Poumon - CBNPC | How I Treat

Adjuvant

Néo-adjuvant

Locally Advanced Inoperable

Métastatique

Non-Squamous

ALK rearrangement

EGFR mutation

EGFR exon 19 deletions or exon 21 L858R point mutations

EGFR neg ALK neg and PDL1 ≥ 50%

EGFR neg ALK neg and any PD-L1

Squameux

PD-L1 ≥ 50%

Any PD-L1 expression

Non-Squamous

All patients should have their tumor biopsy tested for EGFR, ALK and PD-L1. If there’s not enough tissue or the report signals inconclusive results for EGFR and ALK, another biopsy should be done. If treatment needs to be started without these biomarkers, the case should be presented in group meeting . Another alternative would be to start therapy with one cycle of chemo without Nivolumab, rebiopsy and adapt the neoadjuvant afterwards or proceed to surgery.

Many peri-operative strategies are showing positive results, however they were not compared to the current standard of care of Checkmate 816. An indirect meta-analysis suggested that adjuvant post neoadjuvant « may not improve survival outcomes for patients with resectable NSCLC and may be associated with increased adverse events » adding to the high financial toxicity and the burden of months of therapy on the healthcare system.

EGFR neg ALK neg and any PD-L1

Squameux

Any PD-L1 expression

Squameux

The approval for Durvalumab in Canada does not take in consideration any biomarker. Using it in this setting is based on each ones’ personal, clinical and scientific judgement.

I am personally not convinced of its efficacy in the population with PD-L1 < 1%, I still discuss it with my patients but do not recommend it for most of them.

PD-L1 > 1%

PD-L1 < 1%

Non-Squamous

The use of immunotherapy as a consolidation strategy in EGFR mutated or ALK translocated patients and PD-L1 < % deserves a thorough evaluation.

In this algorithm, despite the HC indication not differentiating these subgroups, I will not include Durvalumab as an option for EGFR or ALK patients, and I personally do not recommend it for most of my PD-L1 < 1% patients but will keep it in this subgroup and leave it for physicians’ judgment to use it or not for their PD-L1 < 1% patients. For EGFRm patients, a new potential standard of care with Osimertinib is on the horizon.

EGFR mutation

For EGFRm patients: There is a potential new standard for consolidation therapy in Stage III EGFRm (Ex19del/L858R) NSCLC post CRT. Retrospective data already highlighted this strategy and the LAURA trial showed an » overwhelming efficacy benefit « for Osimertinib in this population. At ASCO 2024, preliminary results showed that Osimertinib reduced the risk of progression or death by 84% compared with placebo (HR, 0.16; 95% CI, 0.10-0.24; P < .001).

However, with no OS yet still available and the 81% crossover in the standard arm, many unanswered question still remain as to whether Osimertinib as maintenance improves survival compared to Osimertinib on progression.

Adding to the lack of efficacy for IO monotherapy in EGFR patients, the use of Osimertinib concomitantly with Durvalumab or within months post Durvalumab has been associated with increased risk of ILD and death.

EGFR exon 19 deletions or exon 21 L858R point mutations

EGFR exon 20 insertion

Uncommon mutations

ALK rearrangement

For ALK positive patients: The use of Immunotherapy for ALK positive patient in the metastatic setting hasn’t been a success. Therefore, these patients have been excluded from all IO trials. Retrospective data started emerging, and were presented at ASCO 2024, and basically mirror what we see in LAURA for EGFRm.

EGFR neg ALK neg and PD-L1 < 1%

For PD-L1 negative patients: Providing pre-CRT tumour tissue was optional in the PACIFIC trial (almost 36.7% of the randomized patients did not provide any tissue and were classified as PD-L1 unknown) and enrolment was not restricted based on PD-L1 expression. However, Durvalumab failed to show improvement in the PFS and OS in the (not pre-planned) post hoc analysis for this PD-L1 <1% subgroup. EMA therefore restricted the use of Durvalumab for this population. This decision was strongly criticized by the many experts including a panel of IASLC.

EGFR neg ALK neg and PD-L1 > 1%

The new drug development strategy is already taking in consideration this issue since the ongoing PACIFIC 8 trial assessing the efficacy and safety of durvalumab (MEDI4736) and domvanalimab (AB154) compared with durvalumab plus placebo (standard PACIFIC regimen) includes only « documented tumour PD-L1 status ≥ 1% by central lab » as well as « documented EGFR and ALK wild-type status (local or central) » in their inclusion criteria.

Squameux

Treatment based on PD-L1 status

PD-L1 ≥ 50%

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PD-L1 1 to 49%

First line

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PD-L1 < 1%

First line

Second line

Third line

Non-Squamous

NGS is mandatory for every patient. AmpliSeq is usually done depending on your corridor of service in each region / Optilab. Usually panel requisitions are filled out by your pathologists and sent out to reference centres, like MUHC, IUCPQ, CHUM…

ctDNA has become increasingly available in specific indications: this section will be updated as soon as I get confirmation from the two running centres in Quebec.

EGFR mutation

Not all EGFR mutations are similar. Fortunately our pathology reports mention the type of mutation and its sensitivity to which agents.

EGFR exon 19 deletions or exon 21 L858R point mutations

Osimertinib is considered the best standard of care for now.

Despite the PFS advantage we see in MARIPOSA, the challenging toxicity profile and the complexity of administering the combination will make it hard for this regimen to become the new SoC.

CT + Osimertinib seems to hold the winning card, however there are still patients that won’t need upfront CT. New strategies such as incoporating ctDNA clearance are eagerly needed to avoid overtreating many.

First line

Your choice of first line will influence second line decisions, but always go for the best treatment first.

Second line

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Third line

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Uncommon mutations

First line

Second line

Third line

EGFR exon 20 insertion

First line

Second line

Third line

ALK rearrangement

There are no comparative data for the best TKI to use upfront. Each has some particular characteristics, a different safety profile and intracranial activity.

For Alectinib and Brigatinib, there was some indirect comparisons and real world data in this setting that suggests that both TKIs are similar in efficacy but have obviously different safety profile. The Phase 3 ALTA-3 trial compared brigatinib to alectinib in ALK+ NSCLC patients who progressed on crizotinib and showed no difference in efficacy but a difference in safety profiles.

Lorlatinib has been scoring and on a different journey than the rest of the TKIs, mainly known for its incredible intracranial activity, the recent extended follow up data presented at ASCO 2024 have been astonishing, giving it a huge leap over all others and becoming the most potent TKI to use upfront. However, its safety profile has been very challenging for many physicians to incorporate it in the first line setting, « A pragmatic approach to managing AEs related to lorlatinib is required » and this was well adressed in this paper.

Unlike in the US, access to Lorlatinib in second line, at least in Quebec has been very difficult and uncertain for most prescribers. Anyway, I wonder if with the recent updates, is it true that « We should not celebrate false kings. » ?

I would advocate for the right TKI for the right patient and would recommend selecting the drug based on the tumor burden, comorbidities and intracranial disease at diagnosis.

First line

Second line

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Forth line

ROS1 rearrangement

First line

Second line

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Forth line

MET exon 14 skipping mutation

Patients with exon-14 altered lung cancer have a bad prognosis and a very modest response to immunotherapy disregarding the expression of PD-L1. There are some random case reports and very small series highlighting few long term responders for whom we don’t have a good understanding of their disease. Many studies and combinations are currently in development, but for now I would not treat these patients with IO single agent, at least not in first or second line.

First line

Second line

Third line

RET rearrangement

Patients with RET-fp NSCLC don’t do well on single agent IO, these come from old retrospective data and recent ones showing the lack of benefit disregarding expression of PDL-1. There are obviously few success stories but should not be taken solely for decision making. Many emerging strategies are being in development and have been published since a while now, showing that they benefit the most from the use of TKIs and therefore should have these drugs incoporated in their treatment as early as possible.

First line

Second line

Third line

NTRK fusion

First line

Second line

Third line

Forth line

BRAF V600

PD-L1 ≥ 50%

First line

Second line

Third line

PD-L1 1 to 49%

First line

Second line

Third line

PD-L1 < 1%

First line

Second line

Third line

KRAS mutation G12C

PD-L1 ≥ 50%

First line

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PD-L1 1 to 49%

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PD-L1 < 1%

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Third line

ERBB2 alterations

ERBB2 encodes for HER2, a receptor tyrosine kinase overexpressed or altered in numerous cancers. ERBB2 alterations comprise a wide spectrum of genomic alterations with some of them considered activating. The main forms of HER2 alterations include: gene mutations, gene amplifications, and protein overexpression.

This area is still under study with many potential breakthrough and challenges. New targeted therapies (such as Posiotinib and Pyrotinib) may play a role in HER2-mutant but it’s Trastuzumab Deruxtecan TDXd that is showing the best results so far as highlighted in the Phase II DESTINY-Lung02 trial.

The benefit of IO is very questionable, with poor responses to IO monotherapy. Until the image gets clearer, my approach for these patients would be CT alone or CT-IO in first line disregarding the PD-L1 status.

First line

Second line

Third line

No actionable driver alteration

PD-L1 ≥ 50%

First line

Second line

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PD-L1 1 to 49%

First line

Second line

Third line

PD-L1 < 1%

First line

Second line

Third line

Neuroendocrine Differentiation

Treat basically like a Small Cell Lung Cancer, I usually do Carbo Etoposide (Cisplatin is not a wrong option, but in metastatic setting it’s not considered superior to Carboplatin, it is more toxic and requires more monitering and chair time).

Adding IO to your Platinum based chemo should be discussed within your group and if approved, it would require a special access and discussion with your pharmacy and subsequent committees, since this population was not included in the SCLC IO-CT trials.

Poumon – CBNPC

Adjuvant

Néo-adjuvant

Locally Advanced Inoperable

Métastatique

Non-Squamous

ALK rearrangement

EGFR mutation

EGFR exon 19 deletions or exon 21 L858R point mutations

EGFR neg ALK neg and PDL1 ≥ 50%

EGFR neg ALK neg and any PD-L1

Squameux

PD-L1 ≥ 50%

Any PD-L1 expression

Non-Squamous

EGFR neg ALK neg and any PD-L1

Squameux

Any PD-L1 expression

Squameux

PD-L1 > 1%

PD-L1 < 1%

Non-Squamous

EGFR mutation

EGFR exon 19 deletions or exon 21 L858R point mutations

EGFR exon 20 insertion

Uncommon mutations

ALK rearrangement

EGFR neg ALK neg and PD-L1 < 1%

EGFR neg ALK neg and PD-L1 > 1%

Squameux

PD-L1 ≥ 50%

First line

Second line

Third line

PD-L1 1 to 49%

First line

Second line

Third line

PD-L1 < 1%

First line

Second line

Third line

Non-Squamous

EGFR mutation

EGFR exon 19 deletions or exon 21 L858R point mutations

First line

Second line

Third line

Uncommon mutations

First line

Second line

Third line

EGFR exon 20 insertion

First line

Second line

Third line

ALK rearrangement

First line

Second line

Third line

Forth line

ROS1 rearrangement

First line

Second line

Third line

Forth line

MET exon 14 skipping mutation

First line

Second line

Third line

RET rearrangement

First line

Second line

Third line

NTRK fusion

First line

Second line

Third line

Forth line

BRAF V600