK combos, even Novartis’ lead combo, face competitive threats from immuno-oncology drugs and future combos,” the analyst said.

Results from a triple combination Phase I study of AstraZeneca PLC’s PD-L1 inhibitor MEDI4736 with Novartis’ Tafinlar/Mekinist in patients who were allowed to have had prior immunotherapy in the adjuvant and metastatic setting were presented at ASCO. Investigators reported that the triple combination was well-tolerated and feasible. BRAF+ patients taking the combination had an ORR of 69%, with response lasting 7.7 months.

Mirabaud Securities analysts commented in a June 1 note that the results sound good unless you consider the results for Novartis’ BRAF/MEK combination (70% ORR, OS 25.1 months).

“It remains to be seen, in our view, whether MEDI4736 adds to survival over and above that achieved with combined BRAF/MEK inhibition. The hope would be that immune cell activation on MEDI4736 would kill malignant cells, held in check by the pathway inhibitors, but there is no indication, yet, that this is the case,” Nick Turner said.