Will the perioperative NSCLC data aid in patient selection or bring out a winner?
Following FDA approval of KEYTRUDA (Ph3 KEYNOTE-671), filing acceptance of OPDIVO (Ph3 CheckMate-77T) and positive data from IMFINZI (Ph3 AEGEAN) in perioperative NSCLC, this year’s ASCO sees key players unsurprisingly delve into trial outcomes stratified in exploratory sub-analyses and HRQoL, in an effort to bolster respective value propositions to physicians.
The presentation titles from key perioperative lung trials at ASCO 2024 do little to move the dial in favor of an individual drug but will address key issues surrounding patient selection. While the absence of standardized guidelines continues to fragment the treatment pathway for early-stage patients, these data will ensure that patients with chances of maximum response receive the appropriate treatment. Despite the promise of perioperative approaches, barriers remain such as concerns of overtreatment at such an early stage with immunotherapy, coupled with the lack of long-term follow-up data. Till the field experiences another paradigm shift, neoadjuvant approaches such as the “practice-changing” CheckMate-816 (4-year follow-up data at ASCO) will ensure OPDIVO’s foothold in the setting [1,2,3].
What is stopping AI from improving patient outcomes?
With the radical explosion of AI applications across industries, the technology is taking centre stage in the oncology space as well. Evidently, Microsoft’s talk, “The Emergence of General Artificial Intelligence for Medicine,” has been included as part of the ASCO Opening Session.
AI-powered diagnostic tools hold the potential to remove subjectivity, drive standardization in data interpretation, and detect novel biomarkers, thereby facilitating enhanced personalized treatment approaches across a range of indications, including prostate, breast, and GI cancers.
While AI is here to stay, the lack of established guidelines and regulatory hurdles continues to delay mainstream clinical adoption of these tools. Data on their clinical validation could instil some confidence in the HCPs, but will it be sufficient to drive the adoption of these technologies? It is imperative to set up channels of continuous conversation with the view of driving adoption in future by the HCPs [4].
Carvykti continues to climb the line of Multiple Myeloma therapy ladder but is there enough space at the top? [5]
Following the success of JNJ’s Carvykti, a BCMA-targeted CAR-T therapy, in later lines of multiple myeloma (MM), several Phase 3 trials are evaluating CAR-T therapies in earlier lines of therapy, tapping into a major commercial opportunity. Recently, Carvykti’s ground-breaking approval in 2L+ BCMA-positive RRMM made it the “first and only” CAR T-cell therapy approved in such early settings of treatment [6].
Legend and Johnson and Johnson continue to conduct multiple Phase 3 label-expansion studies, along with the Phase 2 CARTITUDE-2 trial, to move Carvykti up the MM treatment algorithm. The multicohort CARTITUDE-2 trial so far has demonstrated initial PoC for Carvykti in 2-4L MM (cohorts A and B) and for sequential use of multiple BCMA-targeted treatments in RRMM patients (cohort C) [7,8]. Data to be presented at ASCO 2024 will focus on Cohort D, patients with newly diagnosed MM, providing a first-ever sneak peek into the efficacy and safety of a CAR T-cell therapy in the 1L settings9.
In addition to Carvykti’s success, J&J continues to grow its MM empire, following the accelerated approval of Tecvayli (bsAb) for MM patients who have received at least four prior lines of therapy. The sequencing of BCMA-targeted agents will emerge as a key focus for the clinical community with the increasing adoption of BCMA CAR-T and bispecifics, necessitating comprehensive discussions in this novel area.
Will Astellas’ zolbetuximab open novel avenues for biomarker-driven therapies in gastric cancers? [10]
Whilst unlikely to be significantly different from previous analyses, the final OS data for zolbetuximab + chemotherapy will be important in determining uptake for the novel combination following potential approval in HER2- CLDN18.2+ advanced gastric/ GEJ adenocarcinoma patients. Based on previously presented biomarker data, the potential HER2-, CLDN18.2+ patient segment (tumor cell ≥75% by IHC using the VENTANA CLDN18 (43-14A) RxDx assay) is ~44%, representing a sizable patient population11,12. The future is bright for anti-CLDN18.2 assets, with interest in immunotherapy combinations and their potential in HER2+ patients.
However, Keytruda’s all-comers’ approval, will pose a new challenge for physicians around biomarker sequencing and treatment choice between immunotherapy or zolbetuximab regimens.
Is CDK4/6i recycling the new frontier in breast cancer? [13]
The first large company-led trial, postMONARCH being led by Lilly is investigating CDK4/6i sequencing in breast cancer. It will provide the much-awaited evidence on the possibility of continuing with a CDK4/6i after progression and further delaying chemotherapy.
Following progression on 1L CDK4/6i + aromatase inhibitor (AI) in advanced/metastatic breast cancer (adv/mBC), patients are rechallenged with 2L VERZENIO + fulvestrant (FULV), thereby testing whether a “double switch” of CDK4/6i and endocrine backbone, shows benefit. This follows results from smaller PI-led trials supporting that a “double switch” may indeed be the way forward, with the positive Ph2 MAINTAIN (2L KISQALI + FULV) against the negative Ph2 PACE and Ph2 PALMIRA (2L IBRANCE + FULV) trials, with most patients progressing from 1L IBRANCE + AI.
Notably, postMONARCH will also assess whether VERZENIO + FULV in 1L adv/mBC continues to offer a benefit following progression on VERZENIO + AI in the early setting, potentially maximizing the time of patients on this foundational option while endowing an additional competitive edge to VERZENIO within the CDK4/6i class.
Can MRD be the next patients-selection tool? [14]
Clinical investigation of ctDNA-based technology for early diagnosis / faster detection of cancer relapse is increasingly picking momentum. Several abstracts will showcase the utility of MRD testing to identify patients who will draw increased benefits from treatment across different lines of intervention, across solid and heme tumours.
Of particular note are the initial MRD data from the Ph3 ADAURA trial which led to the US approval of Tagrisso in adjuvant NSCLC with EGFR exon [19] deletions or exon [21] L858R mutations [15]. These data will add to existing evidence from BMS’ CheckMate-8 [16], Roche’s IMpower010 trials demonstrating how a minimally invasive, patient-friendly blood draw could influence treatment selection in early-stage NSCLC.
In the rapidly evolving treatment landscape of early-stage NSCLC, where newly identified biomarkers are leading to increasing patient segmentations, identification of better responders through ctDNA analysis will enable early intervention, accurate treatment selection and improved survival outcomes.
Could Pfizer’s EZH2i be the solution to lack of MDTs in community settings for Prostate Cancer treatment? [16]
This data will likely build off the previously presented data, which highlighted substantial rPFS benefits (17.1 months), comparing favorably to NVS’ Pluvicto’s pivotal data (rPFS: 12 months) [17]. Being part of its prioritized oncology pipeline, Pfizer intends to initiate two Ph3 pivotal trials in 1L and 2L CRPC to establish the EZH2i as the SoC alongside its flagship PC asset, Xtandi18. The presentation of the additional Ph1 dataset at ASCO 2024 and its well-established prostate cancer field relationships will lend Pfizer community interest and support in the novel MoA.
With the CRPC early-stage landscape becoming increasingly crowded with numerous companies attempting to break in with complex therapies (radioligand therapies, T-cell engagers and ADCs), Pfizer’s small molecule inhibitor could represent a much-needed, all-comers approach that could potentially become the treatment of choice, particularly in community settings where MDTs are seldom available.
Blenrep – initiating a comeback campaign in Multiple Myeloma? [19]
GlaxoSmithKline’s ADC belantamab mafodotin (Blenrep) achieved notable recognition as the first BCMA-targeted therapy to garner accelerated approval in 5L relapsed/refractory multiple myeloma (RRMM). However, in 2022, following the failure of the confirmatory Phase III DREAMM-3 trial, it was withdrawn from the US market. Furthermore, in Sept 2023, EU authorities recommended not renewing Blenrep’s conditional marketing authorization.
The prospects of Blenrep are significantly hinged on the outcomes of the two remaining Phase III trials, including DREAMM-8 which recently showed positive topline data. While GSK expects DREAMM-8 data to support regulatory submissions to the US authorities, the likely positioning of Blenrep within the MM treatment paradigm is still unclear, especially regarding the use of CAR-T and bispecifics ahead of Blenrep, and due to its challenging ocular toxicity profile. The unveiling of complete data at ASCO 2024 will seal the final deal on Blenrep’s fate.
Is there any hope left for PARP inhibitors in ovarian cancer? [24,25]
AstraZeneca’s Ph3 ongoing trial investigating IO and PARPi combinations, DUO-O has demonstrated promising data in advanced ovarian cancer. However, with the recent FDA withdrawals of approvals of several PARPi’s, including that of Clovis Oncology, AstraZeneca and GSK’s flagship assets, has shrouded great concerns regarding the use of PARPi’s due to safety concerns.
It is unequivocal that the use of PARPi’s in ovarian cancer needs to be heavily regulated and restricted, the question remains whether there is any significant market opportunity left for this drug class?
As we close-in on the biggest oncology event of the year, we are excited to see the data releases on 20th May and how it may reshape our understanding of cancer treatment. Is there any session that has caught YOUR attention?
Sources:
1] Abs. LBA8007: Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: Results from the phase 3 CheckMate 77T study
2] Abs. 8011: Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): An exploratory subgroup analysis of AEGEAN
3] Abs. 8012: Health-related quality of life (HRQoL) outcomes from the randomized, double-blind phase 3 KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC)
4] ASCO Opening Session – ‘The Emergence of General Artificial Intelligence for Medicine’
5] Ab7505: Efficacy and safety of ciltacabtagene autoleucel ± lenalidomide maintenance in newly diagnosed multiple myeloma with suboptimal response to frontline autologous stem cell transplant: CARTITUDE-2 cohort D
6] Caryvykti receives FDA approval for 2L+ MM; JnJ PR Apr 2024
7] J. Hillengass, et al. Blood, Nov 2023
8] CARTITUDE-2 Cohort C results; JnJ PR Oct 2023
9] CARTITUDE-2 Cohort D study design; JnJ PR May 2024
10] Abs 4036: Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
11] J.A. Ajani et al. LBA 182, ESMO 2023
12] K. Shitara et al. Abs. 4053, ASCO 2023
13] LBA1001: Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial.
14] Abs 8005: MRD analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFRmutated stage IB–IIIA NSCLC
15] Tagrisso receives FDA approval as adjuvant therapy; FDA PR Dec 20202
16] Abs. 5061: Phase 1 trial of mevrometostat (PF-06821497), a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in castration-resistant prostate cancer (CRPC).
17] PhIII PSMAfore trial meets primary endpoint of rPF; Novartis PR Oct 2023
Pfizer Oncology Innovation Day 2024
18] LBA105: Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM)
19] GSK initiates Blenrep withdrawal from the US markets. GSK PR Nov 2022
20] Updated results from Blenrep’s DREAMM-3 trial. GSK PR Nov 2022
21] EMA recommends non-renewal of authorisation of Blenrep; EMA PR, Sep 2023
22] Positive results from PhIII DREAMM-8 trial for Blenrep, GSK PR Mar 2024
23] Abs. e17542: Overall survival in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance: Real-world data of the C-PATROL study
24] Abs. e13102: Ethnic and clinical differences in gBRCA and HRD mutated breast and ovarian cancers and their response to PARP inhibitors
Authors: Neil Saptarshi, Katherine Sung, Cecilia Boz, Maria Zygouropoulou, Heather Baldie, Jamie Mitchell, Emanuela Carollo, Sarah Macklin, Moyin Aiyelabola, Byron Ritson, Anamika Ghosh