Osimertinib Is Most Impactful Addition to 2024 NSCLC NCCN Guidelines and Durvalumab Shakes up SCLC

Jonathan Wesley Riess, MD, MS

Two practice-changing additions to the NCCN Clinical Practice Guidelines in Oncology in the lung cancer paradigm were the inclusion of osimertinib (Tagrisso) for patients with unresectable non–small cell lung cancer (NSCLC) harboring EGFR mutations and durvalumab (Imfinzi) for those with limited stage (LS)-SCLC, according to Jonathan Wesley Riess, MD, MS, member of the NSCLC NCCN panel, and Megan E. Daly, MD,member of the SCLC NCCN panel.

“As a radiation oncologist, I try to discuss these new recommendations with my patients,” Daly said in an interview with OncLive^®. “Typically, Dr Riess or one of the medical oncologists is also discussing these consolidation therapies, but it seems like a lot of our patients are very excited about these new developments and this chance to receive these cutting edge, new drugs. [It’s our job to] remind the patients of what their overall treatment course is going to look like, so there are no surprises in the end and so they understand what the flow of treatment is going to look like for them.”

The Most Notable Recent NCCN Revisions in Lung Cancer:

For SCLC:¹

• For adjuvant therapy of LS pathways:
  • Durvalumab was added as a recommendation (category 1)
• For primary or adjuvant therapy for LS-SCLC:
  • Durvalumab consolidation therapy was added as a preferred regimen (category 1)

For NSCLC:²

• For systemic therapy following surgical resection:
  • Nivolumab (Opdivo) 480 mg every 4 weeks for up to 13 cycles was added as a new regimen for patients with completely resected stage II to IIIB NSCLC who received previous neoadjuvant nivolumab plus chemotherapy and do not have known EGFR mutations or ALK rearrangements (category 1)
• For those with EGFR exon 19 deletion or exon 21 L858R:
  • For first-line therapy:
    • Amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) was added
    • If the mutation was discovered prior to first-line systemic therapy:
      • Amivantamab plus lazertinib was added as to other recommended treatment options
      • Erlotinib (Tarceva) plus ramucirumab (Cyramza), erlotinib plus bevacizumab (Avastin), dacomitinib (Vizimpro; category 1), afatinib (Gilotrif; category 1), erlotinib (category 1) or gefitinib (Iressa; category 1) all changed from other recommended treatment options to useful in certain circumstances
    • If the mutation was discovered during first-line systemic therapy:
      • Amivantamab plus lazertinib was added as a treatment option
  • For progression; asymptomatic, symptomatic (brain and systemic limited):
    • Continuation of amivantamab plus lazertinib was added as a treatment option
  • For progression; multiple lesions:
    • A specification was added: amivantamab (if not previously given) with carboplatin and pemetrexed for patients with nonsquamous disease (preferred regimen; category 1)
  • Osimertinib (Tagrisso) plus pemetrexed and cisplatin or carboplatin was added to other recommended regimens for nonsquamous disease (category 1)
• For subsequent therapy for those with EGFR exon 19 deletion or exon 21 L858R and frontline therapy for those with EGFR exon 20 insertion mutations:
  • Amivantamab plus carboplatin and pemetrexed was added as a preferred regimen for nonsquamous disease (category 1)
• For systemic therapy for patients with no known EGFR mutations or ALK rearrangements:
  • For neoadjuvant systemic therapy in patients who are candidates for immune checkpoint inhibitors:
    • Durvalumab 1500 mg and platinum-based doublet chemotherapy every 3 weeks for 4 cycles and then continued as single-agent durvalumab as adjuvant treatment after surgery was added as a recommendation (category 1)
  • For following surgical resection:
    • Durvalumab 1500 mg every 4 weeks for up to 12 cycles was added as a new regimen for patients with completely resected tumors at least 4 cm and/or node-positive NSCLC who received previous neoadjuvant durvalumab plus chemotherapy (category 1)
• For NTRK1/2/3 gene fusions:
  • For first-line therapy:
    • If the NTRK1/2/3 gene fusion was discovered prior to first-line systemic therapy:
      • Repotrectinib (Augtyro) was added as a preferred treatment option
    • If the NTRK1/2/3 gene fusion was discovered during first-line systemic therapy:
      • Repotrectinib was added: Complete planned systemic therapy, including maintenance therapy, or interrupt, followed by larotrectinib (Vitrakvi), entrectinib (Rozlytrek), or repotrectinib
  • For subsequent treatment:
    • Repotrectinib was added as a treatment option if not previously given
• For stage IIIA unresectable disease as well as stage IIIB and stage IIIC:
  • Osimertinib was added if EGFR exon 19 deletion or L858R mutations are present (category 1)
• For T1-3, N1 nodes positive, M0 disease that is inoperable:
  • Osimertinib was added if EGFR exon 19 deletion or L858R mutations are present (category 1 stage III; category 2A stage II)
• For T1-3, N2 nodes positive, M0 disease:
  • Osimertinib was added if EGFR exon 19 deletion or L858R mutations are present (category 1)
• For consolidation therapy for patients with unresectable stage II/III NSCLC, performance score 0 or 1, and no disease progression after definitive concurrent chemoradiation:
  • Osimertinib was added if EGFR exon 19 deletion or L858R mutations are present (category 1 for stage III; category 2A for stage II)
• For systemic therapy following surgical resection:
  • Alectinib (Alecensa) was added for patients with completely resected stage II to IIIA or stage IIIB (T3, N2) NSCLC and positive for ALK rearrangements (category 1)
  • Three years were added to the dosing schedule of osimertinib
• For systemic therapy for advanced or metastatic disease—subsequent or progression:
  • Fam-trastuzumab deruxtecan-nxki (Enhertu) was added to other recommended option for select patients
• For first-line and subsequent therapy when a ROS1 rearrangement is present:
  • Repotrectinib was added
• For subsequent therapy when a ROS1 rearrangement is present:
  • Asymptomatic disease:
    • Repotrectinib (if not previously given) or lorlatinib (Lorbrena)
  • Symptomatic; brain
    • Entrectinib (if previously treated with crizotinib [Xalkori] or ceritinib) or repotrectinib (if previously treated with crizotinib or ceritinib [Zykadia] or entrectinib) or lorlatinib
  • Symptomatic; systemic with multiple lesions:
    • Repotrectinib (if not previously given) or lorlatinib
• For EGFR S768I, L861Q, and/or G719X mutations:
  • For subsequent therapy:
    • Amivantamab plus carboplatin and pemetrexed (nonsquamous) was added
• For adenocarcinoma, large cell, NSCLC not otherwise specified:
  • Cemiplimab-rwlc (Libtayo) plus pemetrexed and carboplatin or cisplatin moved from other recommended to preferred regimens (category 1)
• For squamous cell carcinoma:
  • Cemiplimab plus paclitaxel and carboplatin or cisplatin moved from other recommended to preferred regimens (category 1)
• For systemic therapy for advanced or metastatic disease:
  • Category designation for tremelimumab-actl (Imjudo) combination regimens changed from category 2A to category 1

In the interview, Riess and Daly provided radiation and medical oncology perspectives on the latest NCCN guideline updates in lung cancer. Daly is a professor in the Division of Radiation Oncology at UC Davis Comprehensive Cancer Center and Riess is medical director of Thoracic Oncology and an associate professor of medicine in the Division of Hematology and Oncology at UC Davis Comprehensive Cancer Center in Sacramento, California.

OncLive: What 2024/2025 version NCCN updates have had an immediate influence on how you practice in lung cancer?

Riess: The two most practice changing [trial] findings [that led to guideline updates] were for consolidation therapy after treatment with chemoradiation. One [trial that affected] the SCLC guidelines was the phase 3 ADRIATIC study [NCT03703297] which [was presented in the] ASCO plenary session this year. The results showed a dramatic improvement in progression-free survival [PFS] and overall survival [(OS) with the addition of adjuvant] durvalumab after concurrent chemoradiation [vs placebo] for patients with LS-SCLC. That was practice changing, and [that regimen] is now a category 1 NCCN recommendation, so I’ve adopted that into my practice.

The other chemoradiation study was the phase 3 LAURA study [NCT03521154], [which was presented in] another ASCO plenary session looking at osimertinib after completion of chemoradiation for patients with unresectable stage III NSCLC harboring the more common EGFR mutations of exon 19 deletion and L858R. The findings showed an impressive PFS benefit [with osimertinib in patients reaching 39.1] months vs [5.6] months for chemoradiation alone. That study was also practice changing and [that regimen now also has] a category 1 recommendation in the NCCN guidelines.

Daly: I agree. Those are the two guideline [updates] that have had the biggest impact to my practice. With the LAURA data adding consolidation osimertinib following chemoradiation, anytime we see a patient with stage III unresectable disease who has one of the canonical EGFR mutations, we’re assuming they’ll likely go on to osimertinib following chemoradiation, so it’s something I keep in mind up front. I mention it to the patient from the beginning, so they know that this is something they’ll likely be receiving. I try to be careful about the development of radiation pneumonitis in these patients. Of course, we’re careful in all patients, but knowing that there’s potential for pneumonitis with osimertinib, we want to make sure the patients get through chemoradiation smoothly and are able to go on to receive osimertinib.

In the SCLC setting, the ADRIATIC [trial data] has had a large impact as well, which has been great to see [because] these are patients who historically have had relatively poor outcomes. Having something with such a remarkable PFS and OS benefit has been wonderful for our patients with LS-SCLC. It does open some questions, for example, [regarding] prophylactic cranial irradiation that are still being answered by ongoing trials like the phase 3 MAVERICK study [NCT04155034], but certainly [I now] let all my patients with LS-SCLC know up front that prior to chemoradiation they’ll likely be receiving durvalumab following completion of chemoradiation.

Are there any other notable guideline updates in lung cancer?

Daly: In the [LS-SCLC] setting, [the guidelines] have been updated to note that not only patients treated with concurrent chemoradiation, but also those treated with sequential chemoradiation, can be considered for consolidation therapy with durvalumab. That’s something that may have already been happening in practice, but that’s now been formalized in the guidelines.

Riess: The other guideline change is the incorporation of chemotherapy with carboplatin [or cisplatin] and pemetrexed plus osimertinib as other [recommended regimens] for patients with metastatic stage IV [NSCLC] and common EGFR mutations [based on data from the] phase 3 FLAURA2 trial [NCT04035486]. The addition of amivantamab plus lazertinib for first-line treatment based on [findings from] the phase 3 MARIPOSA study [NCT04487080] is [also notable]. [Both trials] showed a PFS benefit and a trend towards OS [benefit] with a number of events yet to occur. That’s also in the context of the phase 3 MARIPOSA-2 study [NCT04988295] regimen which was added to the guidelines previously as a preferred regimen after progression on osimertinib.

What is key to note for community oncologists who are adapting to these recent guideline changes?

Daly: Getting upfront molecular testing for all patients, not just for patients with metastatic disease, is important. It is recommended now that all patients should have molecular tumor testing to test for these targetable mutations because it has such a clear difference in how we treat patients. For example, in the unresectable stage III setting whether they would go on to durvalumab or osimertinib. It’s important for physicians of all specialties, regardless of whether you’re the one giving the systemic therapy, to be aware of what the patient will be receiving. It’s a change for our patients in terms of the experience of having their lung cancer treated if they’re going to be going on to a systemic therapy either for a year after treatment or for an indefinite period after treatment, rather than just going through a finite 6-week period of chemoradiation.

Are you communicating or discussing these changes with your patients?

Riess: Now, for the first-line EGFR treatment options, I discuss options with my patients. I still often give osimertinib alone outside of a clinical trial, but for patients who may have higher risk features—such as comutations, positive circulating tumor DNA, [high] tumor [mutational] burden, [or] brain metastases—I discuss the potential for treatment intensification either with adding chemotherapy to osimertinib in the first-line or amivantamab plus lazertinib; that is new for my patients. In patients who completed chemoradiation, we discuss the recommendations for osimertinib for [patients with] EGFR mutations and durvalumab for [patients with] LS-SCLC. In fact, Dr Daly and I had a patient who, when this [guideline update] recently came out, we discussed [the new option] with them quickly and got them on consolidation durvalumab, given the superb data. Those data have influenced our practice.

What guideline changes do you anticipate coming in 2025?

Riess: It’s hard to say. We have a number of trials of targeted therapies for [patients with] oncogene driven mutations. We have the phase 3 PALOMA-3 trial [NCT05388669] that looked at amivantamab plus lazertinib and giving the amivantamab subcutaneously as opposed to intravenously. [Those data] showed a decrease in infusion reactions [with subcutaneous administration], non-inferiority for pharmacokinetic parameters, and intriguingly, a signal of potentially improved clinical outcomes with the subcutaneous formulation. I would anticipate, should that get approved, that would change the guidelines in terms of administering the subcutaneous [formulation] vs the intravenous one. That might be one forthcoming change.

If the phase 3 NeoADAURA trial [NCT04351555] reads out [as positive with] neoadjuvant chemotherapy plus osimertinib, we’ll have to see whether those results change things. There are a number of exciting studies and if they read out and show positive results, they may affect the guidelines, but in the near term, it would be the PALOMA-3 study and the potential FDA approval there which may change guidelines.

Daly: In terms of radiation trials, I’m not sure that there are any huge practice-changing phase 3 trials that will have completed accrual and have full results in 2025. There are certainly some other additional, intriguing studies in the unresectable stage III setting. We may eventually end up moving to some sort of dual consolidation therapy, but I don’t know that we’re going to have any definitive results within the next year. We do know now that concurrent immunotherapy with chemoradiation is not going to be making its way into the guidelines. We’ve seen that fairly definitively with trials that have already reported out. I also anticipate there will likely not be any major changes to the early-stage unresectable [setting] given a couple of these recent trial closures.

In LS-SCLC, it’s possible that if the MAVERICK trial completes accrual, we may have a more definitive answer on prophylactic cranial irradiation, although I would anticipate that would likely be 2026 not 2025.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 3.2025. Accessed November 20, 2024. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf
2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 11.2024. Accessed November 20, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf