Gastric Cancer Highlights
Positive readout shared in February 2023 ESMO plenary showed significant improvement in mPFS and mOS in pembrolizumab + chemotherapy vs. chemotherapy alone; 6.9 months vs. 5.6 months and 12.9 months vs. 11.5 months respectively
Emergence of CLDN18.2 biomarker, as zolbetuximab, an investigational therapy for high CLDN18.2 expressing gastric cancers, is expected to provide additional treatment options for biomarker positive 1L gastric cancer patientsTopic 1: TNBC
Gastric
Gastric cancer patients will have multiple IO options available in 1L
A positive readout for KEYNOTE-859 (pembrolizumab + chemotherapy) at ESMO virtual plenary in February 2023 showed statistically significant and clinically meaningful improvement in mPFS from 5.6 months on chemotherapy (FP or CAPOX regimen) to 6.9 months with pembrolizumab + chemotherapy. CheckMate-649 study presented 3 -year follow up data at ASCO GI 2023 showing mPFS of 6.1 months on chemotherapy vs. 8.3 months on nivolumab + chemotherapy. The KOL sentiment on 20% survival at 36 months for patients treated with nivolumab has been ‘amazing’; and pending pembrolizumab approval, both therapies are expected to continue to provide benefit to 1L patients.
Amazing for this disease to see that 20% of patients survived from CheckMate-649 at 36 months – US KOL
CPS and MSI status may help identify patients that are likely to benefit from IO therapies
Most major 1L IO clinical trials have incorporated Composite Positive Score (CPS) for subgroup analysis and KOLs have relied on this as a metric for informed decision making. While CPS <5 patients remain a space of unmet need, other biomarkers, such as MSI, may offer hope to those patients. KEYNOTE-859 data, for example, was especially promising for MSI-H patients (HR: 0.34) compared to non-MSI-high patients (HR: 0.79).
While it is easy to understand the importance of implementation of these testing strategies in determining patient treatment, the real-world uptake of the biomarker testing has historically been underwhelming in most tumor types, and similar outcomes may be observed in gastric cancer as well. Further, biomarker testing will also highlight the gastric cancer patient population with high unmet needs.
[On KN-859] For CPS≥ 1 and CPS <10 patients, information is needed for informed decision-making… also we need better options for CPS<1. – US KOL
Phase III clinical trial results support the role of CLDN 18.2 as an actionable biomarker in gastric cancer
Zolbetuximab is a first-in-class therapy for 1L patients with high CLDN18.2 expression and has been evaluated in two separate trials in combination with two chemotherapy regimens: mFOLFOX6 (SPOTLIGHT) or CAPOX (GLOW).. At ASCO GI, SPOTLIGHT trial readout showed an improvement of mOS from 15.5 months with mFOLFOX6 alone to 18.2 months with zolbetuximab + mFOLFOX6, and received favorable feedback from the KOLs.
Zolbetuximab will provide a personalized treatment option for 1L gastric patients, particularly patients who have low PD-L1 expression (CLDN18.2 and PD-L1 co-expression is only limited to 13% of the HER2 negative patients).
Once zolbetuximab gets approved, we will be using this agent…the presence of CLDN18.2 helps us personalize therapy much better – US KOL
Pancreatic Cancer Highlights
Positive readout of NAPOLI-3 trial at ASCO GI 2023 opened discussions regarding real-world uptake of nanoliposomal irinotecan (nal-iri)
Positive results from sotorasib in targeting KRAS G12C patients have generated enthusiasm in testing agents targeting other KRAS mutations
In PDAC, novel agents including biologics such as antibody drug conjugates (ADCs), and monoclonal antibodies (mABs), cell therapies, tumor treating fields (TTF), and targeted therapies are generating mixed responses from the KOLs
Pancreatic
NALIRIFOX will become an additional treatment option for PDAC patients
The NAPOLI-3 trial testing NALIRIFOX regimen against gemcitabine+nab-paclitaxel in 1L pancreatic cancer showed a positive readout at ASCO GI 2023. While NALIRIFOX showed a clinically meaningful improvement in both the mPFS and the mOS over gem/nab-paclitaxel, the major value driver for NALIRIFOX is expected to be its superior toxicity profile. In NAPOLI-3, NALIRIFOX showed a higher incidence of GI toxicities in comparison to gem/nab-pac that predominantly showed hematologic toxicities. On the other hand, FOLFIRINOX has historically been related to neuropathic toxicities, with KOLs being mindful of these toxicities while treating patients. Consequently, NALIRIFOX is expected to be added to the armamentarium of treatment options approved and recommended for PDAC patients.
I think toxicity is a major issue. The less neurotoxicity, and hematologic toxicity as well is a big advantage [of NALIRIFOX] over FOLFIRINOX. We know how to manage GI toxicity and select the right patients.” – EU KOL
Results from trials targeting KRAS mutations are eagerly anticipated
KRAS mutations including but not limited to G12C, G12D, and G12V are collectively found in >90% of the PDAC tumors. The approval of KRAS G12C inhibitors, sotorasib and adagrasib have opened new dimensions for treatment of KRAS mutated tumors.
While G12C is only found in 1-2% of PDAC tumors, recently published results in NEJM showed a significant benefit from sotorasib to this patient population. Several trials have been initiated since 2021 that are evaluating either specific KRAS mutations (G12D, G12V, and G12C) or pan-ras inhibition as treatment options for the PDAC patients.
Interim data from these trials are eagerly anticipated by the KOLs due to the large patient population that could be benefit from these therapies.
“The clinical activity of sotorasib against the KRAS p.G12C mutation should invigorate efforts aimed at the design and development of inhibitors relevant to the forms of KRAS mutations that are more common in PDAC.” – Strickler et al, NEJM, 2022
Cell therapies demonstrate benefit to heavily pretreated PDAC, though patient eligibility may restrict benefit to a small population
The triplet immunotherapy regimen in the Immunity Bio’s Nant Cancer Vaccine (NCV) has been delivering robust survival benefit in late line metastatic PDAC. The QUILT-88 trial is evaluating low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (IL-15 superagonist), and an allogeneic PD-L1-targeted high-affinity NK cell (PDL1 t-haNK) infusion in 3L+ mPDAC. Results presented at ASCO GI 2023 showed that NCV almost doubled mOS vs historical OS of 3 mo in this patient population. Based on the positive readout of the Phase II trial, the company has been in talks with the FDA regarding the registrational study. Given the positive momentum for late-line PDAC patients, it is important to identify the patient population that will qualify for a 3+ line treatment given the historically low survival rates in pancreatic cancer and a lack of treatment options.
“3L+ is a very complex population. It is very, very difficult to have something that is working. So, it’s an unmet need. I understand with this data they want to move forward, but I am not so convinced, 3L for PDAC has complex tumor biology.” – US KOL
Multiple novel MOAs and biomarkers are being explored in pancreatic cancer
Several clinical trials are evaluating novel agents, including biologics such as ADCs, cell therapies, and tumor treating fields, though gem/nab-pac continues to be the chemotherapeutic backbone in these trials. Across these trials, the biomarkers being tested include tumor microenvironment such as CLDN18.2, TGFβ, CD40 agonist, CTGF; metabotropic therapies such as SBP-101; and agents targeting intracellular PDAC mutations, especially KRAS as highlighted above. Several of these therapies are in pivotal trials and results are anticipated beginning 2H 2023.
“I think the reason why most of the pharmaceutical companies use Abraxane is simply because of the predictability. But even with NALIRIFOX data, I still think all the proposed clinical trials that have already been opened to enrollment are going to continue.” – US KOL
Closer definitions of Homologous recombination deficiencies (HRD) and DNA Damage Response (DDR) are called for by several experts
An increase in targeted and combinatorial approaches for PDAC treatments have called investigator determined HRD and DDR positivity into question. Several discussions at ASCO GI cemented the need for a standardized definition of each to determine the most responsive patient population for future treatments.
“Maybe we should speak more about DDR-deficient tumors. And then coin the HRD tumors the ones that are responding maybe to PARP. Otherwise, it gets very confusing for the field as well. ”- Dr. Talia Golan, ASCO GI, 2023
Watch Axiom's Year-in-Review, to learn more about tumor and indication-wide recaps of the most pivotal data from 2022. Pillar leads and experts from the Table will facilitate the discussion.
For Details on Axiom’s Capabilities in GI, Contact:
Hafiz Sikder – hs@axiomhcs.com
Mahim Misra – mm@axiomhcs.com
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