Did ASCO 2026 Deliver on Its Biggest Pre-Meeting Predictions?

Ahead of the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, CancerNetwork® spoke with Sivraj Muralikrishnan, MD, a medical oncologist and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, about which trials he was anticipating the most across pancreatic cancer, lung cancer, and head and neck cancer. Muralikrishnan highlighted the phase 3 RASolute 302 trial (NCT06625320) of daraxonrasib in previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) as his standout pick, alongside the phase 3 LIBRETTO-432 trial (NCT04819100) of adjuvant selpercatinib (Retevmo) in RET fusion–positive non–small cell lung cancer (NSCLC) and the phase 3 HARMONi-6 trial (NCT05840016)comparing ivonescimab plus chemotherapy with tislelizumab (Tevimbra) plus chemotherapy in squamous NSCLC.^1-3 He also flagged 2 potential underdogs to watch: the phase 3b TRITON study (NCT06008093) of dual checkpoint blockade in STK11/KEAP1/KRAS-mutated NSCLC, and the 7-year update of the phase 3 CROWN trial (NCT03052608) of lorlatinib (Lorbrena) in ALK-positive NSCLC.^4-5

Following the meeting, CancerNetwork® reconnected with Muralikrishnan to discuss how these trials read out, along with the data he found most compelling in the head and neck space.

Pre-ASCO: What Trials Are You Most Excited to See?

CancerNetwork: Looking to ASCO 2026, what are some trials you are excited to see the results of?

Muralikrishnan: RASolute 302, a study of daraxonrasib, a multi-selective RAS inhibitor, vs chemotherapy in patients with previously treated metastatic pancreatic adenocarcinoma. Results are expected to support a new therapeutic option in this poor prognostic disease.

The LIBRETTO-432 study, evaluating adjuvant selpercatinib in RET fusion–positive stage IB to IIIA NSCLC. Event-free survival [EFS] results are expected to support selpercatinib as a potential standard of care for RET-altered nonmetastatic NSCLC after completion of definitive therapy.

The HARMONi-6 study, comparing ivonescimab plus chemotherapy with tislelizumab plus chemotherapy in previously untreated advanced squamous NSCLC. Overall survival [OS] results will be presented and may further support the superior efficacy of bispecific anti–PD-1/VEGF therapy over established checkpoint inhibitor regimens.

If you could pick 1 trial as the star or standout, which would it be?

RASolute 302 because it addresses a disease with historically limited effective therapies and poor survival outcomes. Early results showing significant improvements in OS and progression-free survival [PFS] vs standard chemotherapy suggest that direct RAS targeting may finally become a viable treatment strategy in pancreatic cancer. If confirmed, these findings could establish a new standard of care and mark a major breakthrough in targeting RAS-driven cancers more broadly.

Are there any underdogs?

The TRITON study, comparing tremelimumab (Imjudo) plus durvalumab (Imfinzi) and chemotherapy with pembrolizumab (Keytruda) plus chemotherapy as first-line treatment for patients with nonsquamous metastatic NSCLC harboring STK11, KEAP1, or KRAS mutations.

[Additionally,] the 7-year follow-up of the CROWN study, comparing lorlatinib vs crizotinib (Xalkori) as first-line treatment for advanced ALK-positive NSCLC—one of the longest PFS benefits seen in advanced NSCLC.

Post-ASCO: How Did the Data Read Out?

CancerNetwork: Based on your attendance, what were the top abstracts from ASCO 2026, and were there any that particularly surprised you or stood out?

Muralikrishnan: The obvious top abstract from ASCO 2026 was the RASolute 302 study of daraxonrasib in metastatic pancreatic cancer. Pancreatic cancer has historically been hard to treat, with a generally poor prognosis, and this study showed that we have promising therapies coming for patients who will have meaningful benefit. The most important finding was the OS benefit—nearly double in patients in the second-line setting with RAS mutations—with a strong hazard ratio [HR] of [0.40], which supports the OS results, as well as the durability of that regimen. Just as important was that the toxicity profile was favorable relative to chemotherapy. I think it represents a new standard of care and is practice changing for the second-line setting. It was probably the single biggest study presentation at ASCO 2026—it received a standing ovation; deservedly so.

Another top abstract presented at ASCO 2026 in the plenary session was the LIBRETTO-432 study, evaluating adjuvant selpercatinib in RET fusion–positive [NSCLC]. What was most important about this study is that it shows precision oncology is moving earlier in the course of these diseases. It involved patients with resected stage IB to IIIA RET fusion–positive NSCLC who received adjuvant selpercatinib for up to 3 years, and it showed a significant reduction in the risk of recurrence or death—around [83%]—compared with our standard, with an EFS [rate] of nearly [92%] compared with [61%]. This effect size is enormous. It reinforces the trend toward molecular testing being done more upfront, regardless of disease stage, no longer reserved just for stage IV disease. This was a very important study in lung cancer, and because it showed such a strong result, I think it will open the door to many more molecularly based studies in this early-stage setting.

Given that the survival benefit was extended even among patients with RAS G12 mutations, other RAS variants, and even wild-type RAS, how do you see these findings in the RASolute trial reshaping the approach to molecular testing and therapeutic sequencing in metastatic PDAC?

In terms of reshaping how we think about this, it shows that the RAS mutation is targetable with [daraxonrasib], and it highlights… how molecular testing is becoming more important not just in lung cancer but in several other cancers, including pancreatic adenocarcinoma. It certainly opens the door to testing these types of regimens in the frontline setting. A lot of pancreatic cancers have RAS mutations, so it is a promising and important target that might show real-world applicability when moved into the first-line setting, whether as a single-agent therapy or in combination treatment—that is something that may be looked at in the future.

In terms of sequencing, specifically, that is debatable in cancer treatment. There is a philosophy with poor prognostic diseases to give your best therapy upfront, which provides the rationale for potentially studying this drug in the frontline setting, if the data are strong enough, and for understanding how it works in combination with other treatments. There is definitely a rationale in [PDAC] to think about sequencing with your best treatment upfront. We are not there yet, but I hope more studies will lead us there.

Considering selpercatinib’s central nervous system penetrance and the 24-month EFS rate of 91.5%, do you believe the LIBRETTO-432 readout establishes a new post-surgical standard in stage IB to IIIA NSCLC? How do you believe it will influence your baseline biomarker screening habits for patients with early-stage disease?

This will be the new standard of care for these RET fusion–positive lung cancers at the earlier stage, and I would certainly consider it in my patients from stage IB up to stage IIIA. In terms of influencing molecular testing, it reinforces the principle that we should be testing for RET as part of our initial workup in patients diagnosed with lung cancer, and the time to getting these results also plays a role in how quickly we can get patients onto these treatments, so it highlights that important point. Another thing to keep in mind is that many patients in this study also received systemic treatment after surgery, so there is still a role for chemotherapy, but it can be a more nuanced discussion with patients about adding that, especially when you have such an effective targeted agent.

How notable is the safety profile observed in the HARMONi-6 protocol, and do you feel the dual-mechanism bispecific anti–PD-1/VEGF approach is ready to replace standard immunotherapy combinations in the frontline squamous NSCLC setting?

Ivonescimab is a PD-1 and VEGF inhibitor. It is making some inroads. Most of these studies, including HARMONi-6, were predominantly conducted in an Asian population, predominantly in China. In terms of making its way into frontline settings outside of [China] or globally, that is what these studies are trying to establish: generalizability. Until we have real-world data outside of China and Asia, the broader applicability remains to be seen. The results of the HARMONi-6 study, however, were impressive; it delivered a meaningful OS advantage and kept toxicity within a range that most oncologists would find manageable with this bispecific regimen.

Historically, we have avoided VEGF inhibition in squamous NSCLC due to risks of hemoptysis, high blood pressure, proteinuria, and other VEGF-related toxicities, so that has always been the challenge with using those types of treatments, including ivonescimab. Interestingly, the safety profile showed a rate of grade 3 hemorrhage of [2.6%] compared with [0.8%] in the immunotherapy comparator arm, which is not terribly high. Most of the grade toxicities from VEGF inhibition were grade 1 to 2; there were just numerically more grade 3 events in the ivonescimab arm.

In general, the safety profile was within reason and does not necessarily scare us away from using this bispecific in the future. Even though it did not show a major reduction in severe toxicity and had numerically higher grade 3 adverse events [AEs], the increase in toxicity was still relatively modest given the magnitude of benefit. The severe bleeding rates remained surprisingly low with this VEGF strategy, and there was still relatively low treatment discontinuation. Those are all important things regarding its safety; the hemorrhagic signal was not as bad as we thought.

Given that specific co-mutations such as STK11, KEAP1, and KRAS are notorious for driving immunotherapy resistance, how does the TRITON readout position dual checkpoint blockade for these difficult-to-treat NSCLC histologies?

The TRITON readout is interesting. It provides maybe one of the strongest prospective signals we have seen for adding CTLA-4 inhibition in combination with PD-1 therapy to help overcome some of these biologically resistant phenotypes, so it is a promising treatment to offer patients with STK11, KEAP1, or KRAS mutations or co-mutations. In general, these mutations have led to more immune-cold microenvironments. They historically do not respond well to PD-1– or PD-L1–based treatments, exhibit a shorter duration of response, and have worse outcomes with standard chemoimmunotherapy. What it shows is that combination therapy improved response rates modestly, but the duration of response was substantially better with this dual checkpoint inhibitor approach. That does lead us, clinically, to think about using these regimens for patients who present with these poor prognostic molecular abnormalities.

Looking at the median PFS curve in the CROWN 7-year update, how do these data change long-term management expectations regarding cumulative toxicities, such as hyperlipidemia and cognitive AEs, for patients on indefinite tyrosine kinase inhibitor (TKI) therapy with ALK-positive NSCLC?

These results are impressive—one of the longest PFS outcomes reported for oncological drugs, especially in lung cancer. The drug itself, lorlatinib, showed significant improvement with good intracranial activity. Because of how successful the drug has been through the 7-year follow-up—the curve started to plateau around year 2—patients are starting to live much longer with these metastatic cancers. It almost becomes a bit like a chronic disease, where they are taking a medication the way they would for hypertension. But with these chronic conditions, patients are also subject to increased risk of toxicity: cholesterol and lipid issues, as well as cognitive issues, which are a notable AE from lorlatinib.

We try to manage it like we would for any other patient with cholesterol issues. You can put them on a statin; there have been some reports of using GLP-1 agonists in this setting to help control the lipid profile associated with these drugs. Then, you educate patients about standard things like eating healthy and exercising because that is good for the whole body and will also help with the cognitive issues. You tend to see those issues more upfront when you start these drugs, but they can certainly develop over time, and that is where you have to be most careful when using these drugs.

We at least have to continue checking in with patients on these treatments every few months and have them reach out if there have been any changes. Many times, depending on the severity, you could stop the drug, allow things to improve, and then dose-reduce and see if those issues resolve—you do not want to stop it for too long because there can be rebound issues. Speaking to the cognitive aspects specifically, ALK-driven lung cancers have a high rate of metastasis to the brain, so you also want to be cognizant of brain imaging, especially if there are any new cognitive changes.

Which specific data set or oral abstract in the head and neck track did you find most clinically impactful, and how might it alter your multidisciplinary management strategy for locally advanced or metastatic disease moving forward?

Dating back to ASCO 2025, we had the KEYNOTE-689 study [NCT03765918], which was the biggest advance in the head and neck space that we utilize today for resectable head and neck cancers with PD-L1 [combined positive] scores over 1%.⁶ That has now been adopted as a fairly standard approach for many of our [patients with] head and neck cancer.

In the head and neck space, there are also a lot of other rare cancers for which we might not have any good treatments, and one thing that stood out as a sleeper this year was REM-422, an MYB mRNA degrader studied in recurrent or metastatic adenoid cystic carcinoma. It was a phase 1/2 study [NCT06118086], but it showed objective response rates of [around 43%].⁷ This [is a] difficult-to-treat patient population, especially when we do not have any good FDA-approved systemic treatments and the treatments we do have available show low response. That was more of a standout specifically for ASCO 2026, but overall, in the head and neck space, KEYNOTE-689 remains the newest and most exciting practice-changing study.

Is there anything else you would like to highlight that we may not have had the opportunity to discuss?

The most important takeaway is that we are getting better at how we treat our [patients with] cancer in terms of precision—we are becoming more molecularly driven as we find new drugs that can effectively target these mutations. That is the future of cancer care: precision and moving away from our historical chemotherapy options. All the studies we talked about, as well as all the studies currently being done, are leading us to a better future for our patients and providing meaningful impact.

References

1. Wolpin BM, Wainberg ZA, Hendifar A, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA5. doi:10.1200/JCO.2026.44.17_suppl.LBA5
2. Goldman JW, Yang X, Hochmair M, et al. Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: primary results of the phase 3 LIBRETTO-432 trial. J Clin Oncol. 2026;44(suppl 17):LBA3. doi:10.1200/JCO.2026.44.17_suppl.LBA3
3. Zhiwei C, Yang F, Luo Y, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: overall survival results of the phase 3 HARMONi-6. J Clin Oncol. 2026;44(suppl 17):LBA4. doi:10.1200/JCO.2026.44.17_suppl.LBA4
4. Skoulidis F, Borghaei H, Garon EB, et al. TRITON: phase 3b study of tremelimumab plus durvalumab vs pembrolizumab, in combination with chemotherapy, in non-squamous metastatic NSCLC with STK11 and/or KEAP1 and/or KRAS mutations. J Clin Oncol. 2026;42(suppl 16):TPS8655. doi:10.1200/JCO.2026.42.16_suppl.TPS8655
5. Mok TS, Solomon BJ, Felip E, et al. Lorlatinib vs crizotinib as first-line treatment for advanced ALK+ non-small cell lung cancer: 7-year update from the phase 3 CROWN study. J Clin Oncol. 2026;44(16_suppl):8502. doi:10.1200/JCO.2026.44.16_suppl.8502
6. Adkins D, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: exploratory efficacy analyses of the phase 3 KEYNOTE-689 study. J Clin Oncol. 2025;43(16_suppl):6012. doi:10.1200/JCO.2025.43.16_suppl.6012
7. Ferrarotto R, Swiecicki P, Ho AL, et al. Clinical activity of REM-422, a MYB mRNA degrader, in recurrent/metastatic adenoid cystic carcinoma: final results from the phase 1/2 dose-escalation cohort. J Clin Oncol. 2026;44(suppl 16):6009. doi:10.1200/JCO.2026.44.16_suppl.6009