With ASCO around the corner, perhaps (HOPEFULLY!!!) I spoke too soon about there being nothing new in the world of melanoma! However, I have been reporting on anti-LAG-3 for YEARS!!!! Here is my first report from 2014!!!! It gives a pretty good breakdown of how our immune system functions and how anti-LAG-3 may give it, especially if combined with anti-PD-1 (nivolumab/Opdivo or pembrolizumab/Keytruda), a boost - How to make anti-PD1 work better with a new player...LAG-3????
And this - ASCO 2017: Anti-LAG-3 plus nivo, for melanoma already treated with anti-PD-1/PD-L1
Now ~ This report (from Evaluate Vantage) regarding the study looking at relatlimab andNivolumab combo, noted: "Relativity-047, a trial in first-line melanoma, has yielded a 12-month progression-free survival rate only slightly below that in Yervoy/Opdivo’s corresponding Checkmate-067 study. But there is a vital advantage: severe treatment-related adverse events were 19% with the relatlimab combo – less than a third of that seen with the notoriously toxic Yervoy."
Gotta love those names, right??? Similarly, there is this from Fierce Biotech regarding the combo for melanoma:
ASCO Bristol Myers, leading the LAG-3 pack, posts phase 3 melanoma data for Opdivo-boosting relatlimab -
"Bristol Myers Squibb is no stranger to mixing checkpoint inhibitors—see the many indications approved and in development for the combination of Opdivo and Yervoy.
Now, the drugmaker is one step closer to offering a new checkpoint inhibitor cocktail for the treatment of advanced melanoma, with the first phase 3 data for a LAG-3 antibody in tandem with the PD-1 blocker Opdivo.
The combination did twice as well as Opdivo at staving off cancer progression: patients who received the combo went a median of 10.1 months before their cancer got worse, compared to 4.6 months for the patients who received Opdivo alone.
The phase 3 results, to be presented virtually at the annual meeting of the American Society for Clinical Oncology, come from more than 700 patients with metastatic melanoma who had not tried any other therapies and whose cancer could not be treated with surgery. About half of the patients received the fixed-dose combination of Opdivo and the LAG-3 antibody relatlimab, while the other half got Opdivo.
At the one-year mark, nearly half (48%) of the patients who received the combo still had not seen their cancer worsen, compared to 36% of those who received Opdivo alone. The trial hasn’t been going long enough to report how long the combination is helping patients live, but the company will present those numbers when they’re ready, said Samit Hirawat, M.D., chief medical officer at BMS.
Patients taking the combination experienced severe or life-threatening side effects at about twice the rate of patients who got Opdivo alone (18.9% versus 9.7%). Side effects led 14.6% of the combo group and 6.7% of the Opdivo group to quit the study and there were three treatment-related deaths in the combo group and two in the Opdivo group, which come out to less than 1% of patients in each group.
... That said, it’s important to note that BMS compared the Opdivo-relatlimab combination to Opdivo alone, and not to Opdivo and Yervoy.
“It’s impossible to say one is better than the other because we did not do that study,” Hirawat said.
So, where does BMS see the new combination in the spectrum of melanoma treatment?
“Currently, patients with melanoma in the firstline setting are divided into thirds: one-third gets I-O plus I-O... One-third gets single-agent I-O and one-third is without an I-O-based regimen,” Hirawat said. “So, one could say 66% of patients are undertreated to an extent because they’re not getting the best treatment available.” Though PD-1 drugs like Opdivo, Merck’s Keytruda and Roche’s Tecentriq have transformed the treatment of melanoma and other cancers, they don’t work for everyone—that’s why so many clinical trials are testing combinations to see which drugs might boost their efficacy. The hope is that adding relatlimab to Opdivo could give doctors another option to get the PD-1 blocker to work in more people.
The LAG-3 protein is an immune checkpoint receptor found on the surface of T cells. In cancer, LAG-3 expression is linked to T-cell exhaustion, which helps tumors resist PD-1 blockade. Blocking LAG-3 as well as PD-1 could reinvigorate tired T cells, allow them to regain their cell-killing function and attack cancer.
“We look forward to discussing these registrational data with health authorities to potentially bring this treatment to patients,” said Jonathan Cheng, M.D., senior vice president and head of oncology development at BMS, in a statement. If all goes well with its studies in other cancer types, such as non-small cell lung cancer and liver cancer, BMS aims to launch additional phase 3 studies of relatlimab and Opdivo in those indications toward the end of this year and early next year, Hirawat said. "
"BMS today announced results from the Phase 2/3 RELATIVITY-047 trial, which showed that the fixed-dose combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, administered as a single infusion, demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit compared to Opdivo (nivolumab) alone in patients with previously untreated metastatic or unresectable melanoma. This is the first regimen to demonstrate a statistical benefit over anti-PD-1 monotherapy in metastatic melanoma. Among patients treated with the combination, the median PFS (mPFS) was significantly longer at 10.12 months vs. 4.63 in those who received Opdivo. The PFS benefit of the fixed-dose combination was observed early, at the time of the first scan, and was consistent over time. In exploratory, descriptive analyses, the combination of relatlimab and nivolumab extended PFS regardless of pre-specified subgroups and stratification factors.
These findings (Abstract #9503), the first from a Phase 3 trial evaluating a LAG-3-blocking antibody, will be presented in an oral abstract session on Sunday, June 6, 2021, from 8:00 a.m. – 11:00 a.m. EDT during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting and have been selected for the official ASCO press program.
“LAG-3 represents a new immunotherapy target and the results of the RELATIVITY-047 study demonstrated the significant benefit of inhibiting both LAG-3 and PD-1 with the novel combination of relatlimab and nivolumab,” said Dr. F. Stephen Hodi, M.D., director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute. “With the observed efficacy and safety profile, the combination with relatlimab may provide an important new treatment option for patients with metastatic melanoma.”
The safety profile of the fixed-dose combination of relatlimab and nivolumab was manageable and consistent with those previously reported for relatlimab and nivolumab. No new safety signals or new types of clinically important events were identified with the fixed-dose combination when compared to Opdivo monotherapy. Grade 3/4 drug-related adverse events were 18.9% in the combination arm compared to 9.7% in the Opdivo arm. Drug-related adverse events leading to discontinuation were 14.6% in the combination arm compared to 6.7% in the Opdivo arm.
Lymphocyte-activation gene 3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumor infiltrating lymphocytes (TILs) and contribute to tumor-mediated T-cell exhaustion. Combination therapy with relatlimab, a novel LAG-3-blocking antibody, and nivolumab, a PD-1 inhibitor, enables T-cell activation, leading to the initiation of an improved immune response and promoting tumor cell death.
Relatlimab (in combination with nivolumab) is the first LAG-3-blocking antibody to demonstrate a benefit for patients in a Phase 3 study. It is the third distinct checkpoint inhibitor (along with anti-PD-1 and anti-CTLA-4) for Bristol Myers Squibb.
“Bristol Myers Squibb is a pioneer in the development of immunotherapy combinations in melanoma. As the global incidence of melanoma has continued to increase, we have leveraged our deep insight into the interplay between tumors and the immune system to develop a novel immunotherapy combination,” said Jonathan Cheng, senior vice president and head of oncology development, Bristol Myers Squibb. “The RELATIVITY-047 data provide evidence that a LAG-3-blocking antibody coupled with nivolumab may bring the benefits of dual immunotherapy to more patients and address a remaining need in this space. While there have been significant treatment advances and long-term survival benefits provided by checkpoint inhibitors over the years, there remain patients with metastatic melanoma who could benefit from another innovative approach. We look forward to discussing these registrational data with health authorities to potentially bring this treatment to patients.”
Globally, the incidence of melanoma has been increasing for the last 30 years. The World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths.
Bristol Myers Squibb thanks the patients and investigators involved in the RELATIVITY-047 clinical trial. The company has several ongoing trials evaluating combination use of relatlimab for the treatment of additional cancers.
About RELATIVITY-047 (CA224-047)
RELATIVITY-047 (CA224-047) is a global, randomized, double-blind Phase 2/3 study evaluating the fixed-dose combination of relatlimab and nivolumab in patients with previously untreated metastatic or unresectable melanoma versus Opdivo alone. The primary endpoint of the trial is progression-free survival (PFS) by Blinded Independent Central Review (BICR) and the secondary endpoints are overall survival (OS) and objective response rate (ORR). A total of 714 patients were randomized 1:1 to receive a fixed-dose combination of relatlimab 160 mg and nivolumab 480 mg or Opdivo 480 mg by intravenous infusion every four weeks until disease recurrence, unacceptable toxicity or withdrawal of consent. Follow-up for the secondary endpoints of OS and ORR is ongoing and the Company remains blinded.
About LAG-3
Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule expressed on effector T cells and regulatory T cells (Tregs) and functions to control T-cell response, activation and growth. Preclinical studies indicate that inhibition of LAG-3 may restore effector function of exhausted T cells and potentially promote an anti-tumor response. Early research demonstrates that targeting LAG-3 in combination with other potentially complementary immune checkpoints may be a key strategy to more effectively potentiate anti-tumor immune activity.
Bristol Myers Squibb is evaluating relatlimab, its LAG-3-blocking antibody, in clinical trials in combination with other agents in a variety of tumor types."
My take: It seems that the combination of relatlimab and nivolumab (Opdivo) has a response rate that is slightly less than that of the ipi/nivo (Ipilimumab/Yervoy and Nivolumab/Opdivo) combo which has proven to be around 50+ percent, but one that is possibly better than the 40% response rate when anti-PD-1 (nivo or pembro) is used alone. Perhaps the two most important things these (still preliminary - after all these years) reports tell us is that ~
1. Side effects, that can be so devastating and difficult in the ipi/nivo combo may be much decreased in the relatlimab/nivo combo.
2. For reasons we don't fully understand, melanoma responds differently to the same treatment in different folks. For me, thus far, nivolumab alone was 100% effective. Obviously that is not the case for most melanoma patients. So having another effective immunotherapy combination, that may well be far less than 100% effective in all of us, may still be completely effective in some.
And, finally, as ever - the drug company did not see fit to configure the trial such that the new combo went up against the old one directly. Why not BMS? Why not???? Why not three arms? One with nivo alone. One with the ipi/nivo combo? And the third with relatimab/nivo? WHY???
AND NOW - Colon cancer alert - Cause, you know? Nothing like having a foot in the door of 2 deadly cancers to keep you on your toes!
There is also this, regarding anti-LAG-3's use in colon cancer, this time combining Merck's version - favezelimab with Keytruda (pembrolizumab) ~ A report from Fierce Biotech states:
"PD-1 inhibitors work well in about one-fifth of patients with colorectal cancer, but the other 80% are not so lucky. Their tumors are immunologically “cold,” meaning they don’t respond to immunotherapies like Merck’s Keytruda.
Enter favezelimab, Merck’s LAG-3-targeting antibody, which helped Keytruda make a dent in metastatic colorectal cancer in very sick patients with microsatellite stable tumors. The phase 1 data will be presented virtually at the annual meeting of the American Society for Clinical Oncology next month. The combination is poised for a phase 3 study in the same type of colorectal cancer.
The combination, given to 80 patients whose cancer had worsened despite trying two other treatments, shrank tumors in five patients (6.3%), one of whom saw their tumors cleared completely. The treatment kept cancer progression at bay for a median of 2.1 months and helped patients live a median of 8.3 months—on par with the six- to nine-month range the investigators had cited in the study abstract.
However, the combination did better in a group of 36 patients whose tumors expressed high levels of PD-L1, as measured by the Combined Positive Score, or CPS. It shrank tumors in 11.1% of patients and helped patients live a median of 12.7 months. After one year of treatment, 51% of these patients were still alive, compared with 40.8% in the overall combo group.
That 11.1% may seem low, but it’s an improvement on the 0% Merck would expect had the patients taken Keytruda alone, said Eric Rubin, M.D., senior vice president of global clinical oncology at Merck Research Laboratories. Because immunotherapies don’t work in this patient group, they rely on chemotherapy and, later on, tyrosine kinase inhibitors. Cancers can develop resistance against the latter, underscoring the need for more treatment options.
“The data are limited, but it does look like PD-L1 staining is predictive for efficacy in this combination. Like any biomarker, it’s not perfect, but I think it identifies a patient population that is more likely to benefit from this treatment,” Rubin said. It will come in handy down the line when Merck starts designing registrational studies for the combination, he added.
Of the 20 patients who received favezelimab alone, none responded to treatment, which was “not terribly surprising” given what Merck has seen in its earlier research.
Side effects struck patients in the monotherapy and combination groups at similar rates: 65.0% and 65.2%, respectively. Slightly more patients who received the combination suffered severe side effects (20%) compared with those who received favezelimab alone (15%).
The most common side effect for the combination was fatigue, affecting 16.9% of patients, while the most common side effects for the LAG-3 drug alone were fatigue and nausea, hitting 20% and 15% of patients, respectively.
Merck and other companies are developing LAG-3 antibodies to make PD-1 blockers like Keytruda work in more people.
“When you look at preclinical models in patients exposed to anti-PD-1s, the LAG-3 pathway is upregulated, suggesting that it might be a compensatory pathway for tumors to evade anti-PD-1 treatments,” Rubin said.
Like PD-1, LAG-3 is an immune checkpoint receptor that acts as a “brake” to stop T cells from attacking tumors. In cancer, LAG-3 expression is linked to T-cell exhaustion, which helps tumors resist PD-1 blockade. Blocking LAG-3 as well as PD-1 could reinvigorate tired T cells, allow them to regain their cell-killing function and attack cancer.
Fevezelimab isn’t the only checkpoint inhibitor that Merck is combining with Keytruda. In September, the company presented data at the annual meeting of the European Society for Medical Oncology showing that Keytruda, along with its TIGIT-blocking antibody vibostolimab, shrank tumors in 29% of patients with non-small cell lung cancer. That combo did even better—as expected—in a subset of patients whose tumors expressed high levels of PD-L1, shrinking tumors in nearly half (46%) of them."
Anti-LAG-3, in at least some of it's machinations! The more you know. Be well. ~ c
Thanks to you I keep my doctor's on their toes. Already let them know I want that ctDNA test prior to dc of tx. All this is so very helpful in navigating through the storm waters. Never would know these options without your investigations. As always, huge gratitude to you.
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