Study news on lung, kidney and intestine

KEYNOTE-042 and CARMENA: Two studies that have the potential to change practice. It’s about lung cancer – as so often lately – but also about renal cell carcinoma. Furthermore, the final evaluation of the FIRE-3 study comes from Germany.

Just over five years ago, the results of the FIRE-3 trial [1–3] emphasized the relevance of RAS mutation analysis (KRAS and NRAS) for treatment decisions in first-line metastatic colorectal cancer (mCRC). The anti-EGFR monoclonal antibody cetuximab (^Erbitux®) showed a significant survival benefit compared to bevacizumab for patients with RAS wild-type tumors.

Background: In addition to KRAS exon 2, rarer mutations in exon 3 and 4 of the KRAS gene and mutations in exon 2, 3, and 4 in the NRAS gene may cause tumor resistance to anti-EGFR drugs. RAS mutations have therefore been identified in several studies as negative predictive biomarkers of anti-EGFR therapy in mCRC.

Compared with chemo alone, an overall survival benefit of more than five months is found in all-RAS wild-type, add anti-EGFR antibody panitumumab to chemotherapy according to FOLFOX4 regimen. In the CRYSTAL trial [4], extended RAS analysis (i.e., all-RAS wild-type) found a median OS benefit of approximately eight months with the addition of cetuximab compared with the FOLFIRI regimen alone.

In turn, compared with bevacizumab plus FOLFIRI, primary combination treatment with the anti-EGFR antibody cetuximab plus FOLFIRI also significantly prolonged overall survival in RAS wild-type tumors (KRAS and NRAS) in FIRE-3, from 25.0 to 33.1 months. 400 patients of the total 592 participants had this mutation status. Progression-free survival was comparable in the two groups at approximately ten months.

The results of a phase II trial called PEAK [5] with the drug panitumumab were in a similar direction, but not the CALGB trial published at about the same time [6–8]. It suggested no overall survival benefit with cetuximab over bevacizumab. Indeed, the current ESMO guidelines [9] consider all chemotherapy-antibody combinations as potential first-line treatments for patients with mCRC and RAS wild-type.

Excitement was generated some time ago by the finding, including from a retrospective analysis of FIRE-3 and CRYSTAL data, that primary tumor location has prognostic value. CALGB and PRIME analyses presented at ESMO 2016 come to similar conclusions, which already makes the ESMO guideline seem outdated again in this respect.

Final data after more than five years

Five years after the last patient, the follow-up period is now over. Consequently, at ASCO 2018, the German study group presented a final update from FIRE-3. The part of the RAS wild-type study population that could be evaluated in the primary endpoint according to the protocol, i.e., those with at least three chemotherapy cycles and at least one CT scan after study entry, included 351 patients (87.8%). Thus, the approximately 49 early study dropouts (due to intolerance or patient request) were calculated out in order to make a final assessment of the primary endpoint, the objective response rate, among other things. In fact, unlike the 2014 primary analysis, the difference in this endpoint now significantly favored cetuximab. Previously, corresponding post-hoc ORR evaluations according to RECIST 1,1 criteria, early tumor shrinkage and median response depth had pointed in this direction. According to the authors, the final ORR data with cetuximab now provide an adequate and plausible complement to the overall survival benefit.

Median follow-up duration to the time of data cutoff in July 2017 was 70.8 months. Compared to previous analyses with 65-68% survival events, significantly more, namely 85.3% events, have now occurred, which again significantly improves the data quality of the long-term survival data. When only the protocol population was considered, there was a significant prolongation of overall survival from 26.1 with bevacizumab to 32.5 months with cetuximab. In the whole RAS wild-type population, median overall survival was 25.6 resp. 31.1 months. Table 1 summarizes the final data from FIRE-3.

FIRE continues

Meanwhile, the FIRE study series continues. FIRE-4, the follow-up study to FIRE-3, will firstly test in the first-line setting whether it is really necessary to give cetuximab until progression or whether it is possible to switch to maintenance under 5-FU and bevacizumab after a certain induction period (switch maintenance). The primary endpoint is progression-free survival. The second question to be answered is: after successfully using anti-EGFR therapy in the first line, can it be used again in the third line after anti-EGFR-free second line therapy, i.e. is it effective again (re-challenge)? Here, there are preliminary data from an Italian study group with approximately 39 patients. FIRE-4 aims to re-examine this in the randomized Phase III trial setting in approximately 230 patients.

FIRE-4.5 has also been open for just over a year. This is about the difficult-to-treat group of BRAF-mutated patients. These 8-10% of mCRC patients have the worst prognosis. To date, only retrospective data suggesting triplet therapy, namely FOLFOXIRI, exist in the first-line setting. FIRE-4.5 is now testing the combination of FOLFOXIRI with cetuximab versus bevacizumab for the first time. Primary endpoint is overall response. Approximately 100 patients are expected to participate. It is currently the only randomized first-line trial in the BRAF-mutated patient population. The recruitment phase should be completed in just over two years.

Lung cancer -Pembrolizumab again “congressional favorite

Anyone working in the oncology field should be familiar with immuno-oncology by now. However, two diseases in particular have benefited from the progress made in recent years: melanoma and non-small cell lung cancer (NSCLC). We last reported from ESMO 2016 on KEYNOTE-024, which caused a veritable drumbeat in the lung cancer scientific community when it became clear that the anti-PD-1 antibody pembrolizumab (Keytruda®) prolongs both progression-free and overall survival in the first-line setting compared to platinum-based chemotherapy, with fewer side effects. Even then, some saw the end of first-line chemotherapy approaching, as in addition to patients with oncogenic driver mutations (such as EGFR and ALK), where new therapeutics were already prominent in the first-line setting at that time, the majority of advanced NSCLC patients without EGFR or ALK mutation or translocation but with PD-L1 expression on at least half of the tumor cells were now also benefiting. However, the latter information is decisive, because it applies to “only” just one third of the cases. Was the KEYNOTE-024 sample, which also excluded individuals with brain metastases, on steroids, or with autoimmune diseases, perhaps not as representative of the rest of the lung cancer population as thought? Some experts speculated that pembrolizumab would ultimately be considered in “only” just 10% of cases in clinical practice.

However, it has long been clear that PD-L1 expression, while one of the best-studied predictive biomarkers from this field, is inadequate in many respects. Time and again, patients with lower or no expression levels in the tumor were still shown to respond and benefit (albeit less) from checkpoint inhibitors. In the future, therefore, it is likely that a “bundle” of biomarkers will be increasingly used, probably including tumor mutation burden.
The KEYNOTE-042 study now presented at ASCO is also in this vein. While the development and approval of pembrolizumab was based on the assumption that PD-L1 expression in tumor tissue is biologically important enough to justify checkpoint inhibition (partly because of the costs involved), this approach now seems shaky after KEYNOTE-042. Currently, the approval text in Switzerland reads, “Keytruda is indicated for the first-line treatment of metastatic NSCLC in adults whose tumors express PD-L1 with a tumor proportion score (TPS) ≥50% and have no EGFR or ALK type genomic tumor aberrations.” How long will this continue?

From the front. The sample of the large phase III KEYNOTE-042 (open-label) trial consisted of 1274 patients. They were randomized to ≤35 cycles of pembrolizumab 200 mg triweekly or ≤6 cycles of paclitaxel and carboplatin or pemetrexed and carboplatin with optional pemetrexed maintenance (non-squamous cell carcinomas only), depending on the treating physicians’ choice. All of this in first-line and metastatic/advanced NSCLC. Just over half of the patients had a TPS ≥50%, but significantly more, two-thirds, had a TPS ≥20%. When the outcome of these two groups was compared with the results of the overall population, whose only criterion was to achieve a TPS of ≥1%, the clear superiority of pembrolizumab over the platinum-based first-line regimen was still evident. Table 2 depicts the results of the primary endpoint (for the first time, it was overall survival). And as expected: Survival was better the higher the PD-L1 expression. After a median of 12.8 months, 13.7% of patients continue to receive pembrolizumab.

Given the clear data, one has to wonder almost two years after the advancement of pembrolizumab into the first-line setting whether another indication adjustment is already needed. Is the PD-L1 expression determination with the original limit of 50% really still tenable when significantly more patients than thought, including those with lower PD-L1 levels, benefit significantly from the checkpoint inhibitor? Ultimately, this would make the agent an option that can be used more broadly, approaching a new first-line standard for a large proportion of patients (the target population for immunomonotherapy could double). Withholding pembrolizumab from advanced NSCLC patients, who according to KEYNOTE-042 would clearly benefit from such an approach, and offering chemotherapy, which is less effective and has significantly more side effects, would thus be ethically questionable. At the same time, the new standard would possibly create cost problems. This is a dilemma that we are encountering more and more frequently in medicine lately. Health policy solutions are indicated.

And: The whole thing is not as simple as thought anyway. The study does not allow a conclusive statement on the extent to which individual patient groups with specific PD-L1 levels benefit exactly (since it was always a matter of a minimum value).Rather, it is obvious that patients with levels above 50% in KEYNOTE-042 contributed the decisive part to the survival benefit. In exploratory analyses, the OS benefit shrank when only the group with ≥1-49% expression was considered (HR 0.92). In general, immunotherapy is making great progress, but NSCLC remains an aggressive disease and further research is needed. It is also still questionable whether pembrolizumab works better alone or in combination with chemo (see KEYNOTE-189, also published shortly before the congress). [10]. Another field of research is the adjuvant area. What is the position of checkpoint inhibition there? What is clear is that, in light of research in recent years, NSCLC can no longer be seen as a “one-size-fits-all” disease where one therapy can be considered for almost all patients. Once again, the discussion ends with biomarker research, which in the future should provide an answer to the question of who benefits most from immunotherapy alone, in combination or together with chemo.

Paradigm shift in advanced renal cancer

In metastatic renal cell carcinoma, particularly large renal tumors, patients may be offered cytoreductive nephrectomy before initiation of drug therapy. However, the latter has improved greatly in recent years. Although the tumor responds poorly to chemotherapy, tyrosine kinase inhibitors that inhibit VEGF and also other receptors have been shown to be effective drugs in metastatic renal cell carcinoma. The orally administered sunitinib (^Sutent®, multikinase inhibitor) is frequently used here. It is approved for the treatment of patients with advanced and/or metastatic renal cell carcinoma. Given the success of targeted therapy and the suggestion that high-risk patients in particular might suffer complications and disease progression during and after surgery, the question arose to what extent and which patient groups should actually be offered cytoreductive nephrectomy before initiating drug therapy. The CARMENA trial addressed the question, and so much up front: surgery appears to be omitted in several patients, sunitinib alone is equally effective or. not inferior to the surgical procedure.

In detail, 450 (of 576 planned) patients in this phase III trial were randomized to either cytoreductive nephrectomy followed by sunitinib at four to six weeks or to sunitinib alone. All had synchronously metastatic clear cell renal cell carcinoma, ECOG performance status of 0 or 1, no symptomatic brain metastases, acceptable organ function, and were eligible for both sunitinib and surgery (the latter decided by the treating urologist). In the former group, 7.1% had not received surgery and 17.7% had not received sunitinib; in the latter, 4.9% had not received sunitinib but 17% had received secondary nephrectomy. Patients who had responded very well to the agent and could therefore undergo surgery after therapy are now being followed up along with other subgroups.

The planned interim analysis showed non-inferiority of drug therapy alone. The safety profile corresponded to what was known. Table 3 shows the concrete figures. The hazard ratio confidence interval for OS ranged from 0.71-1.10, which was below the upper limit for non-inferiority (set at HR 1.20).

In view of the results, cytoreductive nephrectomy needs to be reconsidered as a therapy in the future, at least in certain populations. It should be noted, however, that with 44.4% resp. 41.5% in the respective arm, relatively many CARMENA patients had an unfavorable risk score and thus (as could have been suspected before) benefited less from surgery than were harmed by it. For patients with intermediate prognosis, on the other hand, the situation does not seem quite so clear – although it must be remembered that the MSKCC prognosis score was used instead of the IMDC prognosis score developed in the TKI era. Information on other selection factors commonly involved in the decision for or against nephrectomy is lacking in the study. What may have influenced the surgical outcomes, however, is the fact that approximately 70% patients in the surgical group had T3 or T4 tumors (50% in the sunitinib group). The surgery arm, despite the intention-to-treat principle, was significantly less likely overall to receive the assigned therapy – as noted above – whereas the sunitinib arm received the “extra addition” of delayed surgery relatively frequently. Points to consider when interpreting the study (see per-protocol analysis in the study appendix).

So here, too, according to the new data, one cannot simply claim: “one size fits all”. Nevertheless, similar to KEYNOTE, more patients could be spared a more costly therapy route associated with potentially severe side effects or complications than previously thought. Rather than excluding everyone from the outset (which the study also does not recommend), even more careful selection of patients for nephrectomy seems all the more critical in the future. Various risk models already exist, which can be used to detect people who benefit little from an operational path. After CARMENA, the focus on this has intensified once again. It is completely open at this time how nephrectomy along with immunotherapy will perform in this area. So it remains exciting…
The study was published simultaneously in NEJM [11,12].

Source: American Society of Clinical Oncology (ASCO), June 1-5, 2018, Chicago.

Literature:

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Stintzing S, et al: Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population. Ann Oncol 2014; 25(Suppl 5): abstr LBA11.
Stintzing S, et al: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 2016 Oct; 17(10): 1426-1434.
Van Cutsem E, et al: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015; 33: 692-700.
Schwartzberg LS, et al: PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32: 2240-2247.
Venook AP, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol 2014; 32(15 Suppl): Abstr LBA3.
Lenz HJ, et al: CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC). Ann Oncol 2014; 25(Suppl 5): abstr 501O.
Venook AP, et al: Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA 2017 Jun 20; 317(23): 2392-2401.
Van Cutsem E, et al: ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016 Aug; 27(8): 1386-1422.
Gandhi L, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378: 2078-2092.
Méjean A, et al: Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. NEJM 2018 June 3. DOI: 10.1056/NEJMoa1803675 [Epub ahead of Print].
Motzer RJ: Cytoreductive Nephrectomy – Patient Selection Is Key. NEJM 2018 June 3. DOI: 10.1056/NEJMe1806331 [Epub ahead of Print].