Lymphocyte-activation gene 3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumour-infiltrating lymphocytes (TILs) – white blood cells that migrate to tumours attempting to kill them.
Tumours fight off the attack by stimulating LAG-3 and PD-1, causing the white blood cells to become exhausted.
The combination activates T-cells, beefing up the improved immune response and promoting tumour cell death.
Bristol-Myers Squibb made a splash ahead of the conference with results showing a single infusion of its LAG-3 blocker relatlimab and Opdivo improved progression-free survival in advanced melanoma compared with Opdivo alone.
Not to be outdone, Merck & Co countered with results from its LAG-3 favezelimab, with phase 1 data showing a combination with Keytruda could have potential in metastatic colorectal cancer.
BMS said that this is the first regimen showing a statistical benefit over PD-1 monotherapy such as Opdivo in metastatic melanoma, which has become established as standard of care in the indication in the last decade or so.
Results come from the phase 2/3 RELATIVITY-047 trial in patients with metastatic or unresectable disease.
In those receiving the combination, the median progression-free survival (PFS) was significantly longer at 10.12 months compared with 4.63 months in those receiving 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, BMS said.
Safety-wise no new signals or types of clinically important events were identified with the fixed-dose combination therapy when compared with Opdivo monotherapy.
However there were more grade 3/4 drug-related adverse events – 18.9% in the combination arm compared to 9.7% in the Opdivo arm.
Discontinuation rates were higher in the combination arm (14.6%) compared with 6.7% seen in the Opdivo arm.
BMS said that results will be used as the basis for filings with the FDA and other regulators.
Meanwhile, Merck & Co’s data from favezelimab comes from a small group of patients with metastatic colorectal cancer, showing it shrank tumours in five patients (6.3%), with one seeing their tumours clear completely.
PFS was a median of 2.1 months and overall survival was around 8.3 months, according to the trial.
PD-1 inhibitors have a low response rate in this form of cancer, working in only around a fifth of patients as their tumours aren’t easily targeted by the immune system.
MacroGenics (tebotelimab) and Novartis (LAG525) are among around 20 other companies that are researching LAG3 drugs.
The study’s primary results, which were published earlier this year, showed that the median disease-free survival doubled with nivolumab versus placebo — 22.4 months and 11 months, respectively.
New data at ASCO 2021 showed that distant recurrence was lower with nivolumab versus placebo (29% and 39%, respectively), as was locoregional recurrence (12% and 17%, respectively).
Meanwhile, Keytruda was shown to significantly improve disease-free survival when given to renal cell carcinoma (RCC) patients following surgery, according to results from the phase III KEYNOTE-564 study.
The addition of the drug as adjuvant therapy led to a 32% reduction in the risk of disease recurrence or death compared with placebo.
Adjuvant therapy seemed to be something of a theme at this year’s conference, with Roche’s PARP inhibitor Tecentriq (atezolizumab) also showing that it could improved disease-free survival by more than one-third in people with PD-L1-positive resectable early-stage lung cancer, if administered following surgery and chemotherapy.
Meanwhile, AstraZeneca and Merck & Co’s Lynparza is primed for even wider use in the treatment of breast cancer after a phase 3 trial showed it could extend the time for the cancer to return when used as adjuvant therapy.
Giving Lynparza (olaparib) to women with BRCA-positive, HER2-negative breast cancer straight after chemotherapy and surgery to remove the tumour reduced the risk of recurrence, secondary cancers or death by 42% compared to placebo after 2.5 years of follow-up.
Lynparza is already the most widely-used drug in the PARP inhibitor class, and the new results extend its lead over rivals like Clovis Oncology’s Rubraca (rucaparib), GlaxoSmithKline/Tesaro’s Zejula (niraparib) and Pfizer’s Talzenna (talazoparib).
Results of the phase 1/2 ZUMA-3 trial of Tecartus (brexucabtagene autoleucel) reported at ASCO revealed a 71% complete response rate with the CAR-T in heavily pre-treated adult patients with B-cell precursor ALL.
The median response duration was 12.8 months, while overall survival was more than 18 months for all patients in the study and had not yet been reached for complete responders.
Kymriah (tisagenlecleucel) was approved for relapsed/refractory ALL in 2017, but its label covers use in children and young adults aged up to 25, who account for the bulk of cases of the blood cancer.
Gilead/Kite have taken a different approach with Tecartus, going after an adult patient population initially, but there will be overlap between the two therapies in the young adult category. Around 40% of ALL cases occur in adults, although most occur in people aged under 20.
Kymriah achieved a complete response rate of 81% in its relapsed/refractory ALL trial – called ELIANA – with 95% of patients MRD negative.
But Novartis has an opportunity to fight back and muscle into territory held by Gilead’s other approved CAR-T Yescarta (axicabtagene ciloleucel), after hitting the mark in the phase 2 ELARA trial in relapsed or refractory follicular lymphoma (FL).
The ELARA trial revealed a 66% complete response rate and 86% overall response rate with Kymriah in this form of non-Hodgkin’s lymphoma (NHL), which accounts for around 22% of all cases of the cancer.
Yescarta was only approved by the FDA for FL in March, adding to its earlier green light in B-cell lymphoma, and Novartis now says it intends to file for approval of Kymriah in FL later this year.
However, both Novartis and Gilead may have to watch their backs in the coming years, as relative CAR-T newcomer Allogenemoves forward with its “off the shelf” rival therapy.
Tecartus is also being tested in paediatric and adolescents patients with previously-treated ALL in the ZUMA-4 study, which would put the two therapies in direct contention. However results from that aren’t due to read out until 2023, according to the entry for the study in the clinicaltrials.gov database.
Tecartus is already approved to treat relapsed/refractory mantle cell lymphoma (MCL), becoming the first CAR-T for that indication in mid-2020, and made sales of $31 million in the first quarter of this year.
It was filed for the adult ALL indication in the US in April, and has a priority review from the FDA, with a verdict due in October.
“Outcomes in adults with [ALL] are poor relative to what is observed in children, with less than half of people over 20 years of age expected to survive the illness,” said Bijal Shah of Moffitt Cancer Centre in Florida, who led the ZUMA-3 study.
Importantly, most of the responses seen with the CAR-T were associated with undetectable minimal residual disease (MRD), he added. Undetectable MRD is associated with longer remissions – and potentially longer survival – in ALL and other blood cancers.
Allogene was founded in 2018 by the former leadership team from Kite Pharma, on a mission to outdo the CAR-T therapies they had just sold to Gilead for $12 billion with drugs that could be cheaper and easier to use.
Currently-approved CAR-T therapies are autologous, meaning the the patient’s T cells are harvested and genetically modified to include a new gene that helps then target and kill lymphoma cells, and the modified T cells are then infused back into the patient.
It’s a process that can take at least a couple of weeks, and carries a risk of side effects including cytokine release syndrome (CRS), which can cause fever and flu-like symptoms and can be life-threatening. Around a quarter of patients treated with Tecartus had a severe immune reaction, and there were two deaths in the trial.
Allogene’s allogeneic or “off the shelf” cancer cell therapies, however, are derived from a bank of cells and can be manufactured and administered in bulk like drugs.
In phase 1 results released in the run-up to ASCO, the ALLO-501 lead candidate showed an overall response rate of 75% and a complete response rate 50% in a group of patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL) who had not previously received CAR-T.
The complete response rate was 36% in CAR-T naïve patients with LBCL, data described by a team of analysts at Jefferies as “solid”.
They noted that it “checks all the boxes for a compelling profile versus its autologous peers” adding that the safety profile of ’501 seems to be “clean”.
Overall key opinion leaders viewed the safety profile as “very tolerable and don’t see any outstanding risks over autologous CAR-Ts”.
Another considerable advantage of allogeneic CAR-T products is that they can be administered with a second booster shot, something that is not possible with autologous CAR-Ts.
The Jefferies analysts noted that across two studies, four patients were converted from a partial response to a complete response with the ALLO647 booster shot.
In its analysis Jefferies noted that when asked about the relative importance of attributes for non-Hodgkin lymphoma treatments, doctors prioritise efficacy and patient access.
“In comparison to autologous CAR-Ts, allo-CAR-Ts have a unique advantage in broader patient access through addressing issues such as undesirable wait time, manufacturing failure, and high production cost,” said the team led by equity analyst Kelly Shi.
In a separate note Jefferies analyst Michael Yee said that the strong data from the allogeneic therapies will prompt Gilead to expand the cancer cell therapy infrastructure it built following the acquisition of Kite.
A move into cell therapies for solid tumours, which marketed CAR-Ts cannot tackle, could be next, although continuing research into next-generation CAR-Ts could be an option.
However he added: “That said, Yescarta will also always have much longer durability (over 3 years now) and follow-up, more data and safety.”
Led by former Kite execs Arie Belldegrun and David Chang, Allogene partnered with French firms Cellectis and Servier to develop allogeneic CAR-Ts, after buying out Pfizer and taking over its role in an R&D collaboration.
The drug targets B-cell maturation antigen (BCMA) – making it part of an increasingly crowded category.
Other drugs targeting BCMA include GlaxoSmithKline’s antibody-drug conjugate (ADC) Blenrep (belantamab mafodotin) and Bristol-Myers Squibb/bluebird bio’s Abecma CAR-T therapy (idecabtagene vicleucel).
GlobalData reckons that therapies targeting BCMA now account for approximately 10% of all immuno-oncology drugs in phase 1 to 3 development, but it’s worth noting that most patients diagnosed with myeloma will relapse over the course of their disease and there is some evidence that patients who fail one BCMA-targeting therapy may still gain benefit from another.
At ASCO J&J also highlighted results for another myeloma drug, bispecific antibody teclistamab, which targets CD3 on T-cells as well as BCMA.
Updated results from the MajesTEC-1 study of teclistamab in myeloma patients treated with five prior lines of therapy showed some impressive figures, including a 40% complete response rate and 58% VGPR, that suggest a deepening effect of the drug over time.
There were also no side effects that resulted in dose cuts with teclistamab in the study, which could point to a safety advantage over rival BCMA-targeting bispecific drugs like Pfizer’s elranatamab and Amgen’s pavurutamab, which have both had studies paused this year due to toxicity concerns.
J&J also reported updated results from the phase 1 MonumenTAL-1 study of talquetamab, another bispecific antibody.
Talquetamab also binds to CD3, as well as GPRC5D, a novel multiple myeloma target
After around six months’ follow-up, talquetamab achieved an overall response rate (ORR) of 70% in the 30-patient trial, which recruited subjects who had on average received six prior lines of the therapy for their myeloma.
A sizeable chunk of J&J’s oncology pipeline is dedicated to bispecific antibodies. Like the recently-approved Rybrevant (amivantamab), alquetamab and teclistamab have arisen out of the fruitful collaboration between J&J’s Janssen pharma division and Danish biotech Genmab, which also generated its $4.1 billion myeloma blockbuster Darzalex (daratumumab).
AstraZeneca threw down the gauntlet to AbbVie and Johnson & Johnson with new data for Calquence in chronic lymphocytic leukaemia (CLL) that it says show a safety advantage over Imbruvica – currently dominating the BTK inhibitor market.
In the ELEVATE-RR study, Calquence (acalabrutinib) matched Imbruvica (ibrutinib) when it came to keeping adults with previously treated, high-risk CLL alive without disease progression at a median follow-up of 40.9 months.
Both drugs achieved a progression-free survival (PFS) of 38.4 months, but Calquence was associated with a lower rate of atrial fibrillation.
AZ needs Calquence to deliver financially, as it has invested a lot in the drug. It was originally developed by Acerta Pharma, a company in which AZ bought a majority 55% stake for $4 billion in early 2016.
Novartis’ big investment in radiopharmaceuticals for cancer seems to have paid off, after lead candidate 177Lu-PSMA-617 helped men with advanced prostate cancer and few treatment options live longer in a phase 3 trial.
New data from the VISION study showed that 177Lu-PSMA-617 on top of standard care reduced the risk of death by 38% compared to standard care alone in men with PSMA-positive metastatic castration-resistant prostate cancer (CRPC) who had progressed after three or more anti-androgen and prior chemotherapy regimens.
Novartis has been investing heavily in the radio-oncology category, with its Endocyte acquisition followed by other deals including recent licensing deals with iTheranostics and Artios Pharma.