TMB, Tumor Burden, and Tailoring Immunotherapy in Lung Cancer

This is part 2 of a 2-part series. Read part 1 here.

Tumor mutational burden (TMB) is not a replacement for PD-L1 testing, but it can be a decisive tiebreaker. As Neal Ready, MD, explained during a Case-Based Roundtable event in Cleveland, Ohio, "If I see a tumor that has high TMB and a PD-L1 score less than 1%, I think this tumor has the potential to have neoantigens, and I'm concerned that single-agent PD-1 is not enough." Ready is a medical oncologist at Duke Cancer Center.

In that setting, high TMB becomes one of the factors pushing him toward combined PD-1 and CTLA-4 blockade, on the reasoning that CTLA-4 inhibition may be what is needed to unlock a T-cell response that PD-1 alone cannot activate.

To calculate TMB reliably from a next-generation sequencing panel, Ready noted that the panel must include at least 100 genes. Below that threshold, there simply isn't enough DNA to generate an accurate estimate of mutations per megabase. The generally accepted lower boundary for a "high" TMB designation is 10 or more mutations per megabase, though some analyses have used thresholds of 15 to 18. Whether the sample comes from tumor tissue or blood can also introduce some variability in the result.

What makes the low-PD-L1 setting so difficult to reason about, Ready explained, is that the mechanisms of immune resistance are numerous and often overlapping. "It's amazing that single-agent PD-1 therapy works at all in any patient," Ready observed, "because there are so many possible mechanisms of resistance." He drew a comparison to early HIV medicine, when the field assumed multiple antivirals would always be necessary because any single agent seemed unlikely to overcome the virus's adaptability. Immunotherapy has defied that expectation in many patients, though the reasons why remain incompletely understood.

Smoking history and tumor histology also inform the probability of immune response. KRAS mutations, which are strongly associated with tobacco exposure, tend to predict a reasonable chance of responding to immunotherapy, provided STK11 or KEAP1 co-mutations are absent. Mutations such as BRAF and MET exon 14 skipping, while individually less common, can also carry an elevated likelihood of immune response. By contrast, never-smokers tend to have lower TMB and a lower likelihood of benefiting from immunotherapy, and their tumors are more likely to harbor actionable driver alterations that warrant a targeted therapy approach instead.

Tumor burden and symptom burden at the time of presentation add another layer of complexity to treatment selection, and Ready acknowledged that most experts in the field agree on this point. A patient with high disease burden who is already symptomatic may not survive long enough to reach second-line therapy if the first-line immunotherapy regimen fails to produce a response within the typical 8 to 12 weeks needed for assessment. "You can't fail," Ready said simply. For those patients, the urgency of getting disease under control often justifies including chemotherapy upfront, regardless of PD-L1 score.

That said, patient fitness and comorbidities pull in the other direction. A very high PD-L1 score in a frail or elderly patient may still favor using immunotherapy alone, even with meaningful tumor burden, because the patient may not tolerate chemotherapy. "The higher the PD-L1, the frailer and less good for chemo they are, the more likely I am to just use [immunotherapy]," Ready noted. Similarly, in the low PD-L1 setting, age and comorbidities increase the concern about chemotherapy toxicity.

When treating patients with PD-L1 below 1% who are smokers, particularly if TMB or other features suggest potential neoantigens and CTLA-4 inhibition might be the key to unlocking a response, Ready said he would consider the CheckMate 9LA (NCT03215706) regimen: 2 cycles of chemotherapy combined with nivolumab (Opdivo) plus ipilimumab (Yervoy).¹ That approach provides an early cytotoxic contribution while handing off to durable immune control.

Histology and differentiation grade have emerged as additional predictors, drawing on data from CheckMate 227 (NCT02477826),² a large, randomized trial of nivolumab plus ipilimumab, and CheckMate 568 (NCT02659059), a large phase 2 nivolumab/ipilimumab trial.³ An analysis of nonsquamous patients from those trials found that well-differentiated, low-grade tumors had a low probability of responding to the combination, while poorly differentiated, high-grade nonsquamous tumors had substantially higher response rates. That data has been presented but, as Ready noted, has yet to be formally published. Squamous cell carcinoma, which is strongly linked to smoking and generally carries higher TMB, also shows favorable signals for immunotherapy response.

Taken together, these variables—PD-L1 score, TMB, smoking history, mutation profile, histology, tumor burden, and patient fitness—form an increasingly granular framework for deciding not just whether to use immunotherapy, but which combination and how urgently to add chemotherapy. The field has moved well beyond a one-size-fits-all approach to checkpoint blockade in advanced lung cancer.

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DISCLOSURES: Ready has disclosed a consulting or advisory role with Bristol-Myers Squibb, Novartis, Merck, Abbvie, Celgene, Merck Serono, AstraZeneca, G1 Therapeutics, Jazz Pharmaceuticals, and Remeron and research funding from Bristol-Myers Squibb and Merck.

REFERENCES

1. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. doi: 10.1016/S1470-2045(20)30641-0. Epub 2021 Jan 18. Erratum in: Lancet Oncol. 2021 Mar;22(3):e92. doi: 10.1016/S1470-2045(21)00082-6. PMID: 33476593.

2. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019 Nov 21;381(21):2020-2031. doi: 10.1056/NEJMoa1910231. Epub 2019 Sep 28. PMID: 31562796.

3. Ready N, Hellmann MD, Awad MM, et al. First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers. J Clin Oncol. 2019 Apr 20;37(12):992-1000. doi: 10.1200/JCO.18.01042. Epub 2019 Feb 20. PMID: 30785829; PMCID: PMC6494267.